Batu Empedu Tokyo Guidelines 2018

Article Type: Guideline
Accepted Article
Tokyo Guidelines 2018 surgical management of acute cholecystitis: safe steps in
laparoscopic cholecystectomy for acute cholecystitis (with videos)
Go Wakabayashi, Yukio Iwashita, Taizo Hibi, Tadahiro Takada, Steven M. Strasberg, Horacio
J. Asbun, Itaru Endo, Akiko Umezawa, Koji Asai, Kenji Suzuki, Yasuhisa Mori, Kohji
Okamoto, Henry A. Pitt, Ho-Seong Han, Tsann-Long Hwang, Yoo-Seok Yoon, Dong-Sup
Yoon, In-Seok Choi, Wayne Shih-Wei Huang, Mariano Eduardo Giménez, O. James Garden,
Dirk J. Gouma, Giulio Belli, Christos Dervenis, Palepu Jagannath, Angus C.W. Chan, Wan
Yee Lau, Keng-Hao Liu, Cheng-Hsi Su, Takeyuki Misawa, Masafumi Nakamura, Akihiko
Horiguchi, Nobumi Tagaya, Shuichi Fujioka, Ryota Higuchi, Satoru Shikata, Yoshinori
Noguchi, Tomohiko Ukai, Masamichi Yokoe, Daniel Cherqui, Goro Honda, Atsushi Sugioka,
Eduardo de Santibañes, Avinash Nivritti Supe, Hiromi Tokumura, Taizo Kimura, Masahiro
Yoshida, Toshihiko Mayumi, Seigo Kitano, Masafumi Inomata, Koichi Hirata, Yoshinobu
Sumiyama, Kazuo Inui, Masakazu Yamamoto
The author’s affiliations are listed in the Appendix.
Corresponding author:
Tadahiro Takada, M.D., Ph.D.
Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku,
Tokyo 173-8605, Japan
E-mail: t-takada@jshbps.jp
Keywords: Laparoscopic cholecystectomy, acute cholecystitis, safety, difficult, critical view

of safety
Abstract
In some cases, laparoscopic cholecystectomy (LC) may be difficult to perform in patients
with acute cholecystitis (AC) with severe inflammation and fibrosis. The Tokyo Guidelines
2018 (TG18) expand the indications for LC under difficult conditions for each level of
severity of AC. As a result of expanding the indications for LC to treat AC, it is absolutely
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necessary to avoid any increase in bile duct injury (BDI), particularly vasculo-biliary injury
Accepted Article (VBI), which is known to occur at a certain rate in LC. Since the Tokyo Guidelines 2013
(TG13), an attempt has been made to assess intraoperative findings as objective indicators of
surgical difficulty; based on expert consensus on these difficulty indicators, bail-out
procedures (including conversion to open cholecystectomy) have been indicated for cases in
which LC for AC is difficult to perform. A bail-out procedure should be chosen if, when the
Calot's triangle is appropriately retracted and used as a landmark, a critical view of safety
(CVS) cannot be achieved because of the presence of nondissectable scarring or severe
fibrosis. We propose standardized safe steps for LC to treat AC. To achieve a CVS, it is vital
to dissect at a location above (on the ventral side of) the imaginary line connecting the base
of the left medial section (Segment 4) and the roof of Rouvière’s sulcus and to fulfill the three
criteria of CVS before dividing any structures. Achieving a CVS prevents the
misidentification of the cystic duct and the common bile duct, which are most commonly
confused.
Introduction
Laparoscopic cholecystectomy (LC) was first performed by Mühe (under direct scope vision)
in 1985. Subsequently, the same procedure using a video-laparoscope, which is used today,
was carried out by Mouret in 1987, and was spread worldwide from Europe and the United
States by Dubois and Perissat [1]. In 1992 an NIH consensus concluded that it is a safe,
effective treatment procedure for almost all patients with symptomatic cholelithiasis [2].
However, because surgery is performed remotely from outside the abdominal cavity via
images, and haptic feedback from tissue is weak compared with that in open abdominal
surgery, LC is difficult to perform in some patients with acute cholecystitis (AC) with severe
inflammation and fibrosis. In guidelines published by the Society of American
Gastrointestinal and Endoscopic Surgeons (SAGES) in 1993, AC was described as a relative
contraindication for LC [3]. Subsequent advances in optical and surgical devices and
improvements in surgical techniques, however, have led to the expansion of the surgical
indications for LC and a gradual increase in use of LC to treat AC. Severity assessment
criteria for AC were first set out in 2007, indicating treatment guidelines for AC of different
levels of severity [4]; these guidelines were not changed when they were revised in 2013 [5].
In the Tokyo Guidelines 2007 (TG07) and the Tokyo Guidelines 2013 (TG13), LC was
indicated for Grade I (mild) and Grade II (moderate) AC. For Grade II, however, this was
conditional on the availability of advanced laparoscopic techniques; and for Grade III, LC
was to be performed only after gallbladder (GB) drainage. In this updated Tokyo Guidelines
2018 (TG18), which are based on various reports published since TG13 including a
Accepted Article large-scale Japanese/Taiwanese joint study [6], this has been revised to “If both the patient
and the facilities where the surgery is to be performed meet strict conditions, LC may also be
performed as a straight forward procedure in under certain conditions of Grade III cases.”
[7].
As LC has become more widely performed, bile duct injury (BDI) is known to occur in a
certain proportion of cases, and the prognoses of patients who suffer vasculo-biliary injury
(VBI) in particular has been poor [8]. The surgical difficulty of AC varies greatly depending
on the severity of inflammation and fibrosis. The risk of BDI has been shown to increase in
accordance with the severity of AC [9]. Since TG13, an attempt has been made to assess
intraoperative findings as objective indicators of surgical difficulty; expert consensus on
intraoperative findings as indicators of surgical difficulty was reached by over 400 doctors
from Japan, Korea, and Taiwan [10]. In a Delphi survey, 614 surgeons in Japan, Korea,
Taiwan, the United States, and elsewhere were presented with 29 situations that might
involve the risk of BDI along with preventative measures and asked which of these findings
they regarded as most important [11]. Suggestions for safe LC procedures based on
consensus indicators of surgical difficulty are considered to serve as important guidelines for
reducing BDI for surgeons with various levels of experience who perform LC. It is essential
to avoid any increase in BDI and VBI as a result of the recommendation in TG18 to perform
LC in the surgical management of AC irrespective of its grade. Therefore, we present safe
steps and bail-out procedures that are important when performing LC to treat AC. We also
investigated treatment strategies in the event that choledocholithiasis is also present and
whether the recently-developed reduced port surgery is indicated for AC.
Q1. What are the indicators of surgical difficulty in laparoscopic cholecystectomy for
acute cholecystitis?
Besides preoperative factors and severity of AC, intraoperative findings are

considered to be appropriate indicators of surgical difficulty in LC for AC.
(level D)
Severe inflammation of the GB and its surroundings increases both the difficulty of LC and
the frequency of postoperative complications. The estimated incidence of serious
complications such as BDI and VBI is 2 to 5 times higher for LC than for open
cholecystectomy [12, 13]. As AC is a common disease, even if the frequency of
complications is low, the absolute number of cases is high. To reduce these serious
Accepted Article complications, it is essential to assess the surgical difficulty appropriately and to standardize
treatment strategies. Many previous studies have used factors such as the open conversion
rate, operating time, and the incidence of complications as indicators of surgical difficulty.
An investigation of preoperative data and diagnostic imaging using operating time or the
open conversion rate as indicators of surgical difficulty in cases of symptomatic cholelithiasis
(including AC) identified body-mass index (BMI), non-visualized GB on preoperative
cholangiography, cystic duct length, temperature, and abnormal findings on CT as five
factors that significantly affected the time required for cholecystectomy [14]. Another study
found that the three factors of GB wall thickening, incarcerated stones in the GB neck, and
duration of elevated CRP contributed to prolonged operating time[15], and many other
studies have found that factors including male sex, elevated white blood cell count (WBC),
low albumin, high bilirubin, fluid retention around the GB, and diabetes are predictive of
open conversion [16-19]. A meta-analysis of the collected results of these observational
studies identified GB wall thickening (>4 to 5 mm) on ultrasound, male sex, advanced age,
and obesity as risk factors for open conversion [20]. A recent study has found that the rates of
open conversion and complications were significantly higher in TG13 Grade II and III cases
compared with Grade I cases [21] (Table１).
From these results, the level of surgical difficulty might be predictable on the basis of
factors including preoperative imaging and blood tests, and TG13 grade. Some studies
investigating surgical timing and surgical difficulty also found that if surgery was performed
within 72 h of the onset of AC, there were fewer complications, operating time was shorter,
and surgical difficulty was lower [22, 23]. One issue is that almost all these studies were
observational studies derived from single-center data, and no studies have provided a high
level of evidence.
Questionnaire surveys of Japanese, Korean, and Taiwanese experts have found that operating
time, which is frequently used as an indicator of surgical difficulty, is greatly dependent on
the skill and experience of the operator and that the criteria for conversion to open
cholecystectomy vary among surgeons [10, 24]. Operating time and conversion rate are
useful indicators of surgical difficulty but must be interpreted in light of surgical training,
skill and experience. Some studies have suggested that it may be possible to identity
objective indicators of surgical difficulty on the basis of intraoperative findings, some of
which are not based merely on expert opinion [25] but are also based on a Delphi consensus
Accepted Article among a large number of surgeons of different nationalities [26]. The use and evaluation in
future studies of intraoperative findings (Table 2) as objective, direct indicators capable of
measuring of surgical difficulty is therefore desirable.
Q2. Which surgical procedures are alternatives to difficult laparoscopic
cholecystectomy for acute cholecystitis?
Surgeons should choose bail-out procedures to prevent BDI according to the

intraoperative findings (recommendation 1, level C).
In TG13, conversion to open cholecystectomy was the only recommendation in cases of AC

for which LC was difficult. In the current revisions, the specific bail-out procedures listed
below are suggested, and it is strongly recommended that surgeons make appropriate
judgments and choose a bail-out procedure based on intraoperative findings in order to avoid
secondary damage (level C).
Subtotal cholecystectomy
The procedure involves making an incision in the GB, aspirating the contents, and then
removing as much of the GB wall as possible and treating the stump instead of removing the
entire GB has been in use since the days of open cholecystectomy [27]. Previous studies have
not drawn a clear distinction between partial and subtotal removal, and the situation is
confused. Strasberg et al. designated all procedures in which as much of the GB wall as
possible is removed as subtotal (rather than partial) resection (Figure 1a) and proposed that
resection of the fundus alone should be referred to as “fundectomy” [28]. Subtotal
cholecystectomy is deemed “reconstituting” when a closed gallbladder remnant is left and
“fenestrating” when the remnant is left open or the internal opening of the cystic duct is
closed (Figure 1) [28].
According to a systematic review and a meta-analysis, although postoperative bile leakage
was more common following laparoscopic subtotal cholecystectomy compared with open
conversion, rates of BDI, postoperative complications, reoperation, and mortality were all
lower [29, 30]. More patients whose surgery concluded with drainage because the stump of
the neck of the GB was not closed underwent postoperative endoscopic retrograde
cholangiography compared with those in whom closure was successfully performed, but
there was no change in the rate of complications. In long-term follow-up after subtotal

resection, gallstones recurred in around 5% of patients and these patients have usually had
Accepted Article subtotal reconstituting operations [30]. Although risk of concomitant GB cancer has also been
reported, frequency of occurrence is low [29]. Laparoscopic subtotal cholecystectomy is an
important procedure that should be considered in order to avoid serious damage to the bile
duct or blood vessels. Video 1 shows a typical case of laparoscopic subtotal cholecystectomy.
Open conversion
No randomized controlled trial (RCT) has investigated the merits and demerits of open
conversion, but a meta-analysis found that open conversion had no effect on the rate of local
postoperative complications [31]. However, some studies have pointed out that as LC comes
to account for the great majority of procedures and surgeons have less experience performing
open cholecystectomy, open conversion may not necessarily be safe [32]. In a questionnaire
survey of experts in Japan, South Korea, and Taiwan, only 17.5% of the total responded that
open conversion made surgery easier [24]. Although decision-making on open conversion
may vary greatly between hospitals, appropriate judgment should be made in light of the
surgeon's skill level. Subtotal cholecystectomy may also be done after conversion when it is
found that complete cholecystectomy is dangerous.
Fundus first technique

The procedure in which the separation of the GB from the liver starts at the fundus, without
initially visualizing a cystic artery and cystic duct in the Calot’s triangle (Figure 1d), has not
yet been adequately studied. Even the terminology has yet to be made consistent, with terms
including “dome down,” “fundus first,” and “fundus down” all being used. A search of
PubMed reveals that “fundus first” is the most commonly used. If a difficult case with severe
inflammation of the Calot's triangle is encountered, fundus first LC with subtotal
cholecystectomy may offer an option that enables the completion of LC while avoiding BDI
as an alternative to immediate conversion to open cholecystectomy. The merits and demerits
of the fundus first technique have been reported in previous studies [33, 34], and several case
series have described successful use of the fundus first technique [35-37]. Other studies
described a subtotal cholecystectomy combined with a fundus first technique starting with
retrograde dissection of the GB [38, 39]. However, because of the low event rate of bile duct
injury (approximately 1/333), large numbers of patients are required to demonstrate safety of
a technique in respect to this complication. Therefore, these studies cannot be used to draw a
conclusion that the techniques are safe or better than other techniques in regard to bile duct
injury. Some studies indeed have warned that VBI may occur due to misidentification of the
layer to be dissected when dissecting from the fundus of the GB toward its neck [40, 41].
Accepted Article Importantly, this technique has been shown to be associated with an “extreme” VBI when
performed in patients with marked chronic inflammation with biliary inflammatory fusion
and contraction [40] . Therefore, the plane of dissection should always be kept close to the
GB [42, 43].
Delphi consensus on bail-out procedures in difficult situations

Indications to perform a bail-out procedure have been identified by a recent Delphi consensus
[11]. A bail-out procedure should be chosen if a CVS cannot be achieved because of scarring
or severe fibrosis, as long as the Calot’s triangle is appropriately retracted and is recognized
as a landmark.
Q3. What are the important points to avoid biliary injury in laparoscopic
cholecystectomy for acute cholecystitis?
Early LC before fibrosis: AC for LC should be performed at an early stage before florid
inflammation and fibrosis develop in order to avoid BDI.
Creation of the CVS: To perform LC safely, it is recommended that the three criteria of CVS
be achieved and noted in a “time-out” before clipping or cutting structures.
Dissection along the GB surface with the following landmarks: If the GB surface is
difficult to identify in the Calot's triangle, an attempt should first be made to identify the GB
surface from the dorsal side of the neck of the GB. If the GB surface is still difficult to
identify, bail-out procedures (see Q2) should be considered. The base of Segment 4 and the
roof of Rouvière's sulcus should be used as anatomical landmarks, and any surgical
procedures during cholecystectomy should be performed above the imaginary line connecting
these two landmarks.
Bail-out procedures: Subtotal laparoscopic or open cholecystectomy have been reported to
reduce BDI (see Q2).
Perioperative imaging: Although there is no evidence for the value of intraoperative
cholangiography, preoperative magnetic resonance cholangiopancreatography (MRCP),
intraoperative fluorescence cholangiography, and intraoperative ultrasound may reduce BDI
(level D).
In AC, surgery becomes more difficult as fibrosis progresses in the inflammatory process, so
performing LC early is recommended [5, 44]. Early LC has been found to cause fewer total
complications and to reduce operating time and total cost [44-48]. Because BDI occurs
infrequently, some studies have found that early LC has no impact on BDI [44], whereas
Accepted Article others have found that early LC reduces BDI [45-48]. A recent meta-analysis [47] and a
propensity score matching study [48] found that early LC resulted in significantly fewer cases
of BDI and a 50% reduction in cases of BDI [47].
The CVS concept proposed by Strasberg et al. [49] has been popularized worldwide, and in a
questionnaire survey of members of the UK Association of Upper Gastrointestinal Surgeons
(AUGIS), exposing a CVS was the most commonly recommended option for preventing
intraoperative BDI [50]. Although the CVS is valuable for preventing BDI, greater awareness
of this concept among surgeons is still required; the CVS score is increased [51] and actual
operating time is decreased by resident training [52].
Fibrosis and adhesions surrounding the GB and in the Calot's triangle may be severe in AC,
causing difficulty to identify local anatomy and achieve a CVS [41]. If the GB surface and/or
the anatomy of the Calot's triangle is unclear, then bail-out procedures should be considered
(see Q2 and the following paragraph). A safe procedure is to identify Rouvière's sulcus and
the base of Segment 4 and perform all surgical procedures above the imaginary line
connecting these two landmarks. To maintain the plane of dissection on the GB surface
throughout cholecystectomy is paramount to avoid injury to hilar structures and liver
parenchyma [41, 53, 54].
If severe fibrosis in the Calot's triangle prevents safe completion of LC with/without using
the fundus first technique, BDI can be avoided by subtotal LC or open conversion [55]. In a
retrospective study of patients who underwent subtotal LC or open conversion, BDI occurred
in 3.3% who underwent open conversion but in none of the patients who underwent subtotal
LC [56]. Subtotal LC should be considered as an option when straightforward LC cannot
be completed safely. At the moment, the decision to switch procedures depends on the
subjective judgment of the operator. Intraoperative findings may serve as objective indicators
of surgical difficulty; accordingly, there is a need to establish criteria for switching
procedures based on intraoperative findings [10].
Whether intraoperative cholangiography reduces BDI has been reported with mixed results
[13, 57-60], and its performance is optional [50, 61]. However, it is important to note that
there is evidence that intraoperative cholangiography might reduce the extent of the injury.
Perioperative cholangiography, including preoperative MRCP, decreases complications and
open conversion [55], and laparoscopic ultrasound [62, 63] and fluorescence
Accepted Article cholangiography may prevent BDI. Although these procedures may become standard during
LC, further studies are required [64].
Q4: What are the safe steps in laparoscopic cholecystectomy for acute cholecystitis?
Standardized safe steps are recommended in difficult LC according to the

intraoperative findings (level D).
Based on the recent Delphi consensus [11], we propose the following safe steps in LC for
AC.
Step 1: If a distended GB interferes with the field of view, it should be decompressed by

needle aspiration (Figure 2a).
Step 2: Effective retraction of the GB to develop a plane in the Calot’s triangle area and
identify its boundaries (countertraction). (Fig.2b)
Step 3: Starting dissection from the posterior leaf of the peritoneum covering the neck of the
GB and exposing the GB surface above Rouvière’s sulcus. (Fig.2c)
Step 4: Maintaining the plane of dissection on the GB surface throughout LC. (Fig.2d)
Step 5: Dissecting the lower part of the GB bed (at least one-third) to obtain the critical view
of safety (CVS) (Fig.2e).
Step 6: Creating the critical view of safety (Fig.2f).
*: For persistent hemorrhage, achieving hemostasis primarily by compression and avoiding
excessive use of electrocautery or clipping.
Video 2 shows a typical procedure following these safe steps.
If there is a risk of BDI, intraoperative cholangiography, intraoperative ultrasound,

intraoperative indocyanine green fluorescence imaging, or another imaging modality to
confirm the courses of the bile duct and blood vessels may be useful, but there is no unified
consensus on this.
If there is severe fibrosis and scarring in the Calot’s triangle due to inflammation and
impacted gallstones in the confluence with the cystic duct or if a CVS showing anatomically
important landmarks cannot be achieved, a bail-out procedure should be considered (see Q2).
Even if inflammation is absent or mild, BDI may occur due to misidentification. Particular

care is required not to misidentify the common bile duct as the cystic duct.
Accepted Article Table 3 shows a summary of the content of the recent Delphi consensus [11].
Q5. Is one-stage management for acute cholecystitis associated with common bile duct
stone more effective than two-stage management?
Either approach is acceptable. (level B)
Commentary:
For concomitant common bile duct stone and gallstone, multiple randomized control trials
[65-67] and meta-analyses [68, 69] have shown that one- (laparoscopic common bile duct
exploration plus laparoscopic cholecystectomy or intraoperative laparoendoscopic
rendezvous technique) and two-stage (endoscopic retrograde cholangiopancreatography
followed by sequential laparoscopic cholecystectomy) approaches are equally safe and
feasible. One randomized study [70] and one meta-analysis [71] concluded that a single-stage
management has less morbidity and higher success rate. However, aforementioned studies
have combined patients having acute biliary colic with those accompanying acute
cholecystitis, which are two different entities. The incidence and severity of acute
cholecystitis are not reported in any of these series; therefore, it is difficult to recommend one
way or the other at the moment for patients with AC. The frequency of common bile duct
stone complicating AC range between 7.7% and 14.3% [72-74] and whether patients with AC
are at higher risk of common bile duct stone remains debatable. There is no significant
predictor for the diagnosis of common bile duct stone to date and preoperative magnetic
resonance cholangiography, endoscopic ultrasound, and intraoperative cholangiography are
equally reliable [75].
Based on the randomized control trials since 2010 [65-67, 70], we conducted a meta-analysis
and found no significant difference in the success rate of common bile duct stone removal
(Fig. 3), complication rate (Fig. 4), and in-hospital mortality (Fig. 5). From a patient’s point
of view, it is clear that one-stage management is preferable because only a single procedure is
required, which in turn results in a shorter hospital stay and lesser cost [65-69]. At this time,
the feasibility of one-stage management is determined at the sole discretion of each
institution depending on the skill and preference of endoscopists and surgeons (i.e., whether
an endoscopist is willing to perform endoscopic retrograde cholangiography concurrently
with the operation and whether a surgeon is capable of performing laparoscopic common bile
duct exploration). Moreover, the adoption rate of one-stage strategy in each region and
Accepted Article country remains unclear. There is also a wide variety of healthcare delivery systems and
health economics/policies around the globe. Well-designed, large-scale multicenter
randomized control trial in patients exclusively with confirmed diagnosis of acute
cholecystitis (in accordance with Tokyo Guidelines) associated with common bile duct stone
are warranted.
Q6. What is the role of reduced port surgery for acute cholecystitis?
Because the superiority of reduced port surgery for AC is unclear, it is weakly recommended
for use only in a limited number of appropriately selected patients (level D).
Reduced port surgery was not mentioned in TG13. In the current revisions, LC is designated
as the first-choice treatment by surgical removal. LC seeks to be as minimally invasive as
possible provided that safety is assured. Reduced port surgery is even less invasive than LC
with better cosmetic results. The role of reduced port surgery as a laparoscopic procedure for
AC is therefore mentioned in TG18.
Here, the term “reduced port surgery” is used as a general term for surgical procedures in
which the size or number of trochars or the number of skin incisions is reduced compared to
standard laparoscopic surgery for the purpose of reducing invasiveness or for cosmetic
reasons.
In terms of reducing the number of trochars and skin incisions, the ultimate laparoscopic
surgery is one-wound laparoscopic cholecystectomy, described by Navarra et al. in 1997 [76].
Although this technique is currently known by various names [77], here we use the term
“single incision laparoscopic cholecystectomy” (SILC).
The RCTs comparing SILC with conventional laparoscopic cholecystectomy (CLC) have
either excluded AC or included fewer than 40% of patients with AC [78, 79]. We can thus
say that the role of SILC for AC has yet to be investigated. According to a meta-analysis,
pain assessed on a visual analog scale (VAS) was lower in SILC [80]. However, the
alleviation of pain was only significant at a very early stage after surgery, with no difference
being evident after Day 1 [80]. Although many studies have not found significantly higher

rates of complications associated with SILC [81, 82], the pooled risk ratio for serious
Accepted Article complications (including BDI, reoperation, abdominal fluid retention, bile leakage, and
abdominal infection) and the rate of moderate complications (wound infection and bile
leakage or abdominal fluid retention that improved without treatment) have been found to be
higher for SILC [80]. Furthermore, operating time was longer [81-86] and the number of
trochars added intraoperatively were higher for SILC than for CLC [80, 82].
Although analyses have found that SILC provides better cosmetic results [81, 83, 85, 86], its
superiority has not been demonstrated in terms of postoperative quality of life (QOL) score
[80]. On the other hand, SILC requires a longer operating time and increases the risk of
complications. The multi-channel ports used in SILC are expensive, and the procedure also
requires special instruments. SILC is still at the stage of instrument development and
improving the techniques involved in the procedure.
Reduced port surgery with trochar diameters <3 mm is known as “needlescopic surgery” [87].
Few RCTs have compared needlescopic cholecystectomy (NLC) and CLC for AC, but one
study has found that although NLC requires a longer operating time, the rate of complications
is within tolerable limits [88]. Figure 7 shows the results of a meta-analysis comparing NLC
and CLC. This meta-analysis found that there was no difference in operating time and that
pain tended to be less after NLC. Albeit for RCTs that either excluded AC or included very
few patients with the condition, the ability to deal with inflammatory changes was found to
be limited by technical difficulties related to the characteristics of the instruments [89], and
high rates of conversion from NLC to CLC have been reported [90, 91]. Although NLC
provides better cosmetic results, there is no difference with CLC in terms of patient
satisfaction [92, 93].
These studies indicate that reduced port surgery for AC has no advantages other than
cosmetic results and reduced pain. The extent to which these factors contribute to patient
satisfaction should be investigated. Although it is hoped that the indications for reduced port
surgery are extended in the future by instrument development and improved techniques, at
this point, it should only be performed in a limited number of selected patients.

Acknowledgements
Accepted Article We express our deep gratitude to the Japanese Society of Hepato-Biliary-Pancreatic Surgery,
the Japanese Society of Abdominal Emergency Medicine, the Japanese Society of Surgical
Infection, the Japan Biliary Association, for their substantial support and guidance in the
preparation of the article. We also would like to express our deep gratitude to the Japanese
Society of Hepato-Biliary-Pancreatic Surgery for the article processing managing office of
Tokyo Guidelines 18 to prepare the publication. We appreciate all secretariats of the Japanese
Society of Hepato-Bilialy-Pancreatic Surgery for their technical support.
Conflicts of interest
Goro Honda has received honoraria from Johnson and Johnson and Medtronics.
Appendix
Go Wakabayashi, Department of Surgery, Ageo Central General Hospital, Saitama, Japan;
Yukio Iwashita, Department of Gastroenterological and Pediatric Surgery, Oita University
Faculty of Medicine, Oita, Japan; Taizo Hibi, Department of Surgery, Keio University School
of Medicine, Tokyo, Japan; Tadahiro Takada, Department of Surgery, Teikyo University
School of Medicine, Tokyo, Japan; Steven M. Strasberg, Section of Hepato-Pancreato-Biliary
Surgery, Washington University School of Medicine in St. Louis, MO, USA; Horacio J.
Asbun, Department of Surgery, Mayo Clinic College of Medicine, Florida, USA; Itaru Endo,
Department of Gastroenterological Surgery, Yokohama City University Graduate School of
Medicine, Kanagawa, Japan; Koji Asai, Department of Surgery, Toho University Ohashi
Medical Center, Tokyo, Japan; Akiko Umezawa, Minimally Invasive Surgery Center, Yotsuya
Medical Cube, Tokyo, Japan; Kenji Suzuki and Taizo Kimura, Department of Surgery,
Fujinomiya City General Hospital, Shizuoka, Japan; Yasuhisa Mori and Masafumi Nakamura,
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu
University, Fukuoka, Japan; Kohji Okamoto, Department of Surgery, Center for
Gastroenterology and Liver Disease, Kitakyushu City Yahata Hospital, Fukuoka, Japan;
Henry A. Pitt, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA;
Ho-Seong Han and Yoo-Seok Yoon, Department of Surgery, Seoul National University
Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea;
Tsann-Long Hwang and Keng-Hao Liu, Division of General Surgery, Linkou Chang Gung
Memorial Hospital, Tauyuan, Taiwan; Dong-Sup Yoon, Department of Surgery, Yonsei
University Gangnam Severance Hospital, Seoul, Korea; In-Seok Choi, Department of
Surgery, Konyang University Hospital, Daejeon, Korea; Wayne Shih-Wei Huang, Department
of Surgery, Show Chwan Memorial Hospital, Changhua, Taiwan; Mariano Eduardo Giménez,
Accepted Article Chair of General Surgery and Minimal Invasive Surgery “Taquini” University of Buenos
Aires. Argentina DAICIM Foundation, Argentina; O James Garden, Clinical Surgery,
University of Edinburgh, Edinburgh, UK; Dirk Joan Gouma, Department of Surgery,
Academic Medical Center, Amsterdam, The Netherlands; Giulio Belli, Department of
General and HPB Surgery, Loreto Nuovo Hospital, Naples Italy; Christos Dervenis, First
Department of Surgery, Agia Olga Hospital, Athens, Greece; Palepu Jagannath, Department
of Surgical Oncology, Lilavati Hospital and Research Centre, Mumbai, India; Angus C.W.
Chan, Surgery Centre, Department of Surgery, Hong Kong Sanatorium and Hospital, Hong
Kong, Hong Kong; Wan Yee Lau, Faculty of Medicine, The Chinese University of Hong
Kong, Shatin, Hong Kong; Cheng-Hsi Su, Department of Surgery, Cheng Hsin General
Hospital, Taipei, Taiwan; Takeyuki Misawa, Department of Surgery, The Jikei University
Kashiwa Hospital, Chiba, Japan; Akihiko Horiguchi, Department of Gastroenterological
Surgery, Fujita Health University School of Medicine, Aichi, Japan; Nobumi Tagaya,
Department Of Surgery, Dokkyo Medical University Koshigaya Hospital, Saitma, Japan;
Shuichi Fujioka, Department of Surgery, The Jikei University Kashiwa Hospital, Chiba,
Japan; Ryota Higuchi and Masakazu Yamamoto, Department of Surgery, Institute of
Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan; Satoru Shikata,
Director, Mie Prefectural Ichishi Hospital, Mie, Japan; Yoshinori Noguchi and Masamichi
Yokoe, Department of General Internal Medicine, Japanese Red Cross Nagoya Daini Hospital,
Aichi, Japan; Tomohiko Ukai, Department of Family Medicine, Mie Prefectural Ichishi
Hospital, Mie, Japan; Daniel Cherqui, Hepatobiliary Center, Paul Brousse Hospital, Villejuif,
France; Goro Honda, Department of Surgery, Tokyo Metropolitan Komagome Hospital,
Tokyo, Japan; Atsushi Sugioka, Department of Surgery, Fujita Health University School of
Medicine, Aichi, Japan; Eduardo de Santibañes, Department of Surgery, Hospital Italiano,
University of Buenos Aires, Buenos Aires, Argentina; Avinash Nivritti Supe, Department of
Surgical gastroenterology, Seth G S Medical College and K E M Hospital, Mumbai, India;
Hiromi Tokumura, Department of Surgery, Tohoku Rosai Hospital, Miyagi, Japan; Masahiro
Yoshida, Department of Hemodialysis and Surgery, Ichikawa Hospital, International
University of Health and Welfare, Chiba, Department of EBM and Guidelines, Japan Council
for Quality Health Care, Tokyo, Japan; Toshihiko Mayumi, Department of Emergency
Medicine, School of Medicine University of Occupational and Environmental Health,
Fukuoka, Japan; Seigo Kitano, President, Oita University, Oita, Japan; Masafumi Inomata,
Department of Gastroenterolgical and Pediatric Surgery, Oita University Faculty of Medicine,
Oita, Japan; Koichi Hirata, Department of Surgery, JR Sapporo Hospital, Hokkaido, Japan;
Yoshinobu Sumiyama, Director, Toho University, Tokyo, Japan; Kazuo Inui, Department of
Accepted Article Gastroenterology, Second Teaching Hospital, Fujita Health University, Aichi, Japan
Figure legends
Figure 1. Detailed bail-out procedures for difficult laparoscopic cholecystectomy: a, Subtotal

cholecystectomy; b, Fenestrating (The GB is opened and the cystic duct is closed from
inside); c, Reconstituting (closure of the remnant GB wall); d, Fundus first.
Figure 2. Standardized safe steps in laparoscopic cholecystectomy. a: Decompression of a

distended GB with needle aspiration (arrow). b: Effective retraction of the GB to develop a
plane in the Calot’s triangle area and identify its boundaries (countertraction). c: Starting
dissection from the posterior leaf of the peritoneum covering the neck of the GB and
exposing the GB surface above Rouvière’s sulcus (arrow). d: Maintaining the plane of
dissection on the GB surface throughout laparoscopic cholecystectomy. e: Dissecting the
lower part of the GB bed (at least one-third) to obtain the critical view of safety (broken line).
f: Always obtaining the critical view of safety.
Figure 3. Forest plot of the success rate of common bile duct stone removal.
Figure 4. Forest plot of the complication rate of common bile duct stone removal.
Figure 5. Forest plot of the in-hospital mortality rate of common bile duct stone removal.
Figure 6. Forest plot of the operative time and postoperative pain between Needlescopic and
conventional laparoscopic cholecystectomy.

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Table 1. Risk factors associated with prolonged operative time and open conversion
Accepted Article
Prolonged operative time [8, 9] Conversion [15, 16]
Gallbladder wall>4-5 mm on preoperative

Gallbladder wall thickening
ultrasound
Incarcerated stones in the gallbladder neck Age > 60 or 65
Duration of elevated CRP Male gender
Non-visualized gallbladder on preoperative

Acute cholecystitis (TG13 grade II/III)
cholangiography
Body temperature Contracted gallbladder on ultrasound
Abscess formation Previous abdominal surgery
BMI BMI
ASA score

Table 2. Difficulty score for each intraoperative finding
Accepted Article
Intraoperative findings score
A. Factors related to inflammation of the gallbladder

(a) Appearance around the gallbladder
1. Fibrotic adhesions around the gallbladder due to inflammation 2
2. Partial scarring adhesions around the gallbladder 2
3. Diffuse scarring adhesions around the gallbladder 4
(b) Appearance of the Calot’s triangle area
4. Sparse fibrotic change in the Calot’s triangle area 2
5. Dense fibrotic change but no scarring in the Calot’s triangle area 3
6. Partial scarring in the Calot’s triangle area 4
7. Diffuse scarring in the Calot’s triangle area 5
(c) Appearance of the gallbladder bed
8. Sparse fibrotic change in the gallbladder bed 1
9. Dense fibrotic change but no scarring in the gallbladder bed 2
10. Partial scarring in the gallbladder bed 3
11. Diffuse scarring in the gallbladder bed (includes atrophic gallbladder with
4
no lumen due to severe contraction)
(d) Additional findings of the gallbladder and its surroundings
12. Edematous change around the gallbladder/in the Calot’s triangle area/in the
1
gallbladder bed
13. Easy bleeding at dissection around the gallbladder/in the Calot’s triangle
3
area/in the gallbladder bed
14. Necrotic changes around the gallbladder/in the Calot’s triangle area/in the
4
gallbladder bed
15. Non-iatrogenic, perforated gallbladder wall and/or abscess formation
3
towards the abdominal cavity noted during adhesiolysis around the gallbladder
16. Abscess formation towards the liver parenchyma 4

17. Cholecysto-enteric fistula 5
18. Cholecysto-choledochal fistula (included in the expanded classification of
6
Mirizzi syndrome)
19. Impacted gallstone in the confluence of the cystic, common hepatic, and
5
common bile duct (included in the expanded classification of Mirizzi syndrome)

B. Intra-abdominal factors unrelated to inflammation
Accepted Article
20. Excessive visceral fat 2
21. Inversion of the gallbladder in the gallbladder bed due to liver
4
cirrhosis
22. Collateral vein formation due to liver cirrhosis 4
23. Non-inflammatory (physiological) adhesion around the
1
gallbladder
24. Anomalous bile duct 4
25. Gallbladder neck mounting on the common bile duct 3
Expert surgeons participated in a Delphi process and graded the 25

intraoperative findings using the seven-stage scale ranging from 0 to 6
[0: easiest, 6: most difficult]. The median point for each item was set as
the difficulty score. [5] 。
Table 3
Proposal for avoiding vasculo-biliary injury
based on the Delphi Consensus (2017)
How to prevent?
● Effective retraction of the gallbladder to develop a plane in the Calot’s triangle area and identify
　
its boundaries (countertraction)
● Creating the critical view of safety
● For persistent hemorrhage, achieving hemostasis primarily by compression and avoiding
excessive use of electrocautery or clipping
When to stop?
● Severe fibrosis and scarring in Calot’s triangle due to inflammation
● Impacted gallstone in the confluence of the cystic, common hepatic, and common bile duct
(included in the expanded classification of Mirizzi syndrome)
Where to stop?
●Critical view of safety
●Calot’s triangle area
What are the alternative (bailout procedure)?

●Open conversion
●Subtotal (partial) cholecystectomy
●Fundus first (dome down)
●Cholecystostomy (drainage only)

Fig. 1 Bailout procedures
Accepted Article
d
Open conversion a
Fundus first
Subtotal
b c
Fenestrating Reconstituting

Fig. 2
a b c
Accepted Article
d e f
Fig. 3
Success rate of complete extraction of common bile duct stone.
Fig. 4
Accepted Article Complication rate of complete extraaction of common bile duct stone.
Fig.5
In-hospital mortality of complete ex
xtraction of common bile duct stone.
Fig.6
Accepted Article
Operative time and postoperative pain between needlescopic
and conventional laparoscopic cholecystectomy.

Original article
Accepted Article
Preoperative predictors of conversion as indicators of local
inflammation in acute cholecystitis: strategies for future
studies to develop quantitative predictors
Roheena Z Panni*+ and Steven M Strasberg*
* Division of Hepato-Pancreato-Biliary Surgery, Department of Surgery, Washington

University School of Medicine, St Louis, MO, USA
+ Division of Public Health Sciences, Section of Oncologic Biostatistics, Department of
Surgery, Washington University School of Medicine, St Louis, MO, USA
Corresponding Author
Steven M. Strasberg
Section of HPB Surgery, Washington University in Saint Louis, 4990 Children's Place, Suite
1160, St Louis, MO 63110, USA
Email: strasbergs@wustl.edu
Key Words: predictors of conversion, laparoscopic cholecystectomy, acute cholecystitis
ABSTRACT
Background:
Observational studies have identified risk factors for conversion from laparoscopic to open
cholecystectomy in acute cholecystitis. The aim of this study is to evaluate the reliability of these
predictors and to identify sources of heterogeneity in the studies.
doi: 10.1002/jhbp.493
Methods:
OVID was searched for papers published from 1995 to 2016. Studies with more than 100 patients
Accepted Article
were included. Risk factors for conversion were abstracted and categorized by statistical significance.
Results:
11 studies were evaluated. Inflammation with difficulty in anatomic identification was the most
common reason of conversion. Because of heterogeneity among studies a quantitative approach
was not possible. Therefore, qualitative analysis using a heat map was performed along with
investigation into sources of heterogeneity with the aim of creating a framework for future
quantitative studies. Age, maleness, and WBC count were most commonly identified predictors of
conversion. Sources of heterogeneity were criteria for diagnosis of acute cholecystitis, selection of
patients for laparoscopic cholecystectomy, selection of variables and variations in their thresholds.
Conclusions:
In acute cholecystitis, inflammation is the most common reason for conversion. Age, maleness and
WBC count are common predictors of conversion. Large scale prospective studies with minimal
heterogeneity are needed to establish validity of these and other predictors.
Introduction
In laparoscopic cholecystectomy for acute cholecystitis severe local inflammation is associated with
increased chance of biliary injury (1-3). Therefore, preoperative assessment of the extent of local
inflammation is of importance in guiding surgeons whether to perform early laparoscopic
cholecystectomy or an alternative intervention such as cholecystostomy, open early
cholecystectomy, or delayed cholecystectomy.

Because severe local inflammation is associated with increased operative difficulty there is increased
incidence of conversion from laparoscopic to open cholecystectomy when severe local inflammation
Accepted Article
is present. Consequently, need for conversion has been equated with presence of severe local
inflammation and predictors of conversion have been used as surrogates for predictors of severe
local inflammation, although obviously other indications for conversion might be present in these
patients as they are in patients without acute cholecystitis. Some of the markers of inflammation
used to grade the severity of acute cholecystitis in the Tokyo Guidelines (4) such as white blood cell
count (WBC) and duration of symptoms were derived from studies of predictors of conversion.
To evaluate the reliability of current predictors of local inflammation in acute cholecystitis a review
was performed of studies that have identified preoperative risk factors for conversion of
laparoscopic to open cholecystectomy in patients having early laparoscopic cholecystectomy for
acute cholecystitis. First it was asked whether these studies, in fact, support a conclusion that
conversion can be used as a marker of severity of local inflammation in acute cholecystitis. Then the
preoperatively available risk factors for conversion in this group of studies were analyzed with the
intention of determining the strongest and most reliable predictors. However, because of clinical
and methodological heterogeneity in these studies a quantitative approach using standard meta-
analytic methods was not possible. Therefore, a qualitative analysis of the results of the available
studies was performed along with a detailed investigation into the sources of heterogeneity with the
ultimate aim of creating a framework and guide for future quantitative studies.
Methods
Literature search
The OVID database was searched for papers published from 1995 to the end of 2016 with key words
“laparoscopic cholecystectomy”, “acute cholecystitis” and “conversion” all present in the title. These
papers were then searched for references to papers that might be appropriate for inclusion and
these papers were also selected for study if they met criteria. Only papers with more than 100

patients were included. Papers with patients having interval (delayed) cholecystectomy in the
analysis of results were excluded if the results were not clearly separated from those of patients
Accepted Article
having early cholecystectomy. Papers examining only one risk factor such as timing of
cholecystectomy were excluded. Papers that included a change in management based on a
preliminary analysis and then that performed an analysis that included combined data from before
and after groups were excluded. One center published four studies from 1997 to 2002. The latest
paper using standard multivariable analysis in methods was selected for inclusion (5). A total of 11
papers were left for analysis.
Data extraction
The following variables were extracted from the selected papers: country, type of hospital(s), year
of publication, number of patients, gender, age, number of conversions to open cholecystectomy,
percent converted, reasons for conversion, timing of operation in relation to time of onset of
symptoms and time of presentation, statistical methods, method of diagnosis of acute cholecystitis,
results of univariable or multivariable analysis of risk factors for conversion.
The results of univariable or multivariable analysis of risk factors for conversion were classified as
related to history, physical examination, laboratory, and imaging findings. The clinical factors
searched for included age, gender, weight, comorbidities including diabetes, prior abdominal
surgery, prior attacks of gallbladder pain or cholecystitis, fever at admission, palpable tender
gallbladder, ASA score, and timing of cholecystectomy in relation to time of onset of symptoms and
time of presentation. Laboratory indicators examined were WBC count, C-Reactive protein (CRP),
ESR, serum albumin, AST, ALT, ALP, and bilirubin. Imaging factors that were examined included
thickness of gallbladder wall, pericholecystic fluid, size, position or location and impaction of stones
and evidence of choledocholithiasis including Common Bile Duct (CBD) diameter. Additionally,
imaging characteristics which are already accepted as indicators of marked local inflammation (i.e.
gangrene, emphysematous cholecystitis, perforation abscess) were noted.

Relationship between inflammation and need for conversion
Studies were searched for information regarding the reasons for conversion. These were
Accepted Article
categorized as clearly related to inflammation or not related to inflammation and whether they were
common or uncommon reasons for conversion.
Categorization of risk factors for conversion
Some studies performed univariate analyses only and others performed multivariate analyses. Risk
factors for conversion were categorized by the variables tested in a study and whether univariate or
multivariate methods were used for analysis. Variables were first classified into categories based on
whether they were derived from history including demographics, physical examination, laboratory
tests, ultrasound or imaging as outlined above. These risk factors were then separated according to
the statistical method used (univariate vs multivariate analysis) and the results (significant vs not
significant). The results are presented as a heat map.
Sources of Heterogeneity
Sources of heterogeneity in the studies were sought, the purpose of which was to create a
framework for future improved studies that might be suitable for systematic review and
metaanalysis. Heterogeneity was examined in the following areas: criteria for diagnosis of acute
cholecystitis, criteria for selection of patients with acute cholecystitis to undergo laparoscopic
cholecystectomy, thresholds used in evaluating the predictive value of variables and selection of
variables to be tested.

Results
Demographics
Accepted Article
11 studies published between 2000 and 2015 from 10 countries were evaluated (5-15) (Table 1). In
all there were 9992 patients of whom 7242 were from one large database study. In the other 10
studies the mean number of patients was 275 ± 196.12. 59.3 % of patients were females and 40.6 %
were males (Table 1). All studies were conducted at university affiliated hospitals in urban centers.
Conversion rate
The conversion rate varied from 6% to 32% (Table 2). The lowest conversion rate was in the large
database study from the USA that included more than 7000 patients (13). Other than that study the
conversion rate varied from 14% to 32%. The conversion rate of 6% in the large database study was
less than 50% of the next lowest conversion rate in the other 10 studies (mean conversion rate in
the 11 studies was 21.2%).
Factors influencing decision to convert – role of inflammation
Eight of the 11 studies described the reasons for conversion to open cholecystectomy (Tables 3).
Table 2 lists comments regarding the degree of inflammation encountered in converted cases.
Severe inflammation associated with inflammatory adhesions and difficulty in anatomic
identification were described clearly in all 8 studies. Table 3 lists the reasons for conversion by
frequency. Inflammation and associated adhesions resulting in difficulty of anatomic identification
was responsible for conversion in 75% to 93% of cases, in the 8 studies and these were by far the
most common causes. Therefore, conversion was a good marker for operative difficulty caused by
inflammation in acute cholecystitis. Less common causes of conversion were concern for
malignancy, need for bile duct exploration, inability to create pneumoperitoneum, hypercapnia,
choledochoduodenal fistula, spilled stone, atrial fibrillation and perforation of transverse colon.

Preoperative indicators of the need for conversion
Risk factors for conversion are presented in a color coded heat map for ease of comprehension
Accepted Article
(Figure 1). The map has the advantage that it may be scanned for results within studies and across
studies. Four colors were used for coding - dark red, light red, dark green and light green. Dark red
indicates significance of a variable in a multivariate analysis and light red indicates significance in a
univariate analysis (p<0.05). Dark green indicates non-significance of a variable in a multivariate
analysis and light green indicates non-significance in a univariate analysis (p>0.05). In some studies,
information that a variable was not significant was present only for the univariate analysis and in
that case the information is noted in light green. In most studies the cutoff for including or excluding
a variable from the multivariable analysis was not provided. In two the cutoff was p<0.1 (8, 13). Only
variables that were tested in two or more studies are included in the analysis shown in Figure 1.
Some variables were evaluated in most studies such as male gender, age and WBC count for which
data is available from 10 of 11 studies. Others such as hypertension, comorbidities and CRP level
were examined in only 2 or 3 studies.
Age was identified as a significant predictor of conversion on multivariate analysis in six studies (5, 8,
12-15). Both maleness and WBC count were found to be significant predictors in four of these
studies (5, 8, 12, 13). So in all, four studies identified the three variables maleness, age, and WBC
count to be predictive of conversion in multivariate analysis (5, 8, 12, 13). Additional studies
identified these factors in univariate analysis (Figure 1). Notably maleness and age have also been
shown to be predictive for conversion in elective cholecystectomy in multiple studies (16-18). Long
interval between symptom onset and operation was a positive predictor of conversion in 3 studies in
univariate analyses (6, 7, 11). Other variables in which there are at least 3 positive results and in
which positive results predominate over negative ones are ASA level and pericholecystic fluid (Figure
1). CRP was tested in only two studies (11, 14) but in one study which evaluated both WBC count
and CRP in a multivariate analysis only CRP was predictive (14). Since both are measures of
inflammation this raises the possibility that CRP may be the superior predictive variable. Only one

study evaluated the physical finding of a palpable gallbladder and that study actually found that
inability to palpate the gallbladder was a positive predictor of conversion (5). Note that eight
Accepted Article
variables were found to be significant in the study by Sippey et al. indicating the strength of large
numbers of patients to determine predictive variables.
Sources of Heterogeneity and Areas where Heterogeneity May Be Hidden
Criteria for diagnosis of acute cholecystitis
Five studies used a combination of clinical, laboratory, and imaging results, but not pathological
findings, to make the diagnosis (7-10, 14). Two of these specifically used the Tokyo guidelines for
diagnosis of acute cholecystitis (9, 10). Five other studies accepted the diagnosis of acute
cholecystitis only when the diagnosis was confirmed by microscopic examination of the resected
gallbladder (5, 6, 11, 12, 15). The histologic criteria for diagnosis were usually not stated.
Microscopic findings were used to grade the severity of acute cholecystitis only by Schafer et al (11).
In some other studies severity was estimated by a gross finding such as gangrene or perforation (6).
In one study the diagnosis was based on ICD-9 codes only (13).
Criteria for selecting laparoscopic cholecystectomy as treatment
When patients present with acute cholecystitis only some undergo early laparoscopic
cholecystectomy while others are selected for treatments, for example open cholecystectomy or
delayed laparoscopic cholecystectomy. Preoperative perceived operative difficulty can lead to
variations in streaming into different management options from center to center. This might affect
the composition of the patient population who have early laparoscopic cholecystectomy from study
to study. In order to evaluate this, the disposition of the entire population of patients presenting
with acute cholecystitis during the study period is needed. Most papers gave little or no information
regarding criteria for selection of early laparoscopic cholecystectomy or the disposition of patients
that were not selected for laparoscopic cholecystectomy. Specifically only a few papers provided (5,

6, 9, 11, 15) any information on the number or per cent of patients treated by early open
cholecystectomy versus, subtotal cholecystectomy, cholecystostomy, or non-invasive means in the

Accepted Article
early period followed by interval cholecystectomy. Only one study provided detailed information
about cases selected for early open cholecystectomy (11). This study compared the risk factors and
outcomes of patients who underwent laparoscopic cholecystectomy, lap converted to open and
early open cholecystectomy (11). It should be noted that the problem in this area is not only
heterogeneity but the inability to evaluate whether heterogeneity is present.
Heterogeneity due to variations in thresholds (Figure 1)
The extent to which a variable is able to predict conversion may depend upon the threshold
selected. The threshold for WBC count is a good example. In these studies, the threshold for WBC
count being predictive of conversion has been set as low as any value greater than normal, 12k/
mm3, 15k/ mm3 and 18k/ mm3. Similarly the threshold for age varied from 60-70 years and that for
bilirubin from 1mg/dl to 2mg/dl. ASA was also affected by this problem. However, equally
problematic was the fact that in some cases such as age thresholds were not given. Thus again the
problem is the inability to examine for heterogeneity.
Heterogeneity due to variables tested
Some studies do not include variables that are logically associated with conversion with the potential
result that other variables which are covariate with the excluded variable are identified as
significant. WBC count and CRP is a good example. To allow testing of all logically associated
variables the number of patients in the study needs to be large.

Discussion
Conversion, Inflammation and Prediction of Operative Difficulty

Accepted Article
This study has shown that when performing laparoscopic cholecystectomy for acute cholecystitis the
chief reason for conversion from laparoscopic cholecystectomy is inflammation. While other causes
for conversion exist, inflammation and its consequences are the reason for conversion in the large
majority of cases. Therefore, it can be concluded that conversion is a good marker for operative
difficulty due to inflammation in laparoscopic cholecystectomy for acute cholecystitis. It may also be
concluded that in patients with acute cholecystitis, preoperative identification of risk factors
predictive of conversion will also predict operative difficulty due to inflammation. In the past this
has largely been assumed but now it is shown explicitly. This is of importance since such risk factors
have been used to build severity grading systems for acute cholecystitis such as The Tokyo
Guidelines (19, 20).
Identification of Factors Predictive for Conversion
The original intent of this study was to perform a synthesis of studies that have identified predictors
of conversion of laparoscopic to open cholecystectomy in patients having laparoscopic
cholecystectomy for acute cholecystitis. This was in conjunction with the program to revise the
Tokyo 2013 Guidelines. However the original aim was unattainable because of heterogeneity among
studies and importantly the inability to determine whether heterogeneity was present. As a result
the aim of the study was changed to identify a range of potential predictors and design a definitive
study to fulfill the original purpose.
Despite the considerable heterogeneity among studies three variables maleness, age, and elevated
white blood cell count repeatedly stand out as independent predictors for conversion in multivariate
analyses. Interval over 72 hours from onset of symptoms to operation has been shown to be related
to conversion in the past (21) and is a predictor in the Tokyo Guidelines. In this study it was a
significant but less strong predictor. It was significant in 3 studies using univariate analysis (6, 7, 11).

It would not be surprising if interval is found to be a strong independent predictor in multivariate
analyses since logically it is predictive of the onset of a more vascular and woody type of acute
Accepted Article
inflammation that is not predicted by other independent variables, however that study needs to be
done. ASA like Interval was positive in several univariate analyses. It was also positive in one
multivariate analysis. Pericholecystic fluid, thick gallbladder wall, CRP and serum bilirubin level were
studied less frequently than other variables. Pericholecystic fluid and thickened gallbladder wall are
useful diagnostically in acute cholecystitis but whether they are independent predictors of
conversion is unclear. One study made the interesting observation that wall thickness over 5mm
predicted conversion but milder degrees did not (6). Therefore “wall thickness >5mm” as opposed to
“any increased wall thickness” may be an important predictor. The same might be said of
pericholecystic fluid. CRP already is used as a diagnostic variable in the Tokyo guidelines and as
noted above may actually be superior to WBC count but just has not been tested against it
sufficiently in multivariate analyses to make that determination. Bilirubin levels may rise in acute
cholecystitis due to impingement of the inflamed gallbladder on the bile duct and also as an effect of
sepsis on the liver. Elevated WBC count, interval, pericholecystic fluid, thickened gallbladder wall
and CRP are all effects of inflammation. Large multivariate studies in which all these variables are
included will be needed to determine the strength of these variables as independent predictors of
conversion. It should be noted that “palpable gallbladder” was not a predictor in any of these
studies and that in one study the predictor was actually the absence of ability to palpate a
gallbladder (5). All of these variables are potential predictors for conversion due to increased
inflammation and should be included in future studies to delineate which are the strongest
independent predictors.

Chronic Inflammation in Gallbladder with Acute Cholecystitis
If maleness and age were predictors of conversion just because they predicted acute inflammation it
Accepted Article
would be expected that one or both of these variables would fall out sometimes in multivariate
analyses that contain the variable “elevated white blood cell count” since WBC count is a more
direct measure of acute inflammation, but this was not the case. In all 4 studies in which elevated
WBC count was significant in a multivariate analysis, maleness and age were also significant and
therefore independent predictors of conversion. One clue to the probable explanation lies in the
fact that both maleness and age have been repeatedly shown to be risk factors for conversion in
elective cholecystectomy i.e. in circumstances in which the diagnosis is not acute cholecystitis (16-
18). A second clue is that some of the statements regarding inflammation given in Table 3 referring
to contraction of the gallbladder (10) and adhesions (6, 9-11, 15) are appropriate descriptors for
chronic inflammation. These are good reasons for considering that maleness and age are predictors
for circumstances in which significant chronic inflammation as well as acute inflammation are
present and this contributes to the technical difficulty of the procedure. It is well known that attacks
of acute inflammation of the gallbladder may occur on a background of prior attacks of inflammation
that scar the gallbladder and these may be more common in older males.
Toward a Definitive Study
Eleven surgical studies were identified that attempted to answer the same question – what are the
predictors for conversion in laparoscopic cholecystectomy done for acute cholecystitis? The reason
why the question cannot be answered definitively is related to the presence of heterogeneity and
importantly to the inability to evaluate the degree of clinical heterogeneity among studies. The
inability to evaluate whether heterogeneity is present is actually a greater problem than
heterogeneity itself, since heterogeneity can be measured and risk adjusted. A proposal for an ideal
study follows. In addition to the items in the following list it would be very helpful to create and

publish a database using the standardized tabular reporting approach (22,23) prior to initiating the
studies so that all reporting centers included the same data.

Accepted Article
The ideal study would have the following characteristics
1) The study should be large enough to evaluate at least 20 variables. If the predicted
conversion rate is about 10% and ten events (conversions) are needed per variable then
approximately 2000 patients would be required. This is most likely to be achieved by a large
multiinstitutional registry. However, it could also be reached by studies from multiple
centers using a standardized tabular reporting method.
2) For study purposes the diagnosis of acute cholecystitis must be secure. Only histological
diagnosis is really adequate to eliminate heterogeneity by diagnosis. Using clinical
diagnostic criteria is less secure and ICD code is even less secure. In the USA there is a bias
toward making a clinical diagnosis of acute cholecystitis over biliary colic as the former
results in higher leveling and therefore access to acute care facilities such as operating time.
Obviously including patients in a study group who have biliary colic rather than acute
cholecystitis would tend to reduce conversion rates in that group
3) The severity of acute inflammation should be graded e.g. as by the classification proposed by
Schafer (11). Then predictors can be evaluated as to their ability to predict inflammation as
well as conversion.
4) The severity of chronic inflammation should be graded histologically by extent of fibrosis.
5) The entire cohort of patients presenting with acute cholecystitis should be presented along
with information regarding routing to various treatments. Lack of such information is a form
of potentially hidden heterogeneity. Note that laparoscopic bailouts such as laparoscopic
subtotal cholecystectomies are becoming more common and for study purposes are very
similar to conversions.

6) The data should be evaluated by multivariate analysis. Importantly for purposes of meta
analyses non-significant odds ratio as well as significant odds ratios should be given.
Accepted Article
7) Reporting certain variables e.g. WBC count as a continuous variable is more informative
than dichotomizing and specifying thresholds, which results in loss of information. One
argument for this categorization is that it simplifies the interpretation of results but
assessment of continuous variables across their entire range provides much more
information to detect any relation between a predictor variable and outcome.
8) The reasons for conversion should be described under categories that equate to acute and
chronic inflammation.
In summary, severity grading of acute cholecystitis by examination of predictors of conversion has
provided guidance to the formation of guidelines. A quantitative analysis is not yet possible due to
heterogeneity and the inability to generate heterogeneity however the available studies provide
clues to potentially valuable predictors and a pathway to future studies.
Conflicts of Interest
RZP was supported by funding from National Institutes of Health (NIH) grant number (NIH
5T32CA00962128).
RZP and SMS have no relevant conflicts of interest.
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Legend for Figures
Figure 1. Heat map of variables tested for relation to conversion in patients having laparoscopic
cholecystectomy for acute cholecystitis in 11 studies. “Interval” is the time between onset of
symptoms and cholecystectomy. CRP= C - reactive protein. PC fluid = pericholecystic fluid.
Table 1. Patient characteristics in included studies.

Conversion
Authors Year Country No. of patients Mean age % Female Rate
(n) (years) (%)
Halachmi et al. (6) 2000 Israel 256 55.0 56.6 20.0
Schafer et al. (12) 2001 Switzerland 159 61.4 * 27.6
Simopoulos et al. (13) 2005 Greece 272 52.7 68.4 18.3
Del Rio et al. (8) 2006 Italy 176 61.7 * 32.3
Yetkin et al. (16) 2009 Turkey 108 50.0 63.0 17.6
Dominguez et al. (9) 2011 Colombia 703 47.8 64.4 13.8
Fuks et al. (10) 2012 France 108 58.0 43.5 22.0
Cwik et al. (7) 2013 Poland 542 * * 24.0
Wevers et al. (15) 2013 Netherlands 261 59.5 59.4 24.0
Oymaci et al. (11) 2014 Turkey 165 52.4 67.9 27.9
Sippey et al. (14) 2015 USA 7242 56.1 58.6 6.0
* Information missing

Table 2. Chief comments regarding reason for conversion in eight studies
Study Comments
Accepted Article
Schafer et al.(12) The anatomy of Calot’s triangle was either severely distorted
by the advanced inflammatory reaction or hidden by
adhesions, thus making the dissection hazardous.
Simopoulos et al. (13) Inability to define anatomy in triangle of Calot 11 times more
frequent in AC than in elective cholecystectomy.
Yetkin et al. (16 ) Inability to display anatomy safely due to severe
inflammation and dense adhesions.
Dominguez et al. (9) Severe inflammation.
Fuks et al. (10) The two main reasons were:

(a) difficulty in dissecting the biliary pedicle due to
inflammation with gangrenous acute cholecystitis and
(b) adhesions resulting from local inflammation.
Cwik et al. (7) Impossible identification of the cystic duct. Massive
inflammatory or post-operative adhesions.
Wevers et al. (15) Inability to reach the critical view of safety due to
inflammatory changes.
Oymaci et al. (11 ) Difficulty identifying anatomy (inflammation, biliary or
vascular anomalies) inability to define anatomy including
contracted or fibrotic gallbladder and cystic duct; dense
adhesions of the gallbladder to either the duodenum or the
common bile duct.

Accepted Article
Table 3: Reasons for conversion identified in eight studies.
Schafer Simopoul Yetkin Domingu Fuks et Cwik et Wevers Oymaci
et al. os et al. et al. ez et al. al. (10) al. (7) et al. et al.
(12) (13) (16) (9) (15) (11)
Sample
159 272 108 703 108 542 261 165
size
Conversio
27.6 18.3 17.6 13.8 22.0 24.0 24.0 27.9
n rate (%)
Reasons for conversion n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)
Severe inflammation 38 (86.4) 70 (74.5) 15 (78.9) 90 (92.8) 21 (87.5) 109 (83.8) 54 (87.1) 42( 91.3)
Hemorrhage 1 (2.3) 3 (3.2) 4 (21.1) 4 (4.1) 2 (8.3) 11 (8.5) 5 (8.1) 3 (6.5)
Suspected bile duct injury - 2 (2.1) 3 (3.1) 1 (4.2) 3 (2.3) 2 (3.2) 1 (2.2)
Concern for malignancy - 2 (2.1) - - - - 1 (1.6) -
Need for bile duct exploration 1 (2.3) - - - - 7 (5.4) - -
Inability to create - 9 (9.6) - - - - - -
pneumoperitoneum
Choledochoduodenal fistula - 6 (6.4) - - - - - -
Spilled stone - 2 (2.1) - - - - - -
Perforation of transverse colon 2 (4.5) - - - - - - -
Atrial fibrillation 1 (2.3) - - - - - - -
Hypercapnia 1 (2.3) - - - - - - -

Guideline
Accepted Article
TG18 management strategies for gallbladder drainage in patients with acute
cholecystitis: Updated Tokyo Guidelines 2018 (with videos)
Yasuhisa Mori, Takao Itoi, Todd H. Baron, Tadahiro Takada, Steven M. Strasberg,
Henry A. Pitt, Tomohiko Ukai, Satoru Shikata, Yoshinori Noguchi, Anthony Yuen
Bun Teoh, Myung-Hwan Kim, Horacio J. Asbun, Itaru Endo, Masamichi Yokoe,
Fumihiko Miura, Kohji Okamoto, Kenji Suzuki, Akiko Umezawa, Yukio Iwashita,
Taizo Hibi, Go Wakabayashi, Ho-Seong Han, Yoo-Seok Yoon, In-Seok Choi,
Tsann-Long Hwang, Miin-Fu Chen, O James Garden, Harjit Singh, Kui-Hin Liau,
Wayne Shih-Wei Huang, Dirk Joan Gouma, Giulio Belli, Christos Dervenis, Eduardo
de Santibañes, Mariano Eduardo Giménez, John Albert Windsor, Wan Yee Lau, Daniel
Cherqui, Palepu Jagannath, Avinash Nivritti Supe, Keng-Hao Liu, Cheng-Hsi Su,
Daniel J. Deziel, Xiao-Ping Chen, Sheung Tat Fan, Chen-Guo Ker, Eduard C. Jonas,
Robert Padbury, Shuntaro Mukai, Goro Honda, Atsushi Sugioka, Koji Asai, Ryota
Higuchi, Keita Wada, Masahiro Yoshida, Toshihiko Mayumi, Koichi Hirata,
Yoshinobu Sumiyama, Kazuo Inui, Masakazu Yamamoto
doi: 10.1002/jhbp.504

Correspondence to:
Accepted Article
Tadahiro Takada, MD, PhD, Department of Surgery, Teikyo University School of
Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan. E-mail:
t-takada@jshbps.jp
Keywords: Acute cholecystitis, Gallbladder drainage, Percutaneous transhepatic
gallbladder drainage (PTGBD), Endoscopic transpapillary gallbladder drainage
(ETGBD), endoscopic ultrasound-guided gallbladder drainage (EUS-GBD)
ABSTRACT
Since the publication of the Tokyo Guidelines in 2007 and their revision in
2013, appropriate management for acute cholecystitis has been more clearly
established. Since the last revision, several manuscripts, especially for alternative
endoscopic techniques, have been reported; therefore, additional evaluation and
refinement of the 2013 Guidelines is required. We describe a standard drainage method
for surgically high-risk patients with acute cholecystitis and the latest developed
endoscopic gallbladder drainage techniques described in the updated Tokyo Guidelines
2018 (TG18). Our study confirmed that percutaneous transhepatic gallbladder drainage
should be considered the first alternative to surgical intervention in surgically high-risk
patients with acute cholecystitis. Also, endoscopic transpapillary gallbladder drainage

or endoscopic ultrasound-guided gallbladder drainage can be considered in
high-volume institutes by skilled endoscopists. In the endoscopic transpapillary

Accepted Article
approach, either endoscopic naso-gallbladder drainage or gallbladder stenting can be
considered for gallbladder drainage. We also introduce special techniques and the
latest outcomes of endoscopic ultrasound-guided gallbladder drainage studies.
INTRODUCTION
Although standard treatment for patients with acute cholecystitis (AC) is well
established based on the 2007 Tokyo Guidelines (TG07)(1), revised in Tokyo
Guidelines 2013 (TG13)(2), morbidity and mortality rates in patients at high risk for
surgery with comorbid medical conditions remain high (3-9). In TG07, the detailed
procedure of percutaneous transhepatic gallbladder drainage (PTGBD) was introduced,
while the recommendation of PTGBD for AC was not established. Since then, TG13
stated that PTGBD should be recommended as the first alternative to cholecystectomy
in such patients (2). However, some studies have evaluated the usefulness of
percutaneous transhepatic gallbladder aspiration (PTGBA) without catheter placement
as a simple decompression method (10, 11). Another alternative procedure is
endoscopic gallbladder drainage, which can be performed using either a transpapillary
or transmural approach. The former method is endoscopic transpapillary gallbladder
drainage (ETGBD) including endoscopic naso-gallbladder drainage (ENGBD) and
gallbladder stenting (EGBS) under endoscopic retrograde cholangiopancreatography

(ERCP), through which the gallbladder is drained via the cystic duct with a nasobiliary
tube or stent across the papilla. This procedure appears to be especially suitable for
Accepted Article
patients with severe coagulopathy, thrombocytopenia, or an anatomically inaccessible
location. More recently, endoscopic ultrasound-guided gallbladder drainage
(EUS-GBD) has been reported to be useful as an alternative gallbladder drainage
procedure in patients with AC. TG13 proposed that these endoscopic approaches
provide suboptimal drainage because they have not been fully evaluated. Since the
introduction of TG13, several studies describing alternative endoscopic techniques
have been published; therefore, additional evaluation and refinement of TG13 is
required. We describe a standard drainage method for surgically high-risk patients with
AC, and the latest developed endoscopic gallbladder drainage techniques. We also
discuss the recommendation grades for the procedures, (12, 13) established by the
updated 2018 Tokyo Guidelines (TG18).
Methods of systematic review and meta-analysis
In the updated TG, we performed systematic reviews and meta-analyses related to
each discussion point for gallbladder drainage, where possible, and described the
results based on the PRISMA statement. We systematically searched MEDLINE
(PubMed), the Cochrane Library, and Japan Medical Abstracts (the largest database of
Japanese articles) for studies describing each discussion point for gallbladder drainage.
In MEDLINE, we combined the Centre for Reviews and Dissemination/Cochrane

Highly Sensitive Search Strategy with the Medical Subject Heading (MeSH) terms.
Similar search strategies were adopted in other databases. References from previous
Accepted Article
review articles and meta-analyses were also hand-searched. Two investigators (YM
and TI) thoroughly assessed the quality of each article and selected the final included
articles. Disagreement between investigators was discussed and resolved by consensus.
Meta-analysis was conducted using Cochrane Collaboration Review Manager 5.3
software (Cochrane, London, United Kingdom). Statistical analysis was performed
using the Mantel-Haenszel method, and summary statistics were described as odds
ratio (OR). We used a random-effects model with OR < 1 favoring the investigation
group and the OR point estimate was considered statistically significant at P<0.05 if
the 95% confidence interval (CI) did not include the value 1. We also calculated I2 to
assess homogeneity.
Q1. What are the standard gallbladder drainage methods for AC in surgically
high-risk patients?
We recommend PTGBD as a standard drainage method for surgically high-risk
patients with AC (Recommendation 1, level B). However, ETGBD or EUS-GBD could
be considered in high-volume institutes when performed by skilled endoscopists
(levelB).

PTGBD
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PTGBD should be considered the first alternative to surgical intervention in
surgically high-risk patients with AC because several studies have described PTGBD
as less invasive and having a lower risk of adverse events compared with
cholecystectomy (OS) (14-21) (EO)(22, 23). The PTGBD procedure is described in the
previous guidelines (2), and the technique is relatively easy for general clinicians to
perform. Briefly, after ultrasound-guided transhepatic gallbladder puncture has been
performed with an 18-G needle, a 6- to 10-Fr catheter is placed in the gallbladder using
a guidewire under fluoroscopy. Of note, PTGBD for Grade III (severe) cases based on
the TG13 severity grading was reported to be associated with higher mortality and
mortality, higher readmission rates, and prolonged hospital stay (OS)(24).
Endoscopic drainage
Recently, ETGBD under ERCP including ENGBD and EGBS, and EUS-GBD
have been reported as novel effective alternative gallbladder drainage procedures in
patients with AC in (RCT)(25-27), (OS)(28-43), (SR)(29, 38, 44, 45), (EO)(30, 33,
46), and a case study (CS)(47). Although there are no published papers, to our
knowledge, comparing PTGBD and ETGBD, SRs have shown no significant
difference regarding the technical success rate, clinical success rate, and the frequen cy
of adverse events between PTGBD and EUS-GBD (SR)(32, 38, 44). The internal
drainage obtained with endoscopic gallbladder drainage (EGBS/EUS-GBD) results in

less post-procedure pain than with the external drainage of PTGBD. However, because
these internal procedures require difficult endoscopic techniques, and almost all reports
Accepted Article
regarding endoscopic drainage have been by skilled pancreatobiliary endoscopists
from high-volume centers, these endoscopic techniques have not yet been established
as standard procedures. Therefore, ETGBD and EUS-GBD should be considered in
high-volume institutes by skilled pancreatobiliary endoscopists; otherwise, PTGBD
should be selected as the standard drainage procedure.
PTGBA
Although PTGBA without catheter placement appears to be a simple and easy
decompression method, aspiration could be unsuccessful because of replacement of
bile with dense biliary sludge or pus (RCT)(20), (OS)(11, 20, 21). Therefore, PTGBA
should not be recommended as a standard procedure for all patients with AC.
However, the latest international multicenter study (OS)(48) showed that the clinical
success rate within 3 days of PTGBA was significantly higher than that of PTGBD and
EGBS, although there was no significant difference within 7 days. Also, the
complication rate of PTGBA was lower than that of PTGBD and EGBS. Several
possible reasons are suggested when comparing previous reports, including the
possibility that the PTGBA groups included patients with mild or moderate grade
cholecystitis, and gallbladder lavage using saline during PTGBA was more effective

than simple drainage. Prospective RCTs using standardized techniques and devices for
PTGBD, PTGBA, and endoscopic gallbladder drainage are warranted.

Accepted Article
Gallbladder drainage for patients with coagulopathy or who are receiving
antithrombotic agents
There are few reports discussing PTGBD for patients with AC and coagulopathy
or who are receiving antithrombotic agents (CPG)(49)(MA)(50)(CS)(51). The Society
of Interventional Radiology guidelines suggest that PTGBD can be performed without
discontinuing acetylsalicylic acid if patients have a high risk of thromboembolism;
however, the guidelines also recommend discontinuing clopidogrel for 5 days before
PTGBD (CPG)(49). The guidelines also recommend that PTGBD in patients who are
receiving anticoagulants should be performed with PT-INR < 1.5 and heparin
substitution (CPG)(49). PTGBD for patients receiving both antiplatelet and
anticoagulant agents should be avoided because there is no reliable data in these
patients. ETGBD should be considered in such conditions when skilled
pancreaticobiliary endoscopists are available in the institution.

Q2. What procedure for preoperative drainage should be used for endoscopic
transpapillary gallbladder drainage? ENGBD or EGBS?

Accepted Article
We suggest that either ENGBD or EGBS may be considered for gallbladder
drainage based on the patient’s background and endoscopist’s decision
(Recommendation 1, level B).
Detailed procedures for ENGBD and EGBS
ETGBD could be considered in high-volume institutes by skilled endoscopists as
described in Q1. ETGBD can be divided into two different methods: ENGBD and
EGBS. ENGBD involves placing a naso-gallbladder drainage tube and generally does
not require sphincterotomy. The detailed techniques for ENGBD are as follows: After
successful bile duct cannulation, a 0.025 or 0.035-inch guidewire is advanced into the
cystic duct (Fig. 1a) and subsequently into the gallbladder (Fig. 1b). Next, the catheter
is withdrawn and the guidewire remains in the gallbladder, and a 5 Fr to 8.5 Fr pigtail
naso-gallbladder drainage tube is inserted into the gallbladder (Fig. 1c, Video 1). In
comparison, the EGBS procedure is the same as for ENGBD, but a 6-Fr to 10-Fr
internal stent is placed in the gallbladder, instead. Stent placement is not always
successful because the cystic duct is frequently not visible on cholangiography, severe
cystic duct stenosis and/or impacted stones in the neck of the gallbladder can block
advancement of the guidewire and stent, and the tortuous valves of Heister can be
difficult to traverse with standard guidewires (27). These procedures require skillful

techniques because prolonged or unsuccessful procedures may lead to serious
complications such as post-ERCP pancreatitis and perforation of a cystic duct or

Accepted Article
gallbladder. Therefore, endoscopists should acquire accurate knowledge and technical
skills including selective biliary cannulation and appropriate guidewire technique.
ENGBD vs. EGBS
Recently, several reports evaluating the feasibility, safety, and efficacy of
ETGBD have been published (SR)(31, 44), (OS)(25, 26, 28, 30, 33, 34, 38, 52),
(EO)(32). This procedure appears to be especially suitable for patients with severe
coagulopathy, thrombocytopenia, or an anatomically inaccessible location. To date,
two RCTs (35, 53) and an SR(28) comparing ENGBD and EGBS have been published.
A meta-analysis including these two RCTs was conducted in TG18 and found no
statistically significant difference in technical success [odds ratio (OR): 1.18 (95%
confidence interval (CI): 0.36–3.89)], clinical success [OR: 1.82 (95% CI: 0.40–8.26)],
or adverse events rate [OR: 1.04 (95% CI: 0.29–3.81)] between ENGBD and EGBS
(Fig. 2, 3 and 4, respectively). Note, however, that ENGBD involves cases in which
the tube is removed by patients themselves because of discomfort. While EGBS carries
a risk of stent obstruction, ENGBD has the advantage of flushing the bile via the
transnasal tube (27). Consequently, the advantages and disadvantages of each drainage
method are considered approximately equal, and TG18 suggests that either ENGBD or

EGBS may be considered for gallbladder drainage based on the patient’s background
and endoscopist’s decision.

Accepted Article
Special technique: EUS-GBD
Technique
The gallbladder is punctured from the body or antrum of the stomach or
duodenal bulb under direct EUS visualization. A 0.035-inch guidewire is inserted
through the outer sheath, and dilation of the tract using a mechanical dilator,
electrocautery dilator, or balloon dilator is then performed. Finally, a naso-gallbladder
drainage tube (NGBT), double pigtail plastic stent (PS), or self-expandable metal stent
(SEMS) is inserted into the gallbladder (Fig. 5, Video 2). More recently,
lumen-apposing metal stents (LAMS) (Fig. 6a and b) (54, 55), the flared end of a
covered SEMS (Fig. 6c) (56), and biflanged metal stents (Fig. 6d) (57) provide
effective and safe drainage of gallbladder contents.
Outcomes
The latest outcomes regarding overall technical success rate, clinical success
rate, and frequency of adverse events were 98.0% (194/198), 94.4% (187/198), and
12.1% (24/198), respectively (Table 1) (45). The technical success rate was 100%
using NGBT, 100% using PS, 98.6% using SEMS, and 95.8% using LAMS, and the

clinical success rate was 100%, 100%, 94.5%, and 90.1 % using NGBT, PS, SEMS,
and LAMS, respectively. There were no significant differences among these stents;
Accepted Article
however, LAMS may be ideal for EUS-GBD because it was associated with the lowest
adverse events rate among the stents (40).
Acknowledgments
We express our deep gratitude to the Japanese Society of Hepato-Biliary-Pancreatic
Surgery, the Japanese Society of Abdominal Emergency Medicine, the Japanese
Society of Surgical Infection, and the Japan Biliary Association, for their substantial
support and guidance in the preparation of this article. We also would like to express
our deep gratitude to the Japanese Society of Hepato-Biliary-Pancreatic Surgery for
the Article Processing Managing Office of the Tokyo Guidelines 18 for preparing this
publication. We appreciate all secretariats of the Japanese Society of
Hepato-Bilialy-Pancreatic Surgery for their technical support.
Anthony Yuen Bun Teoh, has received consultant fees from Boston Scientific
Corporation, USA, Cook Medical, USA, and Taewoong Medical, Korea. Goro Honda
has received honoraria from Johnson and Johnson and Medtronics.

Appendix: Authors’ Affiliations
Accepted Article
Yasuhisa Mori, Department of Surgery and Oncology, Graduate School of Medical
Sciences, Kyushu University, Fukuoka, Japan; Takao Itoi and Shuntaro Mukai,
Department of Gastroenterology and Hepatology, Tokyo Medical University Hospital,
Tokyo, Japan; Todd H. Baron, Division of Gastroenterology and Hepatology,
University of North Carolina at Chapel Hill, NC, USA; Tadahiro Takada, Fumihiko
Mira, and Keita Wada, Department of Surgery, Teikyo University School of Medicine,
Tokyo, Japan; Steven M. Strasberg, Section of Hepato-Pancreato-Biliary Surgery,
Washington University School of Medicine, St. Louis, MO, USA; Henry A. Pitt, Lewis
Katz School of Medicine at Temple University, Philadelphia, PA, USA; Tomohiko
Ukai, Department of Family Medicine, Mie Prefectural Ichishi Hospital, Mie, Japan;
Satoru Shikata, Director, Mie Prefectural Ichishi Hospital, Mie, Japan; Yoshinori
Noguchi and Masamichi Yokoe, Department of General Internal Medicine, Japanese
Red Cross Nagoya Daini Hospital, Aichi, Japan; Anthony Yuen Bun Teoh, Department
of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong; Myung-Hwan
Kim, Department of Gastroenterology, University of Ulsan College of Medicine,
Seoul, Korea; Horacio J. Asbun, Department of Surgery, Mayo Clinic College of
Medicine, FL, USA; Itaru Endo, Department of Gastroenterological Surgery,
Yokohama City University Graduate School of Medicine, Kanagawa, Japan; Kohji
Okamoto, Department of Surgery, Center for Gastroenterology and Liver Disease,
Kitakyushu City Yahata Hospital, Fukuoka, Japan; Kenji Suzuki, Department of
Surgery, Fujinomiya City General Hospital, Shizuoka, Japan; Akiko Umezawa,

Minimally Invasive Surgery Center, Yotsuya Medical Cube, Tokyo, Japan; Yukio
Iwashita, Department of Gastroenterological and Pediatric Surgery, Oita University

Accepted Article
Faculty of Medicine, Oita, Japan; Taizo Hibi, Department of Surgery, Keio University
School of Medicine, Tokyo, Japan; Go Wakabayashi, Department of Surgery, Ageo
Central General Hospital, Saitama, Japan; Ho-Seong Han and Yoo-Seok Yoon,
Department of Surgery, Seoul National University Bundang Hospital, Seoul National
University College of Medicine, Seoul, Korea; In-Seok Choi, Department of Surgery,
Konyang University Hospital, Daejeon, Korea; Tsann-Long Hwang, Miin-Fu Chen,
and Keng-Hao Liu, Division of General Surgery, Linkou Chang Gung Memorial
Hospital, Taoyuan, Taiwan; O. James Garden, Clinical Surgery, University of
Edinburgh, Edinburgh, UK; Harjit Singh, Department of Hepato-Pancreato-Biliary
Surgery, Hospital Selayang, Malaysia; Kui-Hin Liau, Liau KH Consulting PL, Mt
Elizabeth Novena Hospital Singapore & Yong Loo Lin School of Medicine, National
University of Singapore, Singapore; Wayne Shih-Wei Huang, Department of Surgery,
Show Chwan Memorial Hospital, Changhua, Taiwan; Dirk Joan Gouma, Department
of Surgery, Academic Medical Center, Amsterdam, The Netherlands; Giulio Belli,
Department of General and HPB Surgery, Loreto Nuovo Hospital, Naples Italy;
Christos Dervenis, First Department of Surgery, Agia Olga Hospital, Athens, Greece;
Eduardo de Santibañes, Department of Surgery, Hospital Italiano, University of
Buenos Aires, Buenos Aires, Argentina; Mariano Eduardo Giménez, Chair of General
Surgery and Minimal Invasive Surgery “Taquini” University of Buenos Aires.
Argentina, DAICIM Foundation, Argentina; John Albert Windsor, Department of

Surgery, The University of Auckland, Auckland, New Zealand; Wan Yee Lau, Faculty
of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong; Daniel
Accepted Article
Cherqui, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France; Palepu
Jagannath, Department of Surgical Oncology, Lilavati Hospital and Research Centre,
Mumbai, India; Avinash Nivritti Supe, Department of Surgical gastroenterology, Seth
G S Medical College and K E M Hospital, Mumbai, India; Cheng-Hsi Su, Department
of Surgery, Cheng Hsin General Hospital, Taipei, Taiwan; Daniel J. Deziel,
Department of Surgery, Rush University Medical Center, Chicago, USA; Xiao-Ping
Chen, Hepatic Surgery Centre, Department of Surgery, Tongji Hospital, Tongji
Medical College, Huazhong University of Science and Technology, Wuhan, China;
Sheung Tat Fan, Department of Surgery, The University of Hong Kong, Queen Mary
Hospital, Hong Kong, Hong Kong; Chen-Guo Ker, Department of Surgery, Yuan’s
General Hospital, Kaohsiung, Taiwan; Eduard C. Jonas, Surgical
Gastroenterology/Hepatopancreatobiliary Unit, University of Cape Town and Groote
Schuur Hospital, Cape Town, South Africa; Robert Padbury, Division of Surgical and
Specialty Services, Flinders Medical Centre, Adelaide, Australia; Goro Honda,
Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan;
Atsushi Sugioka, Department of Surgery, Fujita Health University School of Medicine,
Aichi, Japan; Koji Asai, Department of Surgery, Toho University Ohashi Medical
Center, Tokyo, Japan; Ryota Higuchi and Masakazu Yamamoto, Department of
Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo,
Japan; Masahiro Yoshida, Department of Hemodialysis and Surgery, chemotherapy

research institute Kaken hospital, International University of Health and Welfare,
Chiba, Department of EBM and Guidelines, Japan council for Quality Health Care,
Accepted Article
Tokyo, Japan; Toshihiko Mayumi, Department of Emergency Medicine, School of
Medicine University of Occupational and Environmental Health, Fukuoka, Japan;
Koichi Hirata, Department of Surgery, JR Sapporo Hospital, Hokkaido, Japan;
Yoshinobu Sumiyama, Director, Toho University, Tokyo, Japan; Kazuo Inui,
Department of Gastroenterology, Second Teaching Hospital, Fujita Health University,
Aichi, Japan
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Accepted Article
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Accepted Article
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Accepted Article
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36. Mutignani M, Iacopini F, Perri V, Familiari P, Tringali A, Spada C, et al.
Endoscopic gallbladder drainage for acute cholecystitis: technical and clinical results.
Accepted Article
Endoscopy. 2009;41(6):539-46.
37. Pannala R, Petersen BT, Gostout CJ, Topazian MD, Levy MJ, Baron TH.
Endoscopic transpapillary gallbladder drainage: 10-year single center experience.
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38. Penas-Herrero I, de la Serna-Higuera C, Perez-Miranda M. Endoscopic
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Accepted Article
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Accepted Article
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Accepted Article
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FIGURE LEGENDS
Accepted Article
Figure 1. Detailed procedure for endoscopic naso-gallbladder drainage. After
successful bile duct cannulation, a 0.025- or 0.035-inch guidewire is advanced into the
cystic duct (a) and subsequently into the gallbladder (b). Next, the catheter is
withdrawn, and the guidewire remains in the gallbladder, then a 5-Fr to 8.5-Fr pigtail
naso-gallbladder drainage tube is inserted into the gallbladder (c).
Figure 2. Forest plot analysis of technical success rate of endoscopic naso-gallbladder
drainage versus endoscopic gallbladder stenting.
Figure 3. Forest plot analysis of clinical success rate of endoscopic naso-gallbladder
Figure 4. Forest plot analysis of adverse events of endoscopic naso-gallbladder
Figure 5. Schema of endoscopic ultrasound-guided gallbladder drainage.

Figure 6. Metal stents for endoscopic ultrasound-guided gallbladder drainage. (a)
Fully-covered 10-mm-diameter lumen-apposing stent with dual anchor flanges. (b)

Accepted Article
Fully-covered metal stent with folding-back wide anchoring flanges for lumen
apposition. (c) The flared end of a covered self-expandable metal stent. (d) Biflanged
metal stent.
Video 1. Detailed procedure for endoscopic naso-gallbladder drainage.
Video 2. Detailed procedure for endoscopic ultrasound-guided gallbladder drainage.

Table 1. Comparison of different gallbladder drainage techniques/materials for
technical success, clinical success, and adverse events.

Accepted Article
NGBT: naso-gallbladder drainage tube
PS: plastic stent
SEMS: self-expandable metal stent
LAMS: lumen-apposing stent

Accepted Article

Accepted Article

Accepted Article

Guideline
Accepted Article
Tokyo Guidelines 2018 management bundles for acute cholangitis and cholecystitis
Toshihiko Mayumi, Kohji Okamoto, Tadahiro Takada, Steven M. Strasberg, Joseph S. Solomkin,
David Schlossberg, Henry A. Pitt, Masahiro Yoshida, Harumi Gomi, Fumihiko Miura, O. James
Garden, Seiki Kiriyama, Masamichi Yokoe, Itaru Endo, Horacio J. Asbun, Yukio Iwashita, Taizo
Hibi, Akiko Umezawa, Kenji Suzuki, Takao Itoi, Jiro Hata, Ho-Seong Han, Tsann-Long Hwang,
Christos Dervenis, Koji Asai, Yasuhisa Mori, Wayne Shih-Wei Huang, Giulio Belli, Shuntaro Mukai,
Palepu Jagannath, Daniel Cherqui, Kazuto Kozaka, Todd H. Baron, Eduardo de Santibañes, Ryota
Higuchi, Keita Wada, Dirk J. Gouma, Daniel J. Deziel, Kui-Hin Liau, Go Wakabayashi, Robert
Padbury, Eduard Jonas, Avinash Nivritti Supe, Harjit Singh, Toshifumi Gabata, Angus C.W. Chan,
Wan Yee Lau, Sheung Tat Fan, Miin-Fu Chen, Chen-Guo Ker, Yoo-Seok Yoon, In-Seok Choi,
Myung-Hwan Kim, Dong-Sup Yoon, Seigo Kitano, Masafumi Inomata, Koichi Hirata, Kazuo Inui,
Yoshinobu Sumiyama, Masakazu Yamamoto
Tadahiro Takada, MD, PhD, Department of Surgery, Teikyo University School of Medicine, 2-11-1
Kaga, Itabashi-ku, Tokyo 173-8605, Japan
E-mail: t-takada@jshbps.jp
doi: 10.1002/jhbp.519
Keywords: Cholangitis bundles, Cholecystitis bundles, Guidelines, Acute cholangitis, Acute
Accepted Article cholecystitis
Abstract
Management bundles that define items or procedures strongly recommended in clinical practice
have been used in many guidelines in recent years. Application of these bundles facilitates the
adaptation of guidelines and helps improve the prognosis of target diseases. In Tokyo Guidelines
2013 (TG13), we proposed management bundles for acute cholangitis and cholecystitis. Here, in
Tokyo Guidelines 2018 (TG18), we redefine the management bundles for acute cholangitis and
cholecystitis. Critical parts of the bundles in TG18 include the diagnostic process, severity
assessment, transfer of patients if necessary, and therapeutic approach at each time point. Observance
of these items and procedures should improve the prognosis of acute cholangitis and cholecystitis.
Studies are now needed to evaluate the dissemination of these TG18 bundles and their effectiveness.
Introduction
Detailed guidelines are now being released in many fields of medicine, and it is not easy for
clinical physicians to keep all of the contents of these guidelines in mind when treating patients.
Nevertheless, to improve patient prognosis, such guidelines need to be widely disseminated and used
in clinical practice. Using bundles in health care simplifies complex patient care processes. A bundle
is a selected set of elements of care that are distilled from evidence-based practice guidelines and that,
when implemented as a group, have an effect on outcomes beyond that achieved when the individual
elements are implemented alone.
We proposed management bundles for acute cholangitis and cholecystitis in Tokyo Guidelines
2013 (TG13) [1]. Here, as part of TG18, we propose a new flowchart for the treatment of acute
cholecystitis and have made several changes to the clinical practice guidelines for managing acute
cholangitis and acute cholecystitis.

Efficacy of the bundles
Accepted Article
A good example for the effectiveness of using bundles is the sepsis bundles in the Surviving
Sepsis Campaign Guidelines. Sepsis bundles were introduced in 2008, and improvements in
compliance and survival with the bundles were investigated in a number of studies [2]- [6]. These
reports showed a marked reduction in hospital mortality rates in patients whose care included
compliance with most of the bundles.
To encourage adherence to clinical guidelines and improve care processes, the Institute for
Healthcare Improvement developed the concept of “care bundles” [7] in critical care patients. Various
strategies such as education (86%), reminders (71%), and audit and feedback (63%) have been used to
encourage the implementation of the care bundles in intensive care units ([8], 26276569).
As with TG13, in the process of developing TG18, mandatory items or procedures to be included
in the management bundles have been discussed and defined among Tokyo Guidelines Revision
Committee members. On the basis of the recommendations in TG18, those items that are expected to
yield favorable treatment results have been included in the bundles to assure the appropriate
interventions for acute cholangitis and cholecystitis at the appropriate times. The TG13 checklists also
have been updated to confirm compliance with the bundles.
Acute cholangitis management bundle (Table 1)
Few changes have been made in the TG18 management bundle for acute cholangitis compared
with the TG13 one, with the exception of the addition of recommendations for patient transfer [9]. If
acute cholangitis is suspected, perform a diagnostic assessment by using the TG18 diagnostic criteria
[10]. If a definitive diagnosis cannot be made, reassess the patient every 6 to 12 h using the diagnostic
criteria. Use the severity assessment criteria [9] to assess severity repeatedly: at diagnosis, within 24 h
after diagnosis, and again during the next 24 to 48 h. Provide initial treatment, such as sufficient fluid
replacement, electrolyte compensation, and intravenous administration of analgesics and full-dose
antimicrobial agents, as soon as a diagnosis has been made [11]. Perform biliary drainage, and culture
the blood or bile, or both, if the condition is sufficiently severe [12]. If the hospital is not equipped to

perform endoscopic or percutaneous transhepatic biliary drainage or to provide intensive care, transfer
Accepted Article patients with moderate or severe cholangitis to a hospital that is capable of providing these treatments.
Acute cholecystitis management bundle (Table 2)
If acute cholecystitis is suspected, diagnostic assessment is made by using the TG18 diagnostic
criteria [13]. If a definite diagnosis cannot be made, reassess the patient every 6 to 12 h using the
diagnostic criteria. Use the severity assessment criteria [13] to assess the severity repeatedly: at
diagnosis, within 24 h after diagnosis, and again at 24 to 48 h, and evaluate the surgical risk (e.g.
presence of local inflammation, Charlson comorbidity index, American Society of Anesthesiologists
physical status classification, or the predictive factors). Taking into consideration the need for
cholecystectomy, as soon as a diagnosis has been made, initiate treatment, including sufficient fluid
replacement, electrolyte compensation, fasting, and administration of intravenous analgesics and
full-dose antimicrobial agents [11,13]. Urgent or early laparoscopic cholecystectomy (Lap-C), urgent
or early biliary drainage, and blood or bile culture (or both) should be performed according to the
severity and surgical risk [14-17]. Consider transferring the patient to advanced facilities if facilities
for urgent or emergency Lap-C, biliary drainage, and intensive care are not available [14].
Checklist for the use of management bundles for acute cholangitis and cholecystitis (Tables 3, 4)
Checklists are given to ensure effective use of the bundles. Use of these lists in medical care
ensures that standards are maintained and is thought to improve the effectiveness of the bundles. The
TG13 checklists also have been updated to confirm compliance with the bundles [1]. A checklist of
the procedures, laboratory tests, monitoring, and interventions required should be placed at the
patient’s bedside.

Conclusions
Accepted Article
Bundles consist of important items and procedures for the effective application of TG18. Reports
from various facilities have demonstrated that improved prognosis can be expected through the use of
the Tokyo Guidelines for acute cholangitis and cholecystitis.
Future evaluations of the distribution of TG18 bundles and of changes in prognosis will provide
evidence for the future construction and revision of TG18.
Acknowledgments
We are grateful to the following organizations for their support and guidance in the preparation of
TG18: the Japanese Society of Hepato-Biliary-Pancreatic Surgery, Japanese Society for Abdominal
Emergency Medicine, Japan Biliary Association, and Japan Society for Surgical Infection. We thank
the Japanese Society of Hepato-Biliary-Pancreatic Surgery for managing this publication, and we
thank the members of the secretariat of the Society for their technical support.
Conflicts of interest: None
Appendix
Toshihiko Mayumi, Department of Emergency Medicine, School of Medicine,University of Occupational and

Environmental Health, Fukuoka, Japan; Kohji Okamoto, Department of Surgery, Center for
Gastroenterology and Liver Disease, Kitakyushu City Yahata Hospital, Fukuoka, Japan; Tadahiro Takada,
Fumihiko Miura, and Keita Wada, Department of Surgery, Teikyo University School of Medicine, Tokyo,
Japan; Steven M. Strasberg, Section of Hepato-Pancreato-Biliary Surgery, Washington University School of
Medicine in St. Louis, St. Louis, MO, USA; Joseph S Solomkin, Department of Surgery, University of
Cincinnati College of Medicine, Cincinnati, OH, USA; David Schlossberg, Professor of Medicine, Lewis
Katz School of Medicine at Temple University, Philadelphia, PA, Medical Director, TB Control Program,
Philadelphia, PA, Department of Public Health, Philadelphia, PA, USA; Henry A. Pitt, Lewis Katz School of
Medicine at Temple University, Philadelphia, PA, USA; Masahiro Yoshida, Department of Hemodialysis and
Surgery, Ichikawa Hospital, International University of Health and Welfare, Chiba, Department of EBM and
Guidelines, Japan Council for Quality Health Care, Tokyo, Japan; Harumi Gomi, Center for Global Health,
Mito Kyodo General Hospital, University of Tsukuba, Ibaraki, Japan; O James Garden, Clinical Surgery,

University of Edinburgh, Edinburgh, UK; Seiki Kiriyama, Department of Gastroenterology, Ogaki Municipal
Hospital, Gifu, Japan; Masamichi Yokoe, Department of General Internal Medicine, Japanese Red Cross
Accepted Article
Nagoya Daini Hospital, Aichi, Japan; Itaru Endo, Department of Gastroenterological Surgery, Yokohama City
University Graduate School of Medicine, Kanagawa, Japan; Horacio J. Asbun, Department of Surgery, Mayo
Clinic College of Medicine, Florida, USA; Yukio Iwashita and Masafumi Inomata, Department of
Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita, Japan; Taizo Hibi,
Department of Surgery, Keio University School of Medicine, Tokyo, Japan; Akiko Umezawa, Minimally
Invasive Surgery Center, Yotsuya Medical Cube, Tokyo, Japan; Kenji Suzuki, Department of Surgery,
Fujinomiya City General Hospital, Shizuoka, Japan; Takao Itoi and Shuntaro Mukai, Department of
Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan; Jiro Hata, Department
of Endoscopy and Ultrasound, Kawasaki Medical School, Okayama, Japan; Ho-Seong Han and Yoo-Seok
Yoon, Department of Surgery, Seoul National University Bundang Hospital, Seoul National University
College of Medicine, Seoul, Korea; Tsann-Long Hwang, and Miin-Fu Chen, Division of General Surgery,
Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; Christos Dervenis, First Department of Surgery,
Agia Olga Hospital, Athens, Greece; Koji Asai, Department of Surgery, Toho University Ohashi Medical
Center, Tokyo, Japan; Yasuhisa Mori, Department of Surgery and Oncology, Graduate School of Medical
Sciences, Kyushu University, Fukuoka, Japan; Wayne Shih-Wei Huang, Department of Surgery, Show Chwan
Memorial Hospital, Changhua, Taiwan; Giulio Belli, Department of General and HPB Surgery, Loreto Nuovo
Hospital, Naples Italy; Palepu Jagannath, Department of Surgical Oncology, Lilavati Hospital and Research
Centre, Mumbai, India; Daniel Cherqui, Hepatobiliary Center, Paul Brousse Hospital, Villejuif, France;
Kazuto Kozaka, Department of Radiology, Kanazawa University Graduate School of Medical Sciences,
Kanazawa Japan; Todd H. Baron, Division of Gastroenterology and Hepatology, University of North Carolina
at Chapel Hill, North Carolina, USA; Eduardo de Santibañes, Department of Surgery, Hospital Italiano,
University of Buenos Aires, Buenos Aires, Argentina; Ryota Higuchi and Masakazu Yamamoto, Department
of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan; Dirk J. Gouma,
Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands; Daniel J. Deziel,
Department of Surgery, Rush University Medical Center, Chicago, IL, USA; Kui-Hin Liau, Liau KH
Consulting PL, Mt Elizabeth Novena Hospital, Singapore, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore; Go Wakabayashi, Department of Surgery, Ageo Central General
Hospital, Saitama, Japan; Robert Padbury, Division of Surgical and Specialty Services, Flinders Medical
Centre, Adelaide, South Australia, Australia; Eduard Jonas, Surgical Gastroenterology/Hepatopancreatobiliary
Unit, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa; Avinash Nivritti Supe,
Department of Surgical Gastroenterology, Seth G S Medical College and K E M Hospital, Mumbai, India;
Harjit Singh, Department of Hepato-Pancreato-Biliary Surgery, Hospital Selayang, Selangor, Malaysia;
Toshifumi Gabata, Director, General Kanazawa University Hospital, Ishikawa, Japan; Angus C.W. Chan,
Surgery Centre, Department of Surgery, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong; Wan
Yee Lau, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong; Sheung Tat Fan,
Director, Liver Surgery Centre, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong; Chen-Guo
Ker, Department of Surgery, Yuan’s General Hospital, Kaohsiung, Taiwan; In-Seok Choi, Department of
Surgery, Konyang University Hospital, Daejeon, Korea; Myung-Hwan Kim, Department of Gastroenterology,
University of Ulsan College of Medicine, Seoul, Korea; Dong-Sup Yoon, Department of Surgery, Yonsei
University Gangnam Severance Hospital, Seoul, Korea; Seigo Kitano, President, Oita University, Oita, Japan;
Koichi Hirata, Department of Surgery, JR Sapporo Hospital, Hokkaido, Japan; Kazuo Inui, Department of

Gastroenterology, Second Teaching Hospital, Fujita Health University, Aichi, Japan; Yoshinobu Sumiyama,
Director, Toho University, Tokyo, Japan.
Accepted Article
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11. Gomi H, Solomkin JS, Schlossberg D, Okamoto K, Takada T, Strasberg SM, et al. TG 18:
Antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci.
2018; accepted for publication.
12. Mukai S, Itoi T, Baron TH, Takada T, Strasberg SM, Henry HA, et al. Indications and
techniques of biliary drainage for acute cholangitis in updated Tokyo Guidelines 2018. J
Hepatobiliary Pancreat Sci. 2018; accepted for publication.
13. Yokoe M, Hata J, Takada T, Strasberg SM, Asbun HJ, Wakabayashi G, et al. TG18 diagnostic
criteria and severity grading of acute cholecystitis with Videos. J Hepatobiliary Pancreat Sci.
2018; accepted for publication.
14. Okamoto K, Suzuki K, Takada T, Strasberg SM, Asbun HJ, Endo I, et al. TG18 flowchart for
the management of acute cholecystitis. J Hepatobiliary Pancreat Sci. 2018, accepted for
publication.
15. Wakabayashi G, Iwashita Y, Hibi T, Takada T, Strasberg SM, Asbun HJ, et al. TG18 surgical
management of acute cholecystitis：Safe steps in laparoscopic cholecystectomy for acute
cholecystitis （with videos）J Hepatobiliary Pancreat Sci. 2018, accepted for publication.

16. Panni RZ, Strasberg SM. Preoperative Predictors of Conversion as Indicators of Local
Accepted Article inflammation in Acute Cholecystitis. J Hepatobiliary Pancreat Sci. 2018, accepted for publication.
17. Mori Y, Itoi T, Baron TH, Takada T, Strasberg SM, Pitt HA, et al. TG18 management strategies
for gallbladder drainage in patients with acute cholecystitis; updated Tokyo Guidelines 2018
(with video). J Hepatobiliary Pancreat Sci. 2018, accepted for publication.

Table 1 Management bundle for acute cholangitis
Accepted Article
1. When acute cholangitis is suspected, perform a diagnostic assessment every 6 to 12 h using TG18
diagnostic criteria until a diagnosis is reached ..
2. Perform abdominal US, followed by a CT scan, MRI, MRCP, and HIDA scan as required.
3. Use the severity assessment criteria to assess severity repeatedly: at diagnosis, within 24 h after
diagnosis, and from 24 to 48 h after diagnosis.
4. As soon as a diagnosis has been made, provide initial treatment. The treatment is as follows:
sufficient fluid replacement, electrolyte compensation, and intravenous administration of
analgesics and full-dose antimicrobial agents.
5. In patients with Grade I (mild) disease, if no response to the initial treatment is observed within 24
h, perform biliary tract drainage immediately.
6. In patients with Grade II (moderate) disease, perform biliary tract drainage immediately along with
the initial treatment. If early drainage cannot be performed because of a lack of facilities or skilled
personnel, consider transferring the patient.
7. In patients with Grade III (severe) disease, perform urgent biliary tract drainage along with the
initial treatment and give general supportive care. If urgent drainage cannot be performed because
of a lack of facilities or skilled personnel, consider transferring the patient.
8. In patients with Grade III (severe) disease, supply organ support (e.g. noninvasive/invasive positive
pressure ventilation, use of vasopressors and antimicrobial agents) immediately.
9. Perform blood culture or bile culture, or both, in Grade II (moderate) and III (severe) patients.
10. Consider treating the etiology of acute cholangitis with endoscopic, percutaneous, or operative
intervention once the acute illness has resolved. Cholecystectomy should be performed for
cholecystolithiasis after the acute cholangitis has resolved.

11. If the hospital is not equipped to perform endoscopic or percutaneous transhepatic biliary drainage
Accepted Article or provide intensive care, transfer patient with moderate or severe cholangitis to a hospital capable
of providing these treatments.
US, ultrasonography; CT, computed tomography; MRI, magnetic resonance imaging; MRCP,
magnetic resonance cholangiopancreatography; HIDA, hepatobiliary iminodiacetic acid
Table 2 Management bundle for acute cholecystitis
1. When acute cholecystitis is suspected, perform a diagnostic assessment every 6 to 12 h using TG18
diagnostic criteria until a diagnosis is reached .
2. Perform abdominal US, followed by a CT scan or HIDA scan if needed to make a diagnosis.
3. Use the severity assessment criteria to assess severity repeatedly: at diagnosis, within 24 h after
diagnosis, and from 24 to 48 h after diagnosis. Evaluate the surgical risk (e.g. local inflammation,
CCI, ASA, PS, predictive factors).
4. Taking into consideration the need for cholecystectomy, as soon as a diagnosis has been made,
initiate treatment, with sufficient fluid replacement, electrolyte compensation, fasting, and
administration of intravenous analgesics and full-dose antimicrobial agents.
5. In Grade I (mild) patients, laparoscopic cholecystectomy (Lap-C) at an early stage, i.e. within 7
days (within 72 h is better) of onset of symptoms is recommended.
6. If conservative treatment is selected for patients with Grade I (mild) disease and no response to
initial treatment is observed within 24 h, reconsider early Lap-C if patient performance status is
good and fewer than 7 days have passed since symptom onset or biliary tract drainage.
7. In Grade II (moderate) patients, consider urgent/early Lap-C if patient performance status is good
and the advanced Lap-C technique is available. If the patient’s condition is poor, urgent/early
biliary drainage, or delayed/elective Lap-C, can be selected.

8. In Grade III (severe) patients with high surgical risk*, perform urgent/early biliary drainage. If
Accepted Article there are neither negative predictive factors** nor FOSF*** and the patient has good PS, early
Lap-C at an advanced center can be chosen.
9. Perform blood culture or bile culture, or both, in Grade II (moderate) and III (severe) patients.
10. Consider transferring the patient to advanced facilities if urgent/emergency Lap-C, biliary
drainage, and intensive care are not available.
US, ultrasonography; CT, computed tomography; HIDA, hepatobiliary iminodiacetic acid; CCI;
Charlson Comorbidity Index; ASA, American Society of Anesthesiologists class; PS, performance
status
*high surgical risk: evaluate CCI, ASA, PS, predictive factors, and FOSF
**predictive factors: jaundice (T-Bil ≥2), neurological dysfunction, respiratory dysfunction
***FOSF: favorable organ system failure = cardiovascular or renal organ system failure that is rapidly
reversible after admission and before early Lap-C in acute cholecystitis

Table 3 Acute cholangitis bundle checklist
Accepted Article
□ Repeat the diagnosis every 6 to 12 h
□ Perform diagnostic imaging: abdominal US followed by CT scan, MRI, MRCP, and HIDA scan as
needed.
□ Assess severity at diagnosis, within 24 h; and from 24 to 48 h after diagnosis..
□ After diagnosis, immediately start antibiotic administration and general supportive care.
□ Grade I (mild): perform biliary drainage when no symptom improvement is observed within 24 h.
□ Grade II (moderate): perform biliary drainage immediately.
□ Grade III (severe): apply organ support and emergency biliary drainage.
□ Consider transfer when the above procedures are unavailable.
□ Grade II (moderate) and III (severe): culture blood or bile or both.
□ Consider surgical procedures to remove causes after biliary drainage and amelioration of organ
failure.

Table 4 Acute cholecystitis bundle checklist
Accepted Article
□ Repeat the diagnosis every 6 to 12 h.
□ Perform diagnostic imaging: US, followed by CT and HIDA scan
□ Assess severity at diagnosis and within 24 h after diagnosis; repeat severity assessment every 24 h
and evaluate surgical risk.
□ Immediately initiate antibiotic administration and general supportive care.
□ Grade I (mild): perform laparoscopic cholecystectomy (Lap-C) at an early stage within 7 days
(within 72 h is better) of onset of symptoms.
□ Conservative treatment for Grade I (mild): if condition is worsening or no improvement is observed
within 24 h, reconsider early Lap-C if fewer than 7 days since biliary drainage (cholecystostomy).
□ Grade II (moderate): perform urgent/early Lap-C if patient performance status is good and
advanced Lap-C technique is available. If not, urgent/early biliary drainage or delayed/elective
Lap-C can be selected.
□ Grade III (severe): perform urgent/early biliary drainage in patients with high surgical risk. If there
are neither negative predictive factors nor FOSF and the patient has a good PS, early Lap-C at an
advanced center can be chosen.
□ Grade II (moderate) and III (severe): culture blood or bile or both.
□ Consider transferring the patient to advanced facilities if urgent/emergency Lap-C, biliary drainage,
and intensive care are not available.

J Hepatobiliary Pancreat Sci (2018) 25:31–40
DOI: 10.1002/jhbp.509
GUIDELINE
Tokyo Guidelines 2018: initial management of acute biliary infection

and flowchart for acute cholangitis
Fumihiko Miura Kohji Okamoto Tadahiro Takada Steven M. Strasberg Horacio J. Asbun Henry A. Pitt
Harumi Gomi Joseph S. Solomkin David Schlossberg Ho-Seong Han Myung-Hwan Kim Tsann-Long Hwang
Miin-Fu Chen Wayne Shih-Wei Huang Seiki Kiriyama Takao Itoi O. James Garden Kui-Hin Liau
Akihiko Horiguchi Keng-Hao Liu Cheng-Hsi Su Dirk J. Gouma Giulio Belli Christos Dervenis
Palepu Jagannath Angus C. W. Chan Wan Yee Lau Itaru Endo Kenji Suzuki Yoo-Seok Yoon
Eduardo de Santiba~nes Mariano Eduardo Gimenez Eduard Jonas Harjit Singh Goro Honda Koji Asai
Yasuhisa Mori Keita Wada Ryota Higuchi Manabu Watanabe Toshiki Rikiyama Naohiro Sata

Nobuyasu Kano Akiko Umezawa Shuntaro Mukai Hiromi Tokumura Jiro Hata Kazuto Kozaka
Yukio Iwashita Taizo Hibi Masamichi Yokoe Taizo Kimura Seigo Kitano Masafumi Inomata Koichi Hirata
Yoshinobu Sumiyama Kazuo Inui Masakazu Yamamoto
Published online: 8 January 2018

© 2018 Japanese Society of Hepato-Biliary-Pancreatic Surgery
The author’s affiliations are listed Abstract The initial management of patients with suspected acute biliary infection
in the Appendix. starts with the measurement of vital signs to assess whether or not the situation is
Correspondence to: Tadahiro urgent. If the case is judged to be urgent, initial medical treatment should be started
Takada, Department of Surgery, immediately including respiratory/circulatory management if required, without waiting
Teikyo University School of for a definitive diagnosis. The patient’s medical history is then taken; an abdominal
Medicine, 2-11-1 Kaga, Itabashi-ku, examination is performed; blood tests, urinalysis, and diagnostic imaging are carried
e-mail: t-takada@jshbps.jp out; and a diagnosis is made using the diagnostic criteria for cholangitis/
cholecystitis. Once the diagnosis has been confirmed, initial medical treatment should
DOI: 10.1002/jhbp.509 be started immediately, severity should be assessed according to the severity grading
criteria for acute cholangitis/cholecystitis, and the patient’s general status should be
evaluated. For mild acute cholangitis, in most cases initial treatment including
antibiotics is sufficient, and most patients do not require biliary drainage. However,
biliary drainage should be considered if a patient does not respond to initial
treatment. For moderate acute cholangitis, early endoscopic or percutaneous
transhepatic biliary drainage is indicated. If the underlying etiology requires
treatment, this should be provided after the patient’s general condition has improved;
endoscopic sphincterotomy and subsequent choledocholithotomy may be performed
together with biliary drainage. For severe acute cholangitis, appropriate respiratory/
circulatory management is required. Biliary drainage should be performed as soon as
possible after the patient’s general condition has been improved by initial treatment
and respiratory/circulatory management. Free full articles and mobile app of TG18
are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related
clinical questions and references are also included.
Keywords Acute cholangitis Acute cholecystitis Biliary drainage Guidelines

Initial treatment
32 J Hepatobiliary Pancreat Sci (2018) 25:31–40
Introduction Flowchart for the initial response to acute biliary

infection
Acute biliary infection, particularly acute cholangitis, may
cause a rapid deterioration in condition due to sepsis, and The initial management (Fig. 1) of patients with suspected
prompt and appropriate treatment is therefore required. acute biliary infection starts with the measurement of vital
There were no clear management guidelines available signs to assess whether or not the situation is urgent. If
until 2007, when we first proposed a flowchart illustrating the case is judged to be urgent, initial medical treatment
guidelines for the management of acute cholangitis and should be started immediately including respiratory/circu-
acute cholecystitis according to the severity grades in the latory management if required, without waiting for the
Tokyo Guidelines 2007 (TG07) [1]. The TG07 flowchart definitive diagnosis.
was established on the basis of the consensus reached in A detailed examination (consultation and physical
the International Consensus Meeting held in Tokyo in examination) is then performed, after which blood tests
April 2006. The TG07 flowchart has been cited in numer- and diagnostic imaging are performed; on the basis of the
ous publications and has had a major impact on everyday results, a definitive diagnosis is made following the diag-
clinical practice and clinical research [2]. The Tokyo nostic criteria for acute cholangitis and cholecystitis (clini-
Guidelines were revised in 2013 as the Tokyo Guidelines cal practice guidelines, CPG) [4–9].
2013 (TG13) [2], and the Tokyo Guidelines 2018 (TG18) Once the diagnosis has been confirmed, initial medical
is the third revised version. treatment should be started immediately, the severity
In TG18, part of the flowchart for the management of should be assessed according to the severity grading crite-
moderate acute cholangitis has been somewhat revised from ria for acute cholangitis/cholecystitis, and the patient’s
TG13. The flowchart for the management of acute chole- general status should be evaluated. The Charlson comor-
cystitis, however, has undergone major revisions compared bidity index (CCI) (case series, CS) [10] and the
with TG13. In TG07 and TG13, the flowcharts for the man- American Society of Anesthesiologists (ASA) Physical
agement of acute cholangitis and acute cholecystitis were Status (PS) classification [11] are useful for the evaluation
published together in a single paper, but for the TG18 the of general status. After the severity assessment, a treat-
initial response to acute biliary infection and the flowchart ment strategy should be decided on the basis of the flow-
for management of acute cholangitis are dealt with in this chart for the management of acute cholangitis or acute
paper, while the flowchart for the management of acute cholecystitis, and treatment should immediately be
cholecystitis is reported in a separate publication [3]. provided.
Fig. 1 TG18 flowchart for the initial response to acute biliary infection. *TG18/TG13 diagnostic criteria for acute cholangitis [4] and cholecysti-
tis [7] should be used. †TG18/TG13 severity assessment criteria for acute cholangitis [4] and cholecystitis [7] should be used. ‡Charlson comor-
bidity index (CCI) [10] and the American Society of Anesthesiologists (ASA) Physical Status (PS) classification [11] should be referred to
J Hepatobiliary Pancreat Sci (2018) 25:31–40 33
General status and signs when acute biliary infection is Inflammation in acute cholangitis is difficult to assess
suspected on diagnostic imaging, but it is possible to evaluate dilata-
tion of the bile duct, or bile congestion due to occlusion/
Symptoms indicative of suspected acute biliary infection stenosis of the bile duct or biliary calculus and its cause
are fever, chills, abdominal pain, jaundice, nausea, vomit- (CPG) [12].
ing, and disturbance of consciousness. If even one of The distinctive signs of acute cholecystitis on diag-
these symptoms is present, acute biliary infection is sus- nostic imaging include enlargement of the gallbladder,
pected and it is necessary to proceed to diagnosis (CPG) gallbladder wall thickening, gallbladder calculi, fluid
[12]. retention around the gallbladder, abscess around the
gallbladder, and sludge debris in the gallbladder and the
sonographic Murphy’s sign (pain when the probe
Management of patients with suspected acute biliary presses on the gallbladder) on abdominal ultrasound
infection (CPG) [12].
Vital signs include blood pressure, heart rate, respiration

rate, temperature, urine volume, oxygen saturation (SpO2), Diagnostic criteria for acute biliary infection
and consciousness level. The consultation should include
a detailed medical history of the timing of the appearance Diagnosis is made in light of the findings required for
of symptoms and their nature. Patients should be asked diagnosis, as described above, using the TG13/18 diag-
about their previous medical history and regular medica- nostic criteria for acute cholangitis (Table 1) (CPG) [4–6]
tions. In the physical examination, the evaluation and and the TG13/18 diagnostic criteria for acute cholecystitis
measurement of the patient’s state of consciousness goes (Table 2) (CPG) [8, 9].
without saying, and the presence or absence of yellowing
of the palpebral conjunctiva, the location and severity of
tenderness, and whether or not there are any symptoms of Initial treatment
peritoneal irritation must always be confirmed. The pres-
ence or absence of Murphy’s sign (compression of the Once a definitive diagnosis of acute cholangitis or acute
right upper quadrant causes the patient to catch their cholecystitis has been reached, initial treatment including
breath due to pain when taking a deep breath), which is the infusion of sufficient fluids and antibiotic and anal-
specific to acute cholecystitis, must always be confirmed. gesic administration is started, with careful monitoring of
blood pressure, heart rate, and urine volume. It goes with-
out saying that if the patient is in a state of shock, initial
Tests required for the diagnosis of acute biliary infection treatment should be started without waiting for a definitive
diagnosis. Although there is no high-quality evidence for
Blood tests including white blood cell count, platelet the merits and demerits of fasting in acute cholangitis/c-
count, C-reactive protein (CRP), albumin, alkaline phos- holecystitis, in principle patients should be fasted to
phatase (ALP), gamma-glutamyl transferase (GGT), aspar- enable immediate emergency drainage (CPG) [12].
tate aminotransferase (AST), alanine aminotransferase Despite the concern that analgesic administration may
(ALT), bilirubin, blood urea nitrogen (BUN), creatinine, mask physical signs and cause a mistaken diagnosis, a
prothrombin time (PT), and PT-international normalized randomized controlled trial (RCT) comparing intravenous
ratio (INR) are carried out for the purpose of diagnosis morphine hydrochloride and an intravenous placebo for
and severity grading, and blood gas analysis should also patients examined in the emergency room complaining of
be performed (CPG) [12]. If a high fever is present, blood abdominal pain found no difference between them in the
culture should preferably be performed at this point. rate of diagnosis [13, 14], and analgesics should therefore
In terms of diagnostic imaging, abdominal ultrasound be administered proactively at an early stage. Opioid anal-
and computed tomography (CT) are useful for the diagno- gesics such as morphine hydrochloride and other similar
sis of acute biliary infection, and at least one of these types of drug (such as non-opioid analgesics and penta-
should be performed. Abdominal ultrasound in particular zocine) cause the sphincter of Oddi to contract, which
is minimally invasive, widely used, simple, and cheap, may elevate biliary pressure, and must therefore be admin-
and should therefore be performed first in patients with istered with caution.
suspected biliary infection, despite disadvantages includ- In the case of serious deterioration, such as the appear-
ing the fact that the results are easily affected by the oper- ance of shock (hypotension), disturbance of conscious-
ator’s skill and the patient’s condition (CPG) [6]. ness, acute dyspnea, acute renal dysfunction, hepatic
Table 1 TG18/TG13 diagnostic criteria for acute cholangitis For guidance on antibiotic administration, see TG18:
A. Systemic inflammation antimicrobial therapy for acute cholangitis and cholecysti-
A-1. Fever and/or shaking chills tis (CPG) [15].
A-2. Laboratory data: evidence of inflammatory response
B. Cholestasis
Severity assessment and general status evaluation
B-1. Jaundice
B-2. Laboratory data: abnormal liver function tests
Alongside initial treatment, severity assessment should
C. Imaging
be carried out using the TG13/18 severity assessment
C-1. Biliary dilatation
criteria for acute cholangitis (Table 3) (CPG) [4–6] or
C-2. Evidence of the etiology on imaging (stricture, stone,
the TG13/18 severity assessment criteria for acute chole-
stent, etc)
cystitis (Table 4) (CPG) [8, 9], and the patient’s general
Suspected diagnosis: one item in A + one item in either B or C
status should also be evaluated using the CCI and the
Definite diagnosis: one item in A, one item in B and one item in C
ASA-PS classification. The severity should be reassessed
A-2: Abnormal white blood cell counts, increase of serum
C-reactive protein levels, and other changes indicating frequently in accordance with response to initial treat-
inflammation ment.
B-2: Increased serum ALP, r-GTP (GGT), AST, and ALT levels If the patient cannot be treated appropriately, transfer
Thresholds should be considered to an advanced center capable of
A-1 Fever BT >38°C procedures including emergency surgery, interventional
A-2 Evidence of WBC (91,000/ll) <4 or >10 radiology (IVR), and endoscopy.
inflammatory
response Q1. How was the TG13 flowchart for acute cholangitis
CRP (mg/dl) ≥1 evaluated? [Background question]
B-1 Jaundice T-Bil ≥2 (mg/dl)
B-2 Abnormal liver ALP (IU) >1.5 9 STD It was shown to require partial revision. (Level D)
function tests
cGTP (IU) >1.5 9 STD Although no studies have evaluated the flowchart itself,
AST (IU) >1.5 9 STD a review was carried out of studies that included partial
ALT (IU) >1.5 9 STD investigations of the treatment guidelines for acute cholan-
Cited from Kiriyama et al. [4]
gitis set out in the flowchart. Two observational studies
ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspar-
addressed the timing of biliary drainage by severity grade.
tate aminotransferase, rGTP (GGT) r-glutamyltransferase, STD upper A multicenter joint study carried out in Japan and Taiwan
limit of normal value found that for moderate cholangitis, mortality was signifi-
cantly lower in 944 patients who underwent drainage
Table 2 TG18/TG13 diagnostic criteria for acute cholecystitis within 24 h compared with 1,081 patients who either
A. Local signs of inflammation etc. underwent drainage after longer than 24 h or did not
(1) Murphy’s sign, (2) RUQ mass/pain/tenderness undergo drainage (1.7% vs. 3.4%, P = 0.0172), but that
B. Systemic signs of inflammation etc. there was no significant difference for mild or severe
(1) Fever, (2) elevated CRP, (3) elevated WBC count cholangitis [16]. In the other observational study, which
C. Imaging findings compared 130 patients with mild or moderate cholangitis
Imaging findings characteristic of acute cholecystitis who underwent drainage within 24 h and 82 who under-
Suspected diagnosis: one item in A + one item in B went drainage after longer than 24 h, although there was
Definite diagnosis: one item in A + one item in B + C no significant difference in mortality which was zero in
both groups, the mean duration of hospitalization was sig-
Cited from Yokoe et al. [7]. Acute hepatitis, other acute abdominal
diseases, and chronic cholecystitis should be excluded nificantly shorter for patients who underwent drainage
CRP C-reactive protein, RUQ right upper abdominal quadrant, WBC within 24 h (6.8 days vs. 9.2 days, P < 0.01 (CS) [17].
white blood cell The TG13 flowchart proposed that for patients with
moderate cholangitis, treatment for the underlying etiology
dysfunction, or disseminated intravascular coagulation should be provided electively after early biliary drainage,
(DIC) (reduced platelet count), emergency biliary drainage and that for patients with mild cholangitis due to choledo-
should be considered alongside appropriate organ support cholithiasis, treatment for the underlying etiology such as
and respiratory/circulatory management (such as artificial endoscopic sphincterotomy (EST) and choledocholitho-
ventilation, tracheal intubation, and the use of hyperten- tomy may be performed at the same time as biliary drai-
sive agents) (CPG) [12]. nage [12]. Three observational studies (one of which did
Table 3 TG18/TG13 severity assessment criteria for acute cholangitis

Grade III (severe) acute cholangitis
“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 dysfunction: hypotension requiring dopamine ≥5 lg/kg per min, or any dose of norepinephrine
2. Neurological dysfunction: disturbance of consciousness
3. Respiratory dysfunction: PaO2/FiO2 ratio <300
4. Renal dysfunction: oliguria, serum creatinine >2.0 mg/dl
5. Hepatic dysfunction: PT-INR >1.5
6. Hematological dysfunction: platelet count <100,000/mm3
Grade II (moderate) acute cholangitis
“Grade II” acute cholangitis is associated with any two of the following conditions:
1. Abnormal WBC count (>12,000/mm3, <4,000/mm3)
2. High fever (≥39°C)
3. Age (≥75 years)
4. Hyperbilirubinemia (total bilirubin ≥5 mg/dl)
5. Hypoalbuminemia (<STD 9 0.7)
Grade I (mild) acute cholangitis
“Grade I” acute cholangitis does not meet the criteria of “Grade III (severe)” or “Grade II (moderate)” acute cholangitis at initial diagnosis
STD lower limit of normal value
Table 4 TG18/TG13 severity grading for acute cholecystitis

Grade III (severe) acute cholecystitis
Associated with dysfunction of any one of the following organs/systems:
1. Cardiovascular dysfunction: hypotension requiring treatment with dopamine ≥5 lg/kg per min, or any dose of norepinephrine
2. Neurological dysfunction: decreased level of consciousness
Grade II (moderate) acute cholecystitis
Associated with any one of the following conditions:
1. Elevated white blood cell count (>18,000/mm3)
2. Palpable tender mass in the right upper abdominal quadrant
3. Duration of complaints >72 h
4. Marked local inflammation (gangrenous cholecystitis, pericholecystic abscess, hepatic abscess, biliary peritonitis, emphysematous
cholecystitis)
Grade I (mild) acute cholecystitis
Does not meet the criteria of “Grade III” or “Grade II” acute cholecystitis. Grade I 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
Cited from Yokoe et al. [7]
not use severity assessment criteria) (CS) [17–19] and one that after two-stage lithotomy (6/35 = 17.1% vs. 0/
RCT [20] showed that single-stage lithotomy was safe 33 = 0%, P = 0.025) (RCT) [20]; therefore, caution is
and feasible in cases of mild or moderate acute cholangitis required.
caused by choledocholithiasis. In the RCT, however, the Two studies have compared early and elective laparo-
rate of complications after endoscopic retrograde cholan- scopic choledocholithotomy for patients with mild or mod-
giopancreatography (ERCP) was significantly higher than erate acute cholangitis associated with choledocolithiasis
(CS) [21, 22]. Early laparoscopic choledocholithotomy of evidence, but as there were no serious side-effects, the
was safe and there was no difference in the rate of compli- use of rTM in patients with severe cholangitis complicated
cations, but both studies were carried out in the same insti- by DIC may be considered.
tution, included few subjects [72 (CS) [21] and 73 (CS)
[22], respectively] with a large number of exclusions, and
Flowchart for the management of acute cholangitis
did not demonstrate the safety of single-stage laparoscopic
and cholecystitis
choledocholithotomy in patients with moderate acute
cholangitis.
After severity has been assessed and the patient’s general
At this point, although the value of the TG13 flowchart
status has been evaluated, a treatment strategy should be
for acute cholangitis as a whole is unclear, its core struc-
decided on the basis of the flowchart for the management
ture is based on conservative treatment in mild cases and
of acute cholangitis or acute cholecystitis, and treatment
early biliary drainage in moderate cases, and as the value
should immediately be provided.
of these has been shown in large-scale studies to be
With the exception of part of the management of mod-
highly significant, the value of the flowchart has been
erate cholangitis, the TG18 flowchart for the management
demonstrated to at least some extent. Although the evi-
of acute cholangitis is little changed from TG13 (CPG)
dence for single-stage treatment for the underlying etiol-
[12]. Acute cholangitis should be managed in accordance
ogy in moderate acute cholangitis (EST followed by
with its severity. Biliary drainage and antibiotics are the
choledocholithotomy) is still insufficient, the TG18 flow-
two key pillars of the treatment of acute cholangitis. In
chart for acute cholangitis has been amended to show that
some cases of acute cholangitis, acute cholecystitis may
this is possible in light of the actual situation in clinical
also be present; in this event the treatment strategy should
practice.
be decided in consideration of the severity of both and the
Q2. What treatments other than antibiotics and biliary patient’s general status (CPG) [12]. If blood culture has
drainage are effective for severe cholangitis? [Future not been performed as part of the initial response, it
research question] should be carried out before antibiotic administration. If
biliary drainage is performed, bile samples must always
The administration of recombinant human soluble be sent for culture.
thrombomodulin may be considered for severe For the flowchart for the management of acute chole-
cholangitis complicated with disseminated intravas- cystitis, see TG18: flowchart for the management of acute
cular coagulation. (Level D) cholecystitis (CPG) [3].
Severe cholangitis is often complicated by DIC. Septic

DIC is treated with anticoagulants such as heparin, Flowchart for the management of acute cholangitis
antithrombin III, and protease inhibitors. Although these (Fig. 2)
anticoagulants have been well studied, including in RCTs,
the numbers of cholangitis patients in these studies are Grade I (mild acute cholangitis)
either unknown or very small, and the value of anticoagu-
lants in severe cholangitis is unclear. Two studies have Mild acute cholangitis is defined as cholangitis that does
reported the value of recombinant human soluble thrombo- not meet the TG18 severity assessment criteria for moder-
modulin (rTM) for DIC in patients with acute cholangitis ate or severe cholangitis below (CPG) [9]. In most cases
(CS) [23, 24]. Suetani et al. divided 66 patients diagnosed initial treatment including antibiotics is sufficient, and
with acute cholangitis-induced DIC on the basis of the most patients do not require biliary drainage. However,
TG13 diagnostic criteria into 33 who were treated with biliary drainage should be considered if a patient does not
rTM and 36 who were not, and found that the DIC resolu- respond to initial treatment. EST and subsequent choledo-
tion rate was significantly better in patients given rTM cholithotomy may be performed at the same time as bil-
(83.3% vs. 52.8%, P < 0.01), but that there was no signifi- iary drainage. Postoperative cholangitis usually improves
cant difference in mortality (13.3% vs. 27.8%, P = 0.26) with antibiotic treatment alone, and biliary drainage is not
(CS) [23]. In a study by Nakahara et al. of 13 patients with usually required (CPG) [12].
acute cholangitis-induced DIC, seven patients who were
treated with rTM had significantly lower DIC scores com- Grade II (moderate acute cholangitis)
pared with six who were only treated with antithrombin III
(CS) [24]. Both those studies were case series with insuffi- Moderate acute cholangitis is cholangitis that is not severe
cient numbers of patients to provide more than a low level but requires early biliary drainage. In the TG18 severity
Fig. 2 TG18 flowchart for the management of acute cholangitis. Cited and modified from Miura et al. [12]. *Blood culture should be taken
into consideration before antibiotics are started. Bile samples should be taken during biliary drainage and cultured. †Principles of treatment for
acute cholangitis consist of antimicrobial administration, biliary drainage, and treatment of the etiology. For patients with mild or moderate
choledocholithiasis, if possible the etiology should be treated at the same time as biliary drainage is performed
assessment criteria, moderate cholangitis is assessed if at has been improved by initial treatment and respiratory/
least two of the following five criteria are met: WBC circulatory management. If treatment for the underlying eti-
≥12,000 or <4,000, temperature ≥39°C, age ≥75 years, ology is required, this should be provided after the patient’s
total bilirubin ≥5 mg/dl, or albumin <(lower limit of nor- general status has improved (CPG) [12].
mal value 9 0.73 g/dl) (CPG) [9].
Early endoscopic or percutaneous transhepatic biliary Transfer criteria
drainage is indicated. If the underlying etiology requires
treatment, this should be provided after the patient’s gen- Table 5 shows the transfer criteria for acute cholangitis. If
eral condition has improved (CPG) [12], and EST and a hospital is not equipped to perform endoscopic or percu-
subsequent choledocholithotomy may be performed taneous transhepatic biliary drainage or provide intensive
together with biliary drainage. care, patients with moderate or severe cholangitis should
preferably be transferred to a hospital capable of provid-
Grade III (severe acute cholangitis) ing these treatments, irrespective of whether or not they
are actually required (CPG) [25].
Severe acute cholangitis is cholangitis with sepsis-induced
organ damage. In the TG18 severity assessment criteria,
severe cholangitis is assessed if any one of the following Table 5 Transfer criteria for acute cholangitis
criteria is met: cardiovascular dysfunction (requiring the Severe acute cholangitis (Grade III)
use of dopamine ≥5 lg/kg per min or noradrenaline), neu- Patients who require emergency biliary drainage as well as critical
rological dysfunction (disturbance of consciousness), res- care should be transferred immediately to a hospital where this
can be provided
piratory dysfunction (PaO2/FiO2 ratio <300), renal
Moderate acute cholangitis (Grade II)
dysfunction (oliguria or serum creatinine >2.0 mg/dl),
Patients should be treated in a hospital where biliary drainage and
hepatic dysfunction (PT-INR >1.5), or coagulation disor-
systemic management can be performed. If a hospital is not
der (platelet count <104/ll) (CPG) [9]. equipped to perform biliary drainage, they should be transferred
As the patient’s condition may deteriorate rapidly, a swift to a hospital where this can be provided
response is essential including appropriate respiratory/circu- Mild acute cholangitis (Grade I)
latory management (tracheal intubation followed by artificial If a calculus is present in the common bile duct or there is no
ventilation and the use of hypertensive agents). Endoscopic response to initial treatment (within 24 h), a similar response to
that for moderate acute cholangitis should be considered
or percutaneous transhepatic biliary drainage should be
performed as soon as possible after the patient’s condition Cited from reference [25]
2.5% Conflict of interest Goro Honda has received honoraria from

Strongly agree Johnson and Johnson and Medtronic.
7.6%
36.7% Agree
Appendix: author’s affiliation
Neutral
53.2% Fumihiko Miura, Tadahiro Takada and Keita Wada,
Disagree
Department of Surgery, Teikyo University School of Med-
Strongly*
icine, Tokyo, Japan; Kohji Okamoto, Department of Sur-
disagree gery, Center for Gastroenterology and Liver Disease,
* No panelists selected this option. Kitakyushu City Yahata Hospital, Fukuoka, Japan; Steven
M. Strasberg, Section of Hepato-Pancreato-Biliary Sur-
Fig. 3 Answers to the question “Do you agree to perform treatment
for etiology simultaneously, if possible, with biliary drainage for mod-
gery, Washington University School of Medicine in St.
erate cholangitis?”. No (Strongly disagree) answers from the panelists Louis, St. Louis, MO, USA; Horacio J. Asbun, Depart-
ment of Surgery, Mayo Clinic College of Medicine, Jack-
2.5% sonville, FL, USA; Henry A. Pitt and David Schlossberg,
Strongly agree
7.5% Lewis Katz School of Medicine at Temple University,
Agree Philadelphia, PA, USA; Harumi Gomi, Center for Global
37.5%
Health, Mito Kyodo General Hospital, University of Tsu-
Neutral
52.5%
kuba, Ibaraki, Japan; Joseph S. Solomkin, Department of
Disagree Surgery, University of Cincinnati College of Medicine,
Cincinnati, OH, USA; Ho-Seong Han and Yoo-Seok
Strongly *
disagree Yoon, Department of Surgery, Seoul National University
* No panelists selected this option. Bundang Hospital, Seoul National University College of
Medicine, Seoul, Korea; Myung-Hwan Kim, Department
Fig. 4 Answers to the question “Do you agree to revise flowchart of Gastroenterology, University of Ulsan College of Medi-
for the management of acute cholangitis?” No (Strongly disagree)
cine, Seoul, Korea; Tsann-Long Hwang, Miin-Fu Chen
answers from the panelists
and Keng-Hao Liu, Division of General Surgery, Linkou
Chang Gung Memorial Hospital, Taoyuan, Taiwan;
Results of public hearing Wayne Shih-Wei Huang, Department of Surgery, Show
Chwan Memorial Hospital, Changhua, Taiwan; Seiki Kir-
At the TG18 public hearing held on 9 June 2017, partici- iyama, Department of Gastroenterology, Ogaki Municipal
pants were asked to give their opinions on two questions Hospital, Gifu, Japan; Takao Itoi and Shuntaro Mukai,
about the flowchart for acute cholangitis on an answer Department of Gastroenterology and Hepatology, Tokyo
pad. Medical University Hospital, Tokyo, Japan; O James Gar-
To the first question, “Do you agree to perform treat- den, Clinical Surgery, University of Edinburgh, Edin-
ment for etiology simultaneously, if possible, with biliary burgh, UK; Kui-Hin Liau, Liau KH Consulting PL, Mt
drainage for moderate cholangitis?” 90% of participants Elizabeth Novena Hospital, Singapore and Yong Loo Lin
chose either “Strongly agree” or “Agree” as their response School of Medicine, National University of Singapore,
(Fig. 3). To the second question, “Do you agree to revise Singapore; Akihiko Horiguchi, Department of Gastroen-
flowchart for the management of acute cholangitis?” 90% terological Surgery, Fujita Health University School of
also chose either “Strongly agree” or “Agree” as their Medicine, Aichi, Japan; Cheng-Hsi Su, Department of
response (Fig. 4). This was considered to indicate the Surgery, Cheng Hsin General Hospital, Taipei, Taiwan;
validity of the changes to the current flowchart. Dirk J. Gouma, Department of Surgery, Academic Medi-
cal Center, Amsterdam, The Netherlands; Giulio Belli,
Acknowledgments We express our deep gratitude to the Japanese Department of General and HPB Surgery, Loreto Nuovo
Society of Hepato-Biliary-Pancreatic Surgery, the Japanese Society Hospital, Naples, Italy; Christos Dervenis, First Depart-
of Abdominal Emergency Medicine, the Japanese Society of
ment of Surgery, Agia Olga Hospital, Athens, Greece;
Surgical Infection, and the Japan Biliary Association, for their
substantial support and guidance in the preparation of this article. Palepu Jagannath, Department of Surgical Oncology, Lila-
We also would like to express our deep gratitude to the Japanese vati Hospital and Research Centre, Mumbai, India; Angus
Society of Hepato-Biliary-Pancreatic Surgery for the Article C. W. Chan, Surgery Centre, Department of Surgery,
Processing Managing Office of the Tokyo Guidelines 18 for
Hong Kong Sanatorium and Hospital, Hong Kong, Hong
preparing this publication. We appreciate all secretariats of the
Japanese Society of Hepato-Biliary-Pancreatic Surgery for their Kong; Wan Yee Lau, Faculty of Medicine, The Chinese
technical support. University of Hong Kong, Shatin, Hong Kong; Itaru
Endo, Department of Gastroenterological Surgery, Yoko- cholangitis and cholecystitis: Tokyo Guidelines. J Hepatobiliary
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DOI: 10.1002/jhbp.496
GUIDELINE
Indications and techniques of biliary drainage for acute cholangitis in

updated Tokyo Guidelines 2018
Shuntaro Mukai Takao Itoi Todd H. Baron Tadahiro Takada Steven M. Strasberg Henry A. Pitt
Tomohiko Ukai Satoru Shikata Anthony Yuen Bun Teoh Myung-Hwan Kim Seiki Kiriyama
Yasuhisa Mori Fumihiko Miura Miin-Fu Chen Wan Yee Lau Keita Wada Avinash Nivritti Supe
Mariano Eduardo Gimenez Masahiro Yoshida Toshihiko Mayumi Koichi Hirata Yoshinobu Sumiyama
Kazuo Inui Masakazu Yamamoto
Published online: 5 October 2017

The author’s affiliations are listed Abstract The Tokyo Guidelines 2013 (TG13) include new topics in the biliary
in the Appendix. drainage section. From these topics, we describe the indications and new techniques of
Correspondence to: Tadahiro biliary drainage for acute cholangitis with videos. Recently, many novel studies and
Takada, Department of Surgery, case series have been published across the world, thus TG13 need to be updated
Teikyo University School of regarding the indications and selection of biliary drainage based on published data.
Medicine, 2-11-1 Kaga, Itabashi-ku, Herein, we describe the latest updated TG13 on biliary drainage in acute cholangitis
e-mail: t-takada@jshbps.jp with meta-analysis. The present study showed that endoscopic transpapillary biliary
drainage regardless of the use of nasobiliary drainage or biliary stenting, should be
DOI: 10.1002/jhbp.496 selected as the first-line therapy for acute cholangitis. In acute cholangitis, endoscopic
sphincterotomy (EST) is not routinely required for biliary drainage alone because of
the concern of post-EST bleeding. In case of concomitant bile duct stones, stone
removal following EST at a single session may be considered in patients with mild or
moderate acute cholangitis except in patients under anticoagulant therapy or with
coagulopathy. We recommend the removal of difficult stones at two sessions after
drainage in patients with a large stone or multiple stones. In patients with potential
coagulopathy, endoscopic papillary dilation can be a better technique than EST for
stone removal. Presently, balloon enteroscopy-assisted endoscopic retrograde
cholangiopancreatography (BE-ERCP) is used as the first-line therapy for biliary
drainage in patients with surgically altered anatomy where BE-ERCP expertise is
present. However, the technical success rate is not always high. Thus, several studies
have revealed that endoscopic ultrasonography-guided biliary drainage (EUS-BD) can
be one of the second-line therapies in failed BE-ERCP as an alternative to
percutaneous transhepatic biliary drainage where EUS-BD expertise is present.
Keywords Cholangitis Drainage Endoscopic retrograde

cholangiopancreatography Endoscopic sphincterotomy Gallstones

Introduction
Acute cholangitis varies in severity, ranging from a mild form which can be treated by
conservative therapy to a severe form which leads to a life-threatening state (e.g. shock
state and altered sensorium). In particular, the severe form often causes mortality in
the elderly [1]. Early biliary drainage should be performed for Grade II (moderate) and
Grade III (severe) cases according to the severity grading of the updated Tokyo
Guidelines of 2013 (TG13) [2–4]. Biliary drainage, which pancreatitis [11–14]. The internal drainage by endoscopic
is the most essential therapy for acute cholangitis, is tradi- transpapillary biliary drainage produces less pain after the
tionally divided into three types: (1) surgical, (2) percuta- procedures than the external drainage by percutaneous
neous transhepatic, and (3) endoscopic transpapillary transhepatic biliary drainage (PTBD), also known as per-
drainage. Of these therapies, surgical intervention causes cutaneous transhepatic cholangial drainage (PTCD) [15].
the highest mortality rate [1]. Recently, mortality due to PTCD places more burden on patients owing to cosmetic
acute cholangitis has decreased owing to the development problems, skin inflammation, or bile leakage, compromis-
of percutaneous transhepatic cholangial drainage (PTCD) ing the patient’s quality of life. A single treatment session
[5] and endoscopic transpapillary biliary drainage [6, 7]. for a bile duct stone is possible with the endoscopic
Nevertheless, acute cholangitis can still be fatal unless it transpapillary approach, making the hospitalization dura-
is treated early and properly. tion shorter. However, in patients with an inaccessible
The Tokyo Guidelines of 2007 (TG07) was the first papilla due to upper gastrointestinal tract obstruction, or
global guidelines in which fundamental biliary drainage when skilled pancreaticobiliary endoscopists are not avail-
techniques for acute cholangitis were described [8]. Sub- able in the institution, PTCD is a useful alternative drai-
sequently, TG07 was revised to TG13, which include the nage procedure [5, 16]. Furthermore, PTCD can be used
indications and procedures of newly developed biliary as a salvage therapy when conventional endoscopic
drainage techniques such as endoscopic ultrasonography- transpapillary drainage has failed owing to difficult selec-
guided biliary drainage (EUS-BD) and balloon entero- tive biliary cannulation. Recently, EUS-BD has been
scope-assisted bile duct drainage in patients with surgi- developed and reported as a novel useful alternative drai-
cally altered anatomy [9]. As several reports of these nage technique when standard endoscopic transpapillary
newly developed biliary drainage techniques or the meth- drainage has failed [17, 18].
ods and timing of stone removal after or simultaneously From the results of a randomized controlled trial
with drainage have been published, TG13 needs to be (RCT) and meta-analysis that compared EUS-BD with
updated. Thus, the Tokyo Guidelines Revision Committee PTCD as an alternative drainage technique after failed
was assembled and the committee discussed six argument endoscopic transpapillary biliary drainage, the technical
points on biliary drainage for acute cholangitis as men- success and clinical success rates were approximately the
tioned below. In this article, we describe the latest drai- same at 90–100%, but the rates of PTCD adverse events
nage techniques for acute cholangitis and the treatment such as post-procedure bleeding, cholangitis, and bile
methods for stone removal in the updated Tokyo Guideli- leakage were higher than those of EUS-BD adverse events
nes 2018 (TG18). (Table 1) [19–24]. However, almost all reports about
EUS-BD come from high-volume centers and performed
by skilled pancreaticobiliary endoscopists. A national sur-
Indications and techniques of biliary drainage vey in Spain wherein most of the institutions involved
were not high-volume centers reported a technical success
In the updated TG18, biliary drainage is recommended for rate of only 67.2% from 106 patients [25]. Their data
acute cholangitis regardless of the degree of severity indicated that EUS-BD remains an unestablished proce-
except in some cases of mild acute cholangitis in which dure and is not an easy technique to perform. Therefore,
antibiotics and general supportive care are effective [10]. when skilled pancreaticobiliary endoscopists are available
in an institution, EUS-BD is recommended as an alterna-
Q1. What is the most preferable biliary drainage for
tive drainage procedure. Otherwise, PTCD should be
acute cholangitis? (Surgical vs. endoscopic transpapillary
selected, or transfer of the patient to a high-volume center
vs. EUS-guided vs. percutaneous transhepatic biliary
should be considered.
drainage?)
We recommend endoscopic transpapillary biliary
drainage for acute cholangitis (recommendation 1,
Percutaneous transhepatic cholangial drainage
level B).
*Refer to Q6 in acute cholangitis patients with sur-
Before the widespread use of transabdominal ultrasonog-
gically altered anatomy.
raphy, needle puncture of the bile duct was conducted
Endoscopic transpapillary biliary drainage should be under fluoroscopy [5]. Currently, needle puncture is safely
considered as the first-line drainage procedure because of performed under ultrasonography to avoid intervening
its less invasiveness and lower risk of adverse events than blood vessels [16]. Therefore, in the current PTCD proce-
other drainage techniques despite the risk of post- dure, operators should continuously observe the bile duct
endoscopic retrograde cholangiopancreatography (ERCP) by ultrasonography regardless of the presence of dilation.
Table 1 Comparison of outcomes between EUS-BD and PTBD as an alternative drainage procedure
Author Year Design Method n Technical Clinical success (%) Adverse events (%)
success (%)
Artifon et al. [20] 2012 RCT EUS-BD 13 100 100 15.3

PTBD 12 100 100 25
Bapaye et al. [22] 2013 Cohort EUS-BD 25 92 N/A 20
PTBD 26 100 N/A 46.1
Khashab et al. [23] 2014 Cohort EUS-BD 22 86.4 86.4 18.2
PTBD 51 100 92.2 39.2
Sharaiha et al. [24] 2015 Cohort EUS-BD 47 93.3 62.2 6.6
PTBD 13 91.6 25 53.8
Lee et al. [21] 2016 RCT EUS-BD 34 94.1 87.5 8.8
PTBD 32 96.9 87.1 31.2
EUS-BD endoscopic ultrasound-guided biliary drainage, N/A not available, PTBD percutaneous transhepatic biliary drainage, RCT randomized
controlled trial
PTCD is performed as previously described [5]. In brief, drainage and endoscopic biliary stenting (EBS) for inter-
ultrasonography-guided transhepatic puncture of the intra- nal drainage. Basically, both types of endoscopic biliary
hepatic bile duct is initially performed using an 18-G to drainage can be performed in all forms of acute cholangi-
22-G needle. After confirming the backflow of bile, a tis. In the case of biliary drainage for acute cholangitis
guidewire is advanced into the bile duct. Finally, a 7-Fr to therapy, a precise endoscopic technique is mandatory
10-Fr catheter is placed in the bile duct under fluoroscopic because long and unsuccessful procedures may lead to
control over the guidewire. Puncture using a small-gauge serious complications in critically ill patients. Therefore,
(22-G) needle is safer in patients without biliary dilation endoscopists who perform endoscopic transpapillary bil-
than in patients with biliary dilation. According to the iary drainage should acquire knowledge and skills of
Quality Improvement Guidelines developed by American selective biliary cannulation techniques including the dou-
radiologists, the success rates of drainage are 86% in ble guidewire, pancreatic guidewire, and precut techniques
patients with biliary dilation and 63% in patients without [27].
biliary dilation [16].
Q2. Which procedure should be used for endoscopic
transpapillary biliary drainage? ENBD or EBS?
We suggest that either ENBD or EBS may be consid-
Surgical drainage
ered for biliary drainage according to the patient’s back-
ground and preference (recommendation 1, level A).
Open drainage for decompression of the bile duct is per-
formed as a surgical intervention. When surgical drainage Three RCTs and two cohort studies on the comparison
in critically ill patients with bile duct stones is performed, between ENBD and EBS have shown no statistically sig-
prolonged operations should be avoided and simple proce- nificant difference in clinical settings [28–32]. In the
dures, such as T-tube placement without choledocholitho- updated TG18, the meta-analysis which included the three
tomy, are recommended [26]. At present, surgical RCTs showed no statistically significant difference in the
drainage is extremely rare because of the widespread use technical success rate (OR 2.50, 95% CI: 0.36–17.36)
of endoscopic drainage or PTCD for acute cholangitis (Fig. 1), clinical success rate (OR 1.85, 95% CI: 0.65–
therapy. 5.31) (Fig. 2), adverse events rate (OR 0.98, 95% CI:
0.24–3.96) (Fig. 3), and reintervention rate (OR 0.82,
95% CI: 0.03–19.89) (Fig. 4) between ENBD and EBS.
Endoscopic transpapillary biliary drainage Two RCTs showed that the visual analogue scale score
was higher in the ENBD group than in the EBS group.
Endoscopic transpapillary biliary drainage has become the Therefore, it should be borne in mind that if patients
gold standard technique for acute cholangitis, regardless experience discomfort from the transnasal tube placement,
of a benign or malignant pathology, because it is a mini- they are likely to remove the tube themselves, particularly
mally invasive drainage method [6]. Endoscopic transpap- elderly patients. EBS is an internal drainage technique that
illary biliary drainage is divided into two types: produces neither discomfort nor loss of electrolytes or
endoscopic nasobiliary drainage (ENBD) for external fluid as its advantages. On the other hand, ENBD is an
Fig. 1 Forest plot analysis of technical

success rate of ENBD versus EBS
Fig. 2 Forest plot analysis of clinical

success rate of ENBD versus EBS
Fig. 3 Forest plot analysis of adverse

events rate of ENBD versus EBS
Fig. 4 Forest plot analysis of re-

intervention rate of ENBD versus EBS
external drainage technique that allows monitoring or Endoscopic biliary stenting

washing of the bile via the transnasal tube, particularly if
the bile is very purulent. Two retrospective studies have The EBS procedure is also described in detail in the pre-
shown that the stent occlusion from EBS was more fre- vious clinical practice guidelines [8]. In brief, after selec-
quent than the stent occlusion from ENBD in patients tive biliary cannulation, a 7-Fr to 10-Fr plastic stent is
with hilar cholangiocarcinoma; thus, ENBD may be more placed in the bile duct as an internal drainage over the
suitable in patients with cholangitis due to hilar biliary guidewire (Fig. 6). There are two different stent shapes, a
obstruction [33, 34]. straight type and a double pigtail type. The straight type
Therefore, the balance between the advantages and dis- has a single flap with a side hole (Amsterdam type) or
advantages of each drainage procedure is approximately radial flaps without a side hole (Tannenbaum type) on
equal. In the updated TG18, we suggest that either ENBD both sides. The double pigtail type prevents inward and
or EBS may be considered for biliary drainage by proce- outward stent migration. To our knowledge, there is cur-
dure according to the cause of the cholangitis, bile prop- rently no comparative study between the straight type and
erty, and patient’s preference. pigtail type stents. Therefore, either stent can be selected
according to the endoscopist’s preference.
Endoscopic nasobiliary drainage
Endoscopic nasobiliary drainage procedures are described Endoscopic ultrasonography-guided bile duct drainage
in detail in TG07 [8]. In brief, after selective biliary can-
nulation, a 5-Fr to 7-Fr nasobiliary tube is placed in the The EUS-BD technique and its devices are not yet well
bile duct as an external drainage over the guidewire established. For EUS-BD, three approaches are currently
(Fig. 5). used: (1) EUS-guided intrahepatic bile duct drainage by
strictures; however, EUS-guided antegrade stenting is an

interesting option because of the theoretical physiological
bile flow in patients with inaccessible ampulla [45]. The
most serious issue during and after EUS-BD is the devel-
opment of adverse events such as peritonitis. In fact, pre-
vious studies have reported early adverse event rates of
10–30%, although the severities of most of these adverse
events were mild or moderate [46, 47]. As the procedure
is not yet established, EUS-BD should be performed by
endoscopists who are skilled in both EUS and ERCP.
Theoretically, the intrahepatic bile duct and liver,
including the extrahepatic bile duct do not adhere to the
GI tract. Therefore, bile leakage may occur during the
procedure. If the procedure fails, bile peritonitis can occur.
Standard 19-G and 22-G fine needles are advanced into
the bile duct under EUS visualization after confirming the
Fig. 5 Endoscopic nasobiliary drainage using a 5-Fr nasobiliary
absence of intervening blood vessels to prevent bleeding.
tube After the contrast medium is injected into the bile duct for
cholangiography, a 0.025-inch to 0.035-inch guidewire for
the 19-G needle or a 0.018-inch to 0.021-inch guidewire
for the 22-G needle is advanced into the bile duct. Needle
tract dilation is performed using a standard or tapered
catheter, a cautery dilator, a dilation catheter, and/or a
dilating balloon as necessary. Finally, a plastic stent or a
self-expandable metal stent selected as the case may be is
placed into the bile duct [48]. Recently, several dedicated
stents such as a newly designed 8-Fr plastic stent dedi-
cated for EUS-hepaticogastrostomy (Fig. 7a) or a novel
lumen-apposing biflanged metal stent dedicated for EUS-
guided choledochoduodenostomy (Fig. 7b) have been
developed to reduce the adverse event rates of EUS-BD
[49–51].
Treatment of major papilla and removal of bile duct

stones
Fig. 6 Endoscopic biliary stenting using a 10-Fr plastic stent
Endoscopic sphincterotomy
the transgastric or transjejunal approach; (2) EUS-guided
extrahepatic bile duct drainage by the transduodenal or Endoscopic sphincterotomy (EST) has two major advan-
transgastric approach; and (3) EUS-guided antegrade tages for endoscopic biliary drainage as follows: (1)
stenting. The choice of the drainage method and drainage EST separates the bile duct and pancreatic duct and can
route depends on the presence of a gastric outlet obstruc- therefore prevent occlusion of the pancreatic duct orifice
tion and the stricture site of the bile duct [35]. Several by placement of a large-bore biliary stent (>10-Fr plas-
published data on EUS-guided intrahepatic bile duct drai- tic stent or a self-expandable metal stent); and (2) EST
nage and extrahepatic bile duct drainage have shown a can achieve not only drainage but also removal of bile
high technical success rate of 95%, with 93–100% (inten- duct stones at a single session. However, the efficacy
tion-to-treat) clinical response rates [16–18, 36–44]. It has and safety of EST in patients with acute cholangitis
been reported that the technical success rate of EUS- remain controversial because of EST-induced complica-
guided antegrade stenting (77%) is inferior to those of tions such as hemorrhage [52, 53]. Details of the EST
EUS-guided intrahepatic bile duct drainage and extrahep- procedures are described in TG07 [8]. In brief, after
atic bile duct drainage owing to the difficulty of guidewire selective biliary cannulation, the pull-type sphinctero-
passage and stent delivery system insertion across the tomy incision is performed below the transverse fold.
The push-type sphincterotome is used for EST in systematic review has revealed that EPBD is less success-
patients with Billroth II gastrectomy or Roux-en-Y anas- ful for stone removal, requires higher rates of mechanical
tomosis. When the transverse fold is not present, the lithotripsy, and carries a higher risk of pancreatitis; how-
superior margin of the papilla bulge is used as a land- ever, it also has statistically significant lower rates of
mark to determine the length of the sphincterotome. An bleeding [60]. Thus, EPBD appears to be useful for the
electrosurgical generator with a controlled cutting sys- treatment of patients with coagulopathy and acute cholan-
tem is used for EST. gitis caused by a small stone. Theoretically, as EPBD
aims to preserve the function of the sphincter of Oddi,
Q3. Is endoscopic sphincterotomy necessary in endo-
EPBD alone without biliary drainage is contraindicated
scopic transpapillary biliary drainage?
for the therapy of acute cholangitis. In addition, EPBD
We suggest that the addition of EST may not be
should be avoided in patients with biliary pancreatitis.
required in endoscopic transpapillary biliary drainage
After selective biliary cannulation, a small balloon with a
(recommendation 2, level A).
diameter of up to 10 mm, depending on the diameters of
*Refer to Q4 if stone removal at a single session is
the bile duct and stone, is advanced into the bile duct
considered.
across the papilla. Then, the sphincter of Oddi is gradually
From the results of previous RCTs and cohort studies dilated by inflation of the balloon until the balloon waist
which included patients who had plastic stent (<7-Fr) or disappears. The bile duct stone is then cleared using a
nasobiliary tube placement, the prevention of post-ERCP basket catheter and a balloon catheter.
pancreatitis by the addition of EST to biliary drainage
was not observed [54–58]. Therefore, it is considered that
the addition of EST is not required in acute cholangitis Endoscopic papillary large balloon dilation
because this induces complications (e.g. hemorrhage).
Acute cholangitis is one of the risk factors of post-EST Endoscopic sphincterotomy or EPBD has been used as
hemorrhage. In particular, the use of EST in patients with the gold standard therapy for the removal of bile duct
severe cholangitis complicated by coagulopathy or the stones. However, in patients with large bile duct stones,
administration of antithrombotic agents should be endoscopic mechanical lithotripsy (EML) may be
avoided. required as an additional procedure [61, 62]. Since 2003,
endoscopic papillary large balloon dilation (EPLBD) with
or without EST has been developed to facilitate the
Endoscopic papillary balloon dilation removal of large or difficult bile duct stones, in which
the size of the large balloons used ranged from 12 to
Endoscopic papillary balloon dilation (EPBD) is usually 20 mm [63, 64]. Stone removal by EPLBD has been
used instead of EST for the removal of bile duct stones shown to have a high success rate, and this might reduce
[59]. To date, there has been apparently no comparative the need for EML and the procedure time without
study on the use of EPBD during biliary drainage to treat increasing the risk of severe pancreatitis or bile duct per-
acute cholangitis due to bile duct stones. A previous foration [65–70]. The EPLBD procedure is as follows.
(a) (b)
Fig. 7 Endoscopic ultrasonography-
guided bile duct drainage. (a)
Endoscopic ultrasonography-guided
hepaticogastrostomy using a dedicated
8-Fr plastic stent. (b) Endoscopic
ultrasonography-guided
choledochoduodenostomy using a
lumen-apposing biflanged metal stent
Large balloon dilation is performed using standard dilat- or with coagulopathy. However, the updated TG18 rec-
ing balloons immediately after EST. The balloon catheter ommend bile duct stone removal at two sessions after
is passed over a guidewire and positioned across the drainage in patients with a large stone or multiple stones
papilla. The balloon is then gradually inflated with a con- if EPLBD is required.
trast medium under endoscopic and fluoroscopic guidance
Q5. What is the best approach to patients with acute
until an adequate size is achieved to allow stone removal
cholangitis who have coagulopathy or are receiving
without lithotripsy regardless of the disappearance of the
antithrombotic agents? Biliary stenting, EPBD or
balloon waist. The stones are then removed from the bile
EST?
duct using mechanical lithotripsy, a basket catheter, or a
We recommend biliary stenting in patients with
retrieval balloon.
acute cholangitis who have coagulopathy (recommen-
Q4. Which is the preferred procedure for acute dation 1, level D).
cholangitis associated with choledocholithiasis? Stone We suggest that the approach to patients with acute
removal at a single session or at two sessions? cholangitis who are receiving antithrombotic agents
We suggest that bile duct stone removal following must be selected according to the risks of bleeding and
EST at a single session may be considered in patients thromboembolism.
with mild or moderate acute cholangitis (recommenda-
In the clinical guidelines for the handling of
tion 2, level C).
antithrombotic agents from the European Society of
Bile duct stone is the most frequent cause of cholangi- Gastrointestinal Endoscopy, American Society for Gas-
tis [71]. Previously, two-session treatment has been rec- trointestinal Endoscopy and Japan Gastroenterological
ommended for acute cholangitis with bile duct stone, Endoscopy Society, the original treatment by EST is
which involves biliary drainage as an initial treatment and considered as a high-risk procedure for bleeding
endoscopic stone removal after improvement of cholangi- [77–79]. Therefore, the bleeding risk of EST may even
tis [72]. This recommendation is based on previous be higher in patients with acute cholangitis who have
reports that additional stone removal by EST at a single coagulopathy or who are receiving antithrombotic
session increased the incidence of hemorrhagic complica- agents because cholangitis has been shown to be a risk
tions [52, 53]. However, these reports included cases of factor of bleeding after EST [80–82]. PTCD has a
severe cholangitis accompanied by coagulopathy. Impor- high risk of bleeding when performed in the liver
tantly, the use of EST in patients with severe cholangitis because of the abundance of blood vessels. Thus,
complicated by coagulopathy should be avoided because PTCD should be avoided in patients with acute
of the risk of hemorrhagic complication. These findings cholangitis who have coagulopathy or are receiving
may not always be applicable to mild-to-moderate cholan- antithrombotic agents [83, 84]. Therefore, it is recom-
gitis without coagulopathy. One multicenter prospective mended that ENBD or EBS be initially performed in
study and two retrospective studies of mild-to-moderate patients with acute cholangitis who have coagulopathy
acute cholangitis associated with bile duct stone have or are receiving antithrombotic agents as these are
shown that the cholangitis cure rate and the hemorrhagic low-risk procedures for bleeding. After improvements
complication rate of single-session treatment are equiva- of the coagulopathy and cholangitis, bile duct stone
lent to those of two-session treatment [73–75]. Stone treatment should be performed and antithrombotic
removal at a single session can shorten the hospital stay, agents should be discontinued.
thereby reducing medical cost and the patient’s burden. On the other hand, the easy discontinuation of
Recently, EPLBD with or without EST has been per- antithrombotic agents to avoid the risk of bleeding pre-
formed as a useful technique for the removal of a large sents the risk of causing thromboembolism, which is an
stone or multiple stones. A previous RCT has revealed even more serious rebound phenomenon than bleeding
that EPLBD after EST at a single session in patients with [85]. From the results of cohort and case-control studies
acute cholangitis carries risks or may produce severe indicating that the bleeding risk of EST are not signifi-
adverse events such as hemorrhage or perforation because cantly different between patients with and without the
of a possibly friable bile duct from inflammation and administration of aspirin (an antiplatelet agent), the clin-
increased blood flow around the bile duct [76]. Although ical guidelines for handling antithrombotic agents sug-
further evaluation including a randomized controlled gests that EST without discontinuing aspirin can be
study is required, the updated TG suggest that bile duct performed if patients have a high risk of thromboem-
stone removal following EST at a single session may be bolism [76–78, 80, 82, 86, 87]. However, as bleeding
considered in patients with mild or moderate acute increases in high-risk procedures when a thienopyridine
cholangitis except in patients under anticoagulant therapy derivative (an antiplatelet agent) is administered, the
clinical guidelines recommend its discontinuation 5– performed by an experienced endoscopist, PTCD and
7 days before performing high-risk procedures for bleed- EUS-BD may be considered as alternative methods, or
ing [88]. If patients have a high risk of developing referral to a highly specialized institution may be
thromboembolism, it is recommended that aspirin or considered.
cilostazol be substituted for the thienopyridine derivative
in consultation with the prescribing doctor. The admin-
istration of anticoagulant agents is one of the risk fac- Balloon enteroscopy-assisted bile duct drainage
tors of bleeding after EST, thus heparin substitution is
recommended [89]. Regarding the treatment of the Endoscopic retrograde cholangiopancreatography in
major papilla for the removal of bile duct stones, EPBD patients with surgically altered anatomy can be challeng-
is an alternative technique. A meta-analysis has shown ing. Roux-en-Y anastomosis has been thought to preclude
that the rate of bleeding as an adverse event of EPBD endoscopic access for ERCP because of the extensive
was significantly less than that of EST, thus EPBD is lengths of the afferent limbs that must be traversed to
classified as a low-risk procedure for bleeding [90]. In reach the major papilla or hepaticojejunostomy site.
patients with potential coagulopathy such as those with Recently, single-balloon enteroscopy (SBE) and double-
chronic liver cirrhosis or those with difficulty in discon- balloon enteroscopy (DBE) have enabled successful ERCP
tinuing antithrombotic agents, EPBD can be a better in patients with surgically altered anatomy. Several inves-
technique for the treatment of the major papilla. There- tigators have reported various success rates (40–95%) with
fore, the timing or the method of treatment either by adverse events rates below 5% (Table 2). However, since
EST or EPBD should be decided by evaluating the balloon enteroscopy may be unsuccessful and time-con-
bleeding and thromboembolism risks of individual suming, its indication should be cautiously decided.
cases. Although the ideal operators are those who are skilled in
both balloon enteroscopy and ERCP, in some institutions,
GI endoscopists advance an endoscope to the papilla or
anastomotic site and then pancreaticobiliary endoscopists
Treatment of cholangitis in patients with surgically
perform ERCP. Therefore, if the operators are not good at
altered anatomy
balloon enteroscopy, therapy using this technique should
be avoided. The SBE and DBE systems consist of a video
Q6. What is the best approach to patients with acute
enteroscope, a sliding tube with a balloon, and a balloon
cholangitis and surgically altered anatomy?
controller. The DBE system has a balloon at the endo-
We recommend balloon enteroscopy-assisted ERCP
scope tip in addition to the overtube balloon. When a
(BE-ERCP) for patients with acute cholangitis and sur-
long-type balloon enteroscope with an effective length of
gically altered anatomy when skilled pancreaticobiliary
200 cm and an inner channel diameter of 2.8 mm was
endoscopists are available in the institution (recom-
used, long wire accessories and long devices were
mendation 2, level C).
required. To overcome these limitations, a short-type bal-
An RCT of patients with failed ERCP showed an loon enteroscope with an effective length of 152 cm and
adverse event rate of 25%–31% for PTCD and 8%–15% an inner channel diameter of 3.2 mm has recently been
for EUS-BD. On the other hand, a systematic review of developed [94, 98]. When a short-type balloon entero-
BE-ERCP in patients with surgically altered anatomy scope was used, conventional ERCP instruments could be
showed an adverse event rate of 3.4%. Therefore, BE- used.
ERCP is clearly a less invasive and safer procedure than Endoscopes are usually advanced to the papilla or
PTCD or EUS-BD [91–108]. Furthermore, as BE-ERCP anastomotic site using pushing and pulling techniques. An
enables treatment of the causes of cholangitis such as bile injection catheter and a tapered catheter are used for initial
duct stone or anastomotic stricture at a single session, it cannulation. In patients with Roux-en-Y reconstruction,
appears that BE-ERCP is useful if the procedure is techni- selective biliary cannulation is occasionally challenging
cally successful. However, BE-ERCP is technically because of the difficulty in obtaining a favorable view of
challenging, time-consuming, and requires specialized the papilla. In such cases, a technique in which the endo-
equipment. Therefore, the updated TG18 recommend BE- scope is advanced at the inferior duodenal angle and
ERCP for patients with acute cholangitis and surgically moved in the retroflex position is useful for obtaining a
altered anatomy if the procedure is performed by experi- better view of the papilla [106]. When selective biliary
enced endoscopists who are skilled in both balloon entero- cannulation is not possible, a needle knife is used for pre-
scopy and ERCP. If the endoscopist is not proficient at cutting. After a successful biliary cannulation, guidewires
this technique or if BE-ERCP is difficult even though it is are inserted into the bile duct. Finally, a nasobiliary
Table 2 Outcomes of balloon enteroscopy-assisted ERCP

Author Year Enteroscopy n Scope insertion Technical Adverse
success (%) success (%) events (%)
Aabakken et al. [91] 2007 DBE 13 94 85 0

Emmett et al. [92] 2007 DBE 14 85 80 0
Maaser et al. [93] 2008 DBE 11 82 64 0
Shimatani et al. [94] 2009 DBE 103 98 95 5
Itoi et al. [95] 2010 SBE 13 92 77 0
Wang et al. [96] 2010 SBE 16 81 75 13
Saleem et al. [97] 2010 SBE 56 70 66 0
Itoi et al. [98] 2011 DBE 9 100 100 11
Siddiqui et al. [99] 2013 DBE 79 90 81 5
Yamauchi et al. [100] 2013 SBE 21 91 87 13
Obana et al. [101] 2013 SBE 19 79 53 5
Azeem et al. [102] 2013 SBE 58 91 76 0
Shah et al. [103] 2013 SBE/DBE 129 71 63 12
Trindade et al. [104] 2015 SBE 56 88 71 5
Kawamura et al. [105] 2015 SBE 27 89 70 0
Ishii et al. [106] 2016 SBE/DBE 123 94 88 7
Khashab et al. [107] 2016 SBE/DBE 49 78 65 4
DBE double-balloon enteroscopy, SBE single-balloon enteroscopy
EPLBD, a balloon dilation catheter is used for the papilla

or hepaticojejunostomy site. A basket catheter, a retrieval
balloon catheter, and a mechanical lithotripter are used for
stone removal.
Endoscopic ultrasonography-guided bile duct drainage
Although BE-ERCP allows the enteroscope to advance to

the major papilla or anastomotic site, the success rate of
scope intubation to the targeted site is not always 100%
because of the very long afferent loop (gastric bypass)
and severe adhesion of the intestines even in high-volume
centers. Furthermore, the final procedural success rate, as
evaluated by stenting and stone removal among others, is
not always 100% for several reasons (i.e. difficult cannu-
lation or large stones). In such a case, PTCD has been tra-
ditionally conducted. Recently, several studies have
revealed that EUS-BD can be a second-line therapy in
failed BE-ERCP as an alternative to PTCD [109, 110]
(Fig. 8).
Fig. 8 Endoscopic ultrasonography-guided antegrade approach to a
patient with Roux-en-Y anastomosis
Acknowledgments We would like to express our deep gratitude to
the Japanese Society of Hepato-Biliary-Pancreatic Surgery, the
drainage catheter, a plastic stent, or a self-expandable Japanese Society of Abdominal Emergency Medicine, the Japanese
metallic stent is placed into the bile duct for biliary Society of Surgical Infection, and the Japan Biliary Association, for
their substantial support and guidance in the preparation of this
decompression. In cases requiring EST, the sphinctero-
article. We would also like to express our deep gratitude to the
tome and needle knife are advanced into the bile duct Japanese Society of Hepato-Biliary-Pancreatic Surgery for the
over or alongside the guidewire. In cases of EPBD or Article Processing Managing Office of the Tokyo Guidelines 18 for
preparing this publication. We appreciate all secretariats of the Institute of Gastroenterology, Tokyo Women’s Medical
Japanese Society of Hepato-Biliary-Pancreatic Surgery for their University, Tokyo, Japan.
technical support.
Conflict of interest Anthony Yuen Bun Teoh has received References

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DOI: 10.1002/jhbp.516
GUIDELINE
Tokyo Guidelines 2018: flowchart for the management of acute

cholecystitis
Kohji Okamoto Kenji Suzuki Tadahiro Takada Steven M. Strasberg Horacio J. Asbun Itaru Endo
Yukio Iwashita Taizo Hibi Henry A. Pitt Akiko Umezawa Koji Asai Ho-Seong Han Tsann-Long Hwang
Yasuhisa Mori Yoo-Seok Yoon Wayne Shih-Wei Huang Giulio Belli Christos Dervenis Masamichi Yokoe
Seiki Kiriyama Takao Itoi Palepu Jagannath O. James Garden Fumihiko Miura Masafumi Nakamura
Akihiko Horiguchi Go Wakabayashi Daniel Cherqui Eduardo de Santiba~ nes Satoru Shikata
Yoshinori Noguchi Tomohiko Ukai Ryota Higuchi Keita Wada Goro Honda Avinash Nivritti Supe

Masahiro Yoshida Toshihiko Mayumi Dirk J. Gouma Daniel J. Deziel Kui-Hin Liau Miin-Fu Chen
Kazunori Shibao Keng-Hao Liu Cheng-Hsi Su Angus C. W. Chan Dong-Sup Yoon In-Seok Choi
Eduard Jonas Xiao-Ping Chen Sheung Tat Fan Chen-Guo Ker Mariano Eduardo Gimenez Seigo Kitano
Masafumi Inomata Koichi Hirata Kazuo Inui Yoshinobu Sumiyama Masakazu Yamamoto
Published online: 20 December 2017

The author’s affiliations are listed Abstract We propose a new flowchart for the treatment of acute cholecystitis (AC)
in the Appendix. in the Tokyo Guidelines 2018 (TG18). Grade III AC was not indicated for
Correspondence to: Tadahiro straightforward laparoscopic cholecystectomy (Lap-C). Following analysis of
Takada, Department of Surgery, subsequent clinical investigations and drawing on Big Data in particular, TG18
Teikyo University School of proposes that some Grade III AC can be treated by Lap-C when performed at
Medicine, 2-11-1 Kaga, Itabashi-ku, advanced centers with specialized surgeons experienced in this procedure and for
e-mail: t-takada@jshbps.jp patients that satisfy certain strict criteria. For Grade I, TG18 recommends early Lap-C
if the patients meet the criteria of Charlson comorbidity index (CCI) ≤5 and American
DOI: 10.1002/jhbp.516 Society of Anesthesiologists physical status classification (ASA-PS) ≤2. For Grade II
AC, if patients meet the criteria of CCI ≤5 and ASA-PS ≤2, TG18 recommends early
Lap-C performed by experienced surgeons; and if not, after medical treatment and/or
gallbladder drainage, Lap-C would be indicated. TG18 proposes that Lap-C is
indicated in Grade III patients with strict criteria. These are that the patients have
favorable organ system failure, and negative predictive factors, who meet the criteria
of CCI ≤3 and ASA-PS ≤2 and who are being treated at an advanced center (where
experienced surgeons practice). If the patient is not considered suitable for early
surgery, TG18 recommends early/urgent biliary drainage followed by delayed Lap-C
once the patient’s overall condition has improved. Free full articles and mobile app of
TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47.
Related clinical questions and references are also included.
Keywords Acute cholecystitis Biliary drainage Flowchart Laparoscopic

cholecystectomy Risk factor

Introduction
Flowcharts for the management of acute cholecystitis (AC) were presented in the
Tokyo Guidelines 2007 (TG07) [1] and the Tokyo Guidelines 2013 (TG13) [2]. The
flowcharts allow practitioners in the clinical setting to understand treatment flow at a
glance and have proven useful in the management of AC.

There have been significant changes in clinical manage- continuing the monitoring of respiratory and hemo-
ment since then, including advances in surgical techniques dynamics. (Level C)
and equipment and progress in multidisciplinary treatment.
A number of clinical research papers have been published
suggesting various changes in the AC treatment flowchart When AC is diagnosed, the severity is determined [3]
in TG13. The Tokyo Guidelines flowchart was started as and initial treatment includes monitoring of respiration
a way to show recommended treatments according to the and hemodynamics, as well as sufficient intravenous fluid
severity of AC. However, it did not cover issues like and electrolyte infusion and electrolyte correction and
physical status such as co-morbidities (especially organ treatment with antimicrobials and analgesics. See the
dysfunctions) or other predictive factors/risk factors when paper by Miura et al. for more details on initial treatment
choosing a treatment pathway according to severity. In [4]. The approaches specified in papers by Gomi et al.
addition, until now Grade III AC was considered not suit- regarding the choice of antimicrobial and optimum treat-
able for straightforward laparoscopic cholecystectomy ment duration or blood/bile culture should be reviewed
(Lap-C). In the TG18 guidelines, we propose a modified and implemented; these papers also provide an under-
flowchart based on recent recommendations in the clinical standing of the specific characteristics of bile duct infec-
setting, particularly evidence reported after the publication tions [5–7]. Refer to Gomi et al. on TG18 for the specific
of TG13. We also discuss Clinical Questions (CQs) on names of antimicrobials and other details [6].
the evidence underpinning this flowchart.
We stress that this treatment flowchart is aimed at Q1. Is laparoscopic cholecystectomy recommended for
improving the percentage of lives saved by allowing doc- acute cholecystitis compared to open cholecystectomy?
tors to determine how they can safely treat AC through
the use of decision-making criteria even for severe cases.
We propose Lap-C for AC over open cholecystec-
tomy. (Recommendation 2, level A)
Criteria for the production of the AC treatment flowchart
presented in TG18
There has been ongoing debate for many years over
1. The selection of treatment strategy for patients at each whether Lap-C or open cholecystectomy is the best treat-
severity grade was based on risk factors. The risk factors ment for AC. In the SAGES Guidelines published in
used were: predictive factors, Charlson comorbidity index 1993, AC was considered a relative contraindication for
(CCI) score, and the American Society of Anesthesiolo- Lap-C [8]. Since then, Lap-C has gradually been adopted
gists physical status classification (ASA-PS) score. for AC as surgical techniques have improved and
2. Lap-C to treat AC of moderate and severe grades advances have been made in optical devices and surgical
(Grade II and III) should be performed only at instruments. TG13 states that Lap-C is preferable to open
advanced centers where experienced surgeons practice, cholecystectomy [9].
in addition to the conditions described above. An A search of the literature published between January
advanced center should have both appropriate person- 2013 and December 2016, after the publication of TG13,
nel and facilities to manage the level of patients being and using the keywords “acute cholecystitis,” “laparo-
managed. Surgeons should have training and experi- scopic cholecystectomy,” and “open cholecystectomy”
ence in advanced laparoscopic techniques and intensive returned papers on one systematic review and one ran-
care unit should be available. domized controlled trial. In terms of the incidence of sur-
3. Lap-C can be performed to treat AC if the conditions gical complications, the team producing these guidelines
described above for each Grade are satisfied. performed a meta-analysis using a random-effects model
on four randomized controlled studies [10–13] because
What is the initial medical treatment of acute cholecys- the systematic review [14] used a fixed-effects model even
titis? [Background question] though various differences in the research papers were
detected. The odds ratio for the incidence of surgical com-
While considering indications for surgery and plications is 0.34 (95% CI: 0.07–1.60), which suggests
emergency drainage, sufficient infusion and elec- that laparoscopic surgery may be effective but the differ-
trolyte correction take place, and antimicrobial and ence between Lap-C and open cholecystectomy is not
analgesic agents are administered while fasting statistically significant (Fig. 1). A meta-analysis was
performed on the length of hospital stay in three of the
Fig. 1 Forest plot analysis of the morbidity of laparoscopic cholecystectomy versus open cholecystectomy
Fig. 2 Forest plot analysis of hospital stay (days) of laparoscopic cholecystectomy versus open cholecystectomy
randomized controlled trials [10–12]; the results show that are many benefits of laparoscopy if the procedure can be
patients were hospitalized for shorter periods (approxi- performed safely.
mately 1.7 days shorter) with laparoscopy compared with
open surgery, suggesting that laparoscopy is effective, but
Q2. What is the optimal treatment for acute cholecysti-
the difference is not statistically significant (Fig. 2).
tis according to the grade of severity?
Since TG13, three population-based cohort studies on
AC have been published. In a study in Ontario, Canada
between 2004 and 2011, laparoscopy was chosen for We propose that the treatment strategy be consid-
21,280 of 22,202 patients undergoing surgery for AC ered and chosen after an assessment has been
(95.8%) [15]. According to the Swedish Registry of made of cholecystitis severity, the patient’s general
Gallstone Surgery and Endoscopic Retrograde status and underlying disease.
Cholangiography (GallRiks), between 2006 and 2014, Grade I (mild) AC: Lap-C should ideally be per-
laparoscopy was chosen for 12,522 of 15,760 patients formed soon after onset if the CCI and ASA-PS
(79%) [16]. In a multicenter joint study in Japan and Tai- scores suggest the patient can withstand surgery.
wan between 2011 and 2013, laparoscopy was chosen for If it is decided that the patient cannot withstand
2,356 of 3,325 patients undergoing surgery for AC (71%) surgery, conservative treatment should be per-
[17]. Laparoscopy seems to be the treatment of choice for formed at first and delayed surgery considered
AC around the world, although there are some regional once treatment is seen to take effect.
differences. Grade II (moderate) AC: Lap-C should ideally be
Compared with open surgery, laparoscopy is generally performed soon after onset if the CCI and ASA-PS
expected to result in less pain at incision sites, shorter scores suggest the patient can withstand surgery and
hospital stays and recovery periods, and better quality of the patient is in an advanced surgical center. How-
life. In terms of costs, laparoscopy is expected to involve ever, particular care should be taken to avoid injury
higher surgery costs (cost of disposable equipment) com- during surgery and a switch to open or subtotal
pared with open surgery, but approximately the same cholecystectomy should be considered depending on
overall costs (direct and indirect medical costs) given the the findings. If it is decided that the patient cannot
shorter hospital stays and faster return to society [12]. The withstand surgery, conservative treatment and bil-
choice of surgical technique should consider surgical risk iary drainage should be considered.
to the patient, with safety as the main priority, but there
weighting (1–6) depending on the adjusted risk for the

Grade III (severe) AC: The degree of organ dys- resources used or the mortality rate. The total of all these
function should be determined and attempts made weightings for a patient provides a single patient comor-
to normalize function through organ support, bidity score. A score of zero shows that no comorbidities
alongside administration of antimicrobials. Doctors were discovered. As the score rises, the predicted mortal-
should investigate predictive factors, i.e. a rapid ity rate rises and treatment would require more healthcare
recovery in circulatory dysfunction or renal dys- resources (Table 1) [18].
function after treatment is initiated, and CCI or
ASA-PS scores; if it is decided that the patient can
withstand surgery, early Lap-C can be performed What is the American Society of Anesthesiologists
by a specialist surgeon with extensive experience in physical status classification?
a setting that allows for intensive care manage-
ment. If it is decided that the patient cannot with- The ASA-PS score is an index developed by the Ameri-
stand surgery, conservative treatment including can Society of Anesthesiologists to provide an understand-
comprehensive management should be performed. ing of a patient’s health status before surgery. Table 2 is
Early biliary drainage should be considered if it is a tabulated version of a chart about the ASA-PS score
not possible to control the gallbladder inflamma- provided on the Society’s website [23].
tion. (Recommendation 2, level D) The flowchart includes specific examples for applica-
tion purposes.
What is the Charlson comorbidity index? Predictive factor
The CCI is a method to categorize a patient’s comorbidi- TG13 defines Grade III organ dysfunction as cardiovascu-
ties based on International Classification of Diseases lar dysfunction, neurological dysfunction, respiratory dys-
(ICD) codes used in regulatory data such as hospital sum- function, renal dysfunction, hepatic dysfunction, or
mary data [18–22]. Each comorbid category is given a hematological dysfunction. Straightforward Lap-C is con-
traindicated if dysfunction occurs in these organ systems.
Table 1 Charlson comorbidity index [18] However, in 2017, Yokoe et al. reported on joint research
Assigned weights Conditions in Japan and Taiwan showing that Lap-C was performed
for diseases fairly frequently in Grade III cases [17, 24]. Furthermore,
1 Myocardial infarction Endo et al. analyzed data on 5,329 AC patients from the
Congestive heart failure same joint research in Japan and Taiwan and reported that
Peripheral vascular disease the patients with Grade III AC accompanied by organ dys-
Cerebrovascular disease function included some patients who could have under-
Dementia gone cholecystectomy safely [25]. Based on these studies,
Chronic pulmonary disease the TG18 guidelines define neurological dysfunction, respi-
Connective tissue disease ratory dysfunction, and coexistence of jaundice (TBil
Peptic ulcer disease ≥2 mg/dl) as negative predictive factors in Grade III AC,
Mild liver disease as multivariate analysis has shown these independent fac-
Diabetes mellitus (uncomplicated) tors to be associated with a significant increase surgical
2 Hemiplegia mortality rates (mortality rate within 30 days of surgery).
Moderate or severe chronic kidney disease However, renal dysfunction and cardiovascular dysfunction
Diabetes mellitus with end-organ damage are considered types of favorable organ system failure
Any solid tumor (FOSF) and are therefore defined as “non-negative predic-
Leukemia tive factors,” because these dysfunctions may often be
Malignant lymphoma reversibly improved by initial treatment and organ support.
3 Moderate or severe liver disease We performed a literature search for the period after cre-
6 Metastatic solid tumor ating the TG13 guidelines (January 2013–December 2016)
Acquired immune deficiency syndrome (AIDS) using the key words acute cholecystitis, severity, laparo-
Assigned weights for each conditions that a patient has scopic cholecystectomy, cholecystectomy, and biliary drai-
The total equals the score nage. We identified two cohort research papers [26, 27]
Reprinted with permission from Elsevier (No. 4183730675295) and eight case series studies [25, 28–34]. In the two cohort
Table 2 American Society of Anesthesiologists physical status classification system (ASA-PS) [23]
ASA-PS Definition Examples, including, but not limited to:
classification
ASA I A normal healthy patient Healthy, non-smoking, no or minimal alcohol use

ASA II A patient with mild systemic disease Mild diseases only without substantive functional limitations. Examples
include (but not limited to): current smoker, social alcohol drinker,
pregnancy, obesity (30 < BMI < 40), well-controlled DM/HTN,
mild lung disease
ASA III A patient with severe systemic disease Substantive functional limitations; one or more moderate to severe diseases.
Examples include (but not limited to): poorly controlled DM or HTN,
COPD, morbid obesity (BMI ≥40), active hepatitis, alcohol dependence
or abuse, implanted pacemaker, moderate reduction of ejection fraction,
ESRD undergoing regularly scheduled dialysis, premature infant
PCA <60 weeks, history (>3 months) of MI, CVA, TIA, or CAD/stents
ASA IV A patient with severe systemic Examples include (but not limited to): recent (<3 months) MI, CVA, TIA, or
disease that is a constant threat to life CAD/stents, ongoing cardiac ischemia or severe valve dysfunction, severe
reduction of ejection fraction, sepsis, DIC, ARD or ESRD not undergoing
regularly scheduled dialysis
ASA V A moribund patient who is not Examples include (but not limited to): ruptured abdominal/thoracic aneurysm,
expected to survive without the operation massive trauma, intracranial bleed with mass effect, ischemic bowel in the
face of significant cardiac pathology or multiple organ/system dysfunction
ASA VI A declared brain-dead patient whose
organs are being removed for donor purposes
ARD acute respiratory disease, CAD coronary artery disease, COPD chronic obstructive pulmonary disease, CVA cerebral vascular accident,
DIC disseminated intravascular coagulation, DM diabetes mellitus, ESRD end stage renal disease, HTN hypertension, MI myocardial infarction,
PCA post-conceptual age
Reprinted with permission from the American Association of Anesthesiologists
The addition of “E” denotes Emergency surgery: (An emergency is defined as existing when delay in treatment of the patient would lead to a
significant increase in the threat to life or body part)
research papers, no differences in bile duct injury and mor- treatments more accurately according to patient status,
tality rates were observed before and after the introduction shorten overall hospital stays, and decrease medical costs
of treatment strategies in line with severity grading, but [25, 38]. We expect large-scale clinical studies will be per-
overall hospital stays were shorter and medical costs lower formed to produce high-level evidence on the optimum
following the introduction of this method. In some of the treatment strategy for each severity grade and for this evi-
case series studies, survival rates and complication rates dif- dence to be used to further improve these guidelines.
fered for each severity grading, so the authors were in Patient factors like predictive factors and CCI or ASA-
agreement with the TG13 treatment strategies that are based PS scores can be used to decide whether surgery is possi-
on severity [26–30]. In other case series studies, surgical ble. See CQ5 for more details.
outcomes were equivalent across the cholecystitis severity At the Consensus Meeting, some participants stated
gradings for patients assessed as capable of withstanding that the guidelines should stress that surgical procedures
surgery and who underwent early surgery; so, other authors should be performed only at facilities where advanced
considered TG13 to be too restrictive [33, 34]. laparoscopic surgeons practice, in order to ensure that sur-
A study on the usefulness of biliary drainage according gery was safe for patients with Grade II or Grade III AC.
to severity showed that this method was effective in allevi-
ating symptoms and reducing the inflammatory response in Q3. What is the optimal timing of cholecystectomy for
blood tests [35]. However, two retrospective analyses acute cholecystitis?
showed that patients undergoing biliary drainage had longer
operating times, longer hospital stays, and higher mortality
If a patient is deemed capable of withstanding sur-
rates than patients not undergoing biliary drainage, with the
gery for AC, we propose early surgery regardless
same percentage of patients being switched to open surgery;
of exactly how much time has passed since onset.
these studies therefore showed biliary drainage did not have
(Recommendation 2, level B)
an useful effect on surgical outcomes [36, 37].
The introduction of systems to select treatment strategies
according to severity grading is expected to have many ben- TG07 recommended that surgery for AC be performed
efits, as this method should allow doctors to choose soon after hospital admission, whereas TG13
recommended that surgery be performed soon after admis- 4 days in one study [51]; within 1 week since onset in
sion and within 72 h after onset. When managing AC, it one study [52]; and as soon as possible after patient pre-
is difficult to determine precisely how many hours have sentation (with the actual timing not recorded) in two
passed since disease onset. Some patients only present studies [39, 53]. Delayed was defined in various different
after 72 h have already passed since onset. For “early sur- ways, including after diagnosis or after the symptoms
gery” as described in TG07 and TG13, we have added diminished, but was most commonly defined as after at
further considerations on whether the “within 72 h” rule least 6 weeks. We therefore identified two sub-categories
should be strictly observed and what is the optimal timing of early: within 72 h (of onset, presentation, or admission)
for surgery. and within one week including within 72 h (including
We based our considerations on a search of the litera- those studies that stated “as early as possible”). Of the 17
ture after the publication of the TG13 guidelines (using randomized controlled trials, we excluded one study for
the key words: acute cholecystitis, laparoscopic cholecys- which data could not be extracted [54]. We also excluded
tectomy, early cholecystectomy, delayed cholecystectomy, another study where we thought there might be some bias,
timing), which returned 17 randomized controlled trials, because the incidence of bile duct injury was higher than
six meta-analyses, and three systematic reviews. in normal clinical practice [55]. We performed a meta-
Lap-C was performed in the studies described by all of analysis on the remaining 15 studies.
these papers. Diagnosis of AC was based on TG13 in one
paper [39], and biochemical data, diagnostic imaging, and Meta-analysis
subjective/objective symptoms in the remaining 14 papers.
Surgery timing was indicated as early cholecystectomy or We compared early cholecystectomy (early surgery within
delayed cholecystectomy. Early was defined as within 1 week or within 72 h) with delayed cholecystectomy.
72 h since onset (as recommended in TG13) in two Key outcomes were operating times, incidence of bile duct
papers [40, 41]; within 24 h of hospital admission in two injury, length of hospital stay, and overall cost of treat-
papers [42, 43]; within 24 h since the study began in one ment. Operating times for delayed cholecystectomy tended
paper [44]; within 72 h since patient presentation (or to be shorter than for early cholecystectomy (both within
admission) or the study start in six papers [45–50]; within 72 h and within 1 week), although the difference is not
Fig. 3 Forest plot analysis of operation time (minutes) of early laparoscopic cholecystectomy versus delayed cholecystectomy. (Upper panel:
surgery within 72 h vs. delayed surgery after at least 6 weeks; lower panel: surgery within 1 week vs. delayed surgery after at least 6 weeks)
Fig. 4 Forest plot analysis of biliary injury of early laparoscopic cholecystectomy versus delayed cholecystectomy. (Upper panel: surgery
within 72 h vs. delayed surgery after at least 6 weeks; lower panel: surgery within 1 week vs. delayed surgery after at least 6 weeks)
statistically significant (P = 0.16, P = 0.06) (Fig. 3). The more than 72 h–1 week previously, and those whose
incidence of bile duct injury did not differ between early symptoms suddenly recurred during the waiting period
(both within 72 h and within 1 week) and delayed chole- such that emergency Lap-C had to be performed were also
cystectomy (P = 0.45, P = 0.72) (Fig. 4). However the discontinued from consideration for delayed surgery.
total number of patients in the meta-analysis is much too Therefore, it is not clear how many of the AC cases
low to draw any conclusions in this regard (“Absence of included cases with chronic inflammation and acute exac-
evidence is not evidence of absence”). Length of hospital erbations. In the 15 randomized controlled trials, 6–23%
stay was shorter for early cholecystectomy (both within of patients underwent emergency Lap-C when symptoms
72 h and within 1 week) than delayed cholecystectomy suddenly recurred during the waiting period. With delayed
(P < 0.0001, P < 0.00001) (Fig. 5). However, there was cholecystectomy, AC can flare up again during the waiting
no difference in length of hospital stay after surgery period. Tissues become progressively more scarred with
(P = 0.33) (Fig. 6). Overall cost of treatment was lower repeated episodes of inflammation, making surgery more
for early cholecystectomy within 72 h than delayed chole- difficult. From this perspective, delayed cholecystectomy is
cystectomy (P = 0.002) (Fig. 7). This meta-analysis on 15 associated with greater risk. The TG13 guidelines basically
randomized controlled trials shows that early cholecystec- recommended early surgery as the treatment for AC, with
tomy was not inferior to delayed cholecystectomy in terms a specific recommendation for cholecystectomy soon after
of mortality rates and incidence of complications. There hospitalization if no more than 72 h has passed since
was no difference in length of hospital stay after surgery, symptom onset. Two randomized controlled trials com-
but total hospital stays were shorter for early cholecystec- pared delayed cholecystectomy versus early cholecystec-
tomy and therefore overall cost of treatment was also tomy in patients where symptoms started no more than
lower. The five studies in these randomized controlled 72 h previously [40, 41]. In both of these trials, the early
trials excluded the cases in which symptom onset began surgery group had shorter total hospital stays and shorter
Fig. 5 Forest plot analysis of all hospital stay of early laparoscopic cholecystectomy versus delayed cholecystectomy. (Upper panel: surgery
within 72 h vs. delayed surgery after at least 6 weeks; lower panel: surgery within 1 week vs. delayed surgery after at least 6 weeks)
Fig. 6 Forest plot analysis of hospital stay after operation of early laparoscopic cholecystectomy versus delayed cholecystectomy. (Surgery
within 72 h vs. delayed surgery after at least 6 weeks)
Fig. 7 Forest plot analysis of medical costs of early laparoscopic cholecystectomy versus delayed cholecystectomy. (Surgery within 72 h vs.
delayed surgery after at least 6 weeks)
operating times. No mention was made of the incidence of There are no randomized controlled trials on the best
bile duct injury. time for Lap-C after PTGBD. Four observational studies
The meta-analysis of the case study reports found that, featured various different times before surgery after
compared with delayed cholecystectomy, early cholecys- PTGBD, and we assign these studies as evidence level C.
tectomy for cases within 72 h of patient presentation or Table 3 provides a summary of these studies [59–62].
symptom onset was associated with lower mortality rates, PTGBD is used for therapeutic purposes if the patient
complication rates, incidence of bile duct injury, and has problematic complications or comorbidities. In a
switching to open surgery. Similar results were also large-scale case series study in Japan and Taiwan, mortal-
obtained with early cholecystectomy for cases where ity risk with urgent surgery was higher in patients scoring
patient presentation/symptom onset occurred 72 h–1 week CCI ≥6 or body mass index (BMI) ≤20 if they had Grade
previously [56]. Therefore, for AC patients for whom I or II AC according to the TG13 severity grading and in
more than 72 h has passed since symptom onset, there patients with jaundice (TBil ≥2.0 mg/dl), cranial neuropa-
still are benefits to performing surgery early. thy, or respiratory dysfunction if they had Grade III AC
A comparison of early surgery performed within 24 h [25]. For such high-risk patients, early/urgent surgery is
of symptom onset and early surgery performed within not recommended and PTGBD is indicated. When
72 h shows that the outcomes from the former group were PTGBD is performed for high-risk patients, it is assumed
not superior to those in the latter group [57]. Even if there that it would be difficult to perform surgery immediately
are benefits to early surgery, this does not mean that after the PTGBD procedure. In practice, studies have
urgent surgery after hours should be performed. Ideally, shown various outcomes in high-risk patients who under-
surgery should be performed by surgeons experienced in went PTGBD followed by early/urgent surgery, including
laparoscopy or at facilities with a long history of laparo- longer operating times and increased bleeding [60, 61].
scopic procedures [58]. That said, one study reported that the differences were not
Compared with delayed cholecystectomy, early chole- substantial between the two approaches [62]. Furthermore,
cystectomy performed within 72 h if possible and even two studies comparing surgery after PTGBD to early sur-
within 1 week may reduce costs, as the overall hospital gery without PTGBD (one randomized controlled trial
stays are shorter and there is less chance the patient will [63] and one cohort study [64]) both reported good out-
require additional treatments or emergency surgery due to comes when Lap-C was performed after waiting 4–
symptoms suddenly recurring during the waiting period. 6 weeks after PTGBD for the factors bleeding volume,
operating times, percentage of patients switched to open
Q4. When is the optimal timing for cholecystectomy surgery, and incidence of complications. These results
following percutaneous transhepatic gallbladder drai- suggest that risks may be increased further when Lap-C is
nage (biliary drainage)? [Future research question] performed at a relatively early stage after PTGBD in
high-risk patients. From a cost perspective, however,
another study reported that costs were lower in patients
There are no reports providing quality scientific
treated with early Lap-C after PTGBD [59]. At this stage,
evidence on the best timing for surgery after per-
a consensus has yet to be reached on the timing of sur-
cutaneous transhepatic gallbladder drainage
gery after PTGBD. Ideally, the physician treating the
(PTGBD; also called cholecystostomy), so a con-
patient will determine the optimum timing for managing
sensus has not been reached. (Level C)
the patient while bearing in mind patient risk. We look
Table 3 Time until Lap-C after PTGBD and outcomes (all OS)
Author Time until surgery after PTGBD Summary of outcomes
Early surgery Delayed surgery
group (n) group (n)
Han et al. 2012 [59] <72 h (21) ≥72 h (46) Early group had higher incidence of postoperative complications, longer
operating times. Percentage of patients switched to open surgery was the
same in the two groups. Early group had shorter total hospital stays
Choi et al. 2012 [60] <72 h (63) ≥5 days (40) Early group had higher bleeding volumes and longer operating times
Jung et al. 2015 [62] <10 days (30) ≥10 days (44) Equivalent rates between the two groups for postoperative complication rates,
operating times, percentage of patients switched to open surgery, and total
hospital stays
Tanaka et al. 2016 [61] <14 days (16) ≥14 days (47) Higher bleeding volumes in the early group
PTGBD percutaneous transhepatic gallbladder drainage
forward to more studies like the CHOCOLATE trial cur- straightforward cholecystectomy is performed, and in
rently underway [65] to build up a body of quality group B, surgery is performed after drainage. There is
evidence. no significant 30-day and 90-day mortality rate between
A and B in Grade III without predictive factors (neuro-
Q5. What is the risk factor which should postpone an logical dysfunction, respiratory failure, coexistence of
operation for acute cholecystitis? [Future research jaundice) [25].
question] The ASA-PS is also reported as a risk factor in AC
in several articles. ASA-PS 3 or over is high risk for
emergency cholecystectomy [66–69]. ASA-PS score
For Grade I and II patients, we propose scores of (from 2 to 5) was a significant risk factor for death [70].
CCI ≥6 and ASA-PS ≥3 as surgical risk factors. Based on the above, ASA-PS was also adopted. How-
For risk factors for Grade III patients, we propose ever, one study reported no deaths after cholecystectomy
the negative predictive factors of neurological dys- when patients with ASA-PS ≥3 were operated on at
function, respiratory dysfunction, and coexistence advanced centers (where experienced surgeons practice)
of jaundice (TBil ≥2 mg/dl). We propose scores of [67]. We hope that more case series data will be gath-
CCI ≥4 and ASA-PS ≥3 as risk factors indicating ered for future analysis.
that the patient might not withstand surgery.
(Level C)
Flowchart for the management of acute cholecystitis
In a cohort analysis by Endo et al. of 5,459 AC
patients in Japan and Taiwan, multivariate analysis Grade I
showed a statistically significant increase in 30-day mor-
tality patients with Grade I or II AC who had CCI ≥6 Figure 8 shows a treatment flowchart for Grade I AC.
(Table 4) [25]. Multivariate analysis was also used to There are no substantial differences with the TG13 guide-
analyze 30-day mortality risk factors in Grade III lines, but the flowchart does include additional considera-
patients (Table 5) [25]. Grade III patients of AC have tions on patient risk factors.
at least one organ failure. Among prescribed organ dis-
orders in TG13, neurological and respiratory failure Explanation of flowchart of Grade I AC (Fig. 8)
were predictive factors. Furthermore, coexistence of
jaundice is another predictive factor in addition to one
or more organ dysfunction regulated by TG13. Predic- In principle, early Lap-C is the first-line treatment
tive factors for 30-day and 90-day mortality were also for the cases of Grade I. However, in patients with
investigated in Grade III patients undergoing straightfor- surgical risk (broken line) using CCI and ASA-PS,
ward cholecystectomy and Grade III patients undergoing antibiotics and general supportive care are firstly
cholecystectomy after PTGBD (Table 6) [25]. The top necessary. Then, after improvement with initial med-
of Table 6 shows the 30-day mortality rate and the bot- ical treatment, they could be indicated to Lap-C.
tom shows the 90-day mortality rate. In group A,
Table 4 Survival analysis of 30-day mortality in patients with Grade I and Grade II acute cholecystitis [25]
Survivor (n = 2,677) Non-survivor (n = 21) Univariate P-value Multivariate P-value Odds ratio 95% CI
Body mass index

<20 349 9 <0.01 0.011
>20 to <25 1,360 7 <0.01 0.241 0.088–0.659
>25 968 5 0.032 0.290 0.094–0.898
PS
0–2 2,571 17 <0.01 0.054
3–4 106 4
CCI
0–5 2,140 9 <0.01 <0.01 4.433 1.816–10.822
≥6 537 12
Source: Endo et al. [25], reprinted with permission from John Wiley & Sons (No. 4177091307865)
Table 5 Survival analysis of 30-day mortality in patients with Grade III acute cholecystitis [25]
Survivor (n = 591) Non-survivor (n = 20) Univariate P-value Multivariate P-value Odds ratio 95% CI
PS
0–2 532 14 <0.01 0.156
3–4 59 6
CCI
0–5 304 7 0.148 0.380
26 287 13
Jaundice
477 9 <0.01 <0.01 6.470 2.446–17.110
+ 114 11
Cardiovascular
457 13 0.198 0.493
+ 134 7
Neurological
518 12 <0.01 <0.01 4.346 1.640–11.515
+ 73 8
Respiratory
528 13 <0.01 <0.01 5.843 2.052–16.635
+ 63 7
Renal
385 10 0.164 0.073
+ 206 10
Hepatic
371 14 0.510 0.360
+ 220 6
Hematological
459 17 0.437 0.513
+ 132 3
Table 6 Mortality rate in each therapeutic groups of Grade III acute cholecystitis according to prognostic factors [25]
Group A (n = 260) Group B (n = 180) Group C (n = 93) Group B + C (n = 273) P-value
30-day mortality
No positive 0 0 2 2 NA (A vs. B)
PF 0.00 0.00 4.55 1.27 0.040 (A vs. C)
0.226 (A vs. B+C)
Any positive 8 0 7 7 0.010 (A vs. B)
PFs 9.30 0.00 14.29 6.09 0.403 (A vs. C)
0.426 (A vs. B+C)
Group A (n = 219) Group B (n = 168) Group C (n = 74) Group B + C (n = 242) P-value
90-day mortality
No positive 2 0 6 6 0.513 (A vs. B)
PF 1.31 0.00 16.22 4.14 0.001 (A vs. C)
0.164 (A vs. B+C)
Any positive 7 0 9 9 0.014 (A vs. B)
PFs 10.61 0.00 24.32 9.28 0.089 (A vs. C)
0.794 (A vs. B+C)
Group A: cholecystectomy, Group B: cholecystectomy after PTGBD
NA statistical value could not be analyzed, PF jaundice, neurological dysfunction, respiratory dysfunction
The patient’s status should be fully understood and sur-

gery performed with a focus on safety. For information on should take the difficulty of cholecystectomy into
early treatment, doctors should refer to the description of ini- consideration in selecting a treatment method.
tial treatment for bile duct inflammation from Miura et al. Early Lap-C could be first indicated if advanced
[4] and to guidelines on antimicrobials from Gomi et al. [6]. laparoscopic techniques are available. When the
judgment of cholecystectomy is made, general
condition should be evaluated using CCI and
Grade II ASA-PS. Elective cholecystectomy after the
improvement of the acute inflammatory process
Figure 9 shows a treatment flowchart for Grade II AC. could be indicated in the poor conditional
patients (broken line). If a patient does not
Explanation of flowchart of Grade II AC (Fig. 9) respond to initial medical treatment, urgent or
early gallbladder drainage is required (broken
line). CCI 6 or greater and ASA-PS 3 or greater
Grade II (moderate) AC is often accompanied by are high risk. If not, transfer to advanced center
severe local inflammation. Therefore, surgeons should be considered.
Antibiotics
and general Observation
supportive care
Grade I
Early LC
(mild)
Fig. 8 TG18 flowchart for the management of acute cholecystitis Grade I. k, CCI 5 or less and/or ASA class II or less (low risk); µ, CCI 6
or greater and/or ASA class III or greater (not low risk); M, in case of serious operative difficulty, bail-out procedures including conversion
should be used. ASA-PS American Society of Anesthesiologists physical status. [Colour figure can be viewed at wileyonlinelibrary.com]
And advanced LC
technique
Urgent/early LC
available
Antibiotics
Grade II and general
(moderate) supportive care Delayed/
elective
LC
Urgent/early
GB drainage
Fig. 9 TG18 flowchart for the management of acute cholecystitis Grade II. α, antibiotics and general supportive care successful; /, antibiotics
and general supportive care fail to control inflammation; k, CCI 5 or less and/or ASA-PS class II or less (low risk); µ, CCI 6 or greater
and/or ASA-PS class III or greater (not low risk); ※, performance of a blood culture should be taken into consideration before initiation of
administration of antibiotics; †, a bile culture should be performed during GB drainage; M, in case of serious operative difficulty, bail-out
procedures including conversion should be used. ASA-PS American Society of Anesthesiologists physical status, CCI Charlson comorbidity
index, GB gallbladder, LC laparoscopic cholecystectomy. [Colour figure can be viewed at wileyonlinelibrary.com]
The patient’s risk factors should be fully understood

and it is essential that surgery be performed in a facility performed by expert surgeon who often completed
capable of conducting such procedures safely. If the medi- additional training beyond their basic general sur-
cal facility is not capable of providing treatment such as gical education under intensive care. If not, trans-
early cholecystectomy or biliary drainage, the patient fer to advanced center should be considered.
should be transferred to an appropriate medical facility as
soon as possible. For biliary drainage, PTGBD is cur-
rently recommended [38] and doctors should refer to the With Grade III AC, the patient’s overall status has
paper by Mori et al. [71]. deteriorated significantly and treatment should be chosen
When surgery is performed, it is important to be aware based on full and careful consideration of the patient’s
that the degree of surgical difficulty can vary widely background, including complications and comorbidities
depending on the level of inflammation and fibrosis. Dur- (organ failure). When Lap-C is chosen, we stress that it is
ing surgery, findings on the difficulty index should be absolutely vital for this to be performed by someone with
confirmed and Lap-C should be undertaken safely making advanced skills. Ideally the patient should be transferred
sure to avoid risks [72–76]. In case of serious operative quickly to a suitable medical facility if the initial medical
difficulty, bail-out procedures including conversion should facility is not capable of providing complete intensive care
be used [76]. and treatments like early cholecystectomy and biliary drai-
nage. PTGBD is recommended for biliary drainage, as
with Grade II patients [38]; for more details on the
Grade III method, doctors should refer to the paper by Mori et al.
[71].
Figure 10 shows a treatment flowchart for Grade III AC. After considering predictive factors and FOSF, even
when surgery is performed on patients whose overall sta-
Explanation of flowchart of Grade III AC (Fig. 10) tus allows resection, rigorous whole-body management is
vital to manage organ dysfunction and other issues, and
surgeons need to bear in mind the possibility that the sur-
Grade III AC is accompanied by organ dysfunc- gery may be extremely difficult, so difficulty indicators
tion. Appropriate organ support such as ventila- should be monitored during surgery and every effort
tory/circulatory management (noninvasive/invasive should be made to avoid risks to ensure the Lap-C is per-
positive pressure ventilation and use of vasopres- formed safely [72–76]. If the cholecystectomy proves dif-
sors, etc) in addition to initial medical treatment is ficult, surgeons should not hesitate to perform bail-out
necessary. Early or urgent cholecystectomy can be surgery [76].
possible under intensive care, when the judgment
of cholecystectomy is made using predictive factor,
FOSF, CCI and ASA-PS. The predictive factors in Criteria for transfer to an “advanced center” (Table 7)
Grade III are jaundice (TBil ≥2), neurological dys-
function, and respiratory dysfunction. As early In TG18 there is increased attention to the effect of
operation is best in those patients who have patient health status and facility on selection of treatment.
rapidly reversible failure of cardiovascular and/or Also for the first time there is a pathway for early chole-
renal failure, we advocate FOSF. FOSF means car- cystectomy in selected types of Grade III severity cases as
diovascular or renal organ system failure which is indicated in the Grade III flowchart. There are also recom-
rapidly reversible after admission and before early mendations in regard to patient status and facility in the
Lap-C in AC. Because Grade III patients have one other severity grades. Certain recommendations shown in
or more organ dysfunction, CCI 6 is too high score the flowcharts are made on the condition that the treating
and not cutoff value of high risk for cholecystec- facility meets criteria such as having surgeons who are
tomy. CCI 4 or greater and ASA-PS 3 or greater specialized in laparoscopic skills and intensive care units.
are eligible high risk factor for cholecystectomy in These types of facilities are referred to as “advanced cen-
Grade III. If not, urgent or early gallbladder drai- ters”. Based on the foregoing there is the opportunity to
nage should be performed. Elective cholecystec- facilitate treatment of elected patients by transfer to an
tomy may be performed after the improvement of advanced center [77, 78]. The following are suggested cri-
acute illness has been achieved by gallbladder teria for doing so (Table 7). At the moment, clinical evi-
drainage. Lap-C in Grade III of AC should be dence is scarce on patient selection for transfer to
advanced facilities and warrants further investigation.
68
No negative Advanced center Ψ

predictive and good PS* Early LC
factors #
Antibiotics and
Grade III
and general FOSF
(severe)
organ support
Poor PS*
or not Ψ
Delayed/
Negative Good PS* elective
predictive Urgent/early LC
factors present # GB drainage†
and/or
no FOSF Poor PS* Observation
Fig. 10 TG18 flowchart for the management of acute cholecystitis Grade III. ※, performance of a blood culture should be taken into consideration before initiation of administration of
antibiotics; #, negative predictive factors: jaundice (TBil ≥2), neurological dysfunction, respiratory dysfunction; Φ, FOSF: favorable organ system failure = cardiovascular or renal organ sys-
tem failure which is rapidly reversible after admission and before early LC in AC; *, in cases of Grade III, CCI (Charlson comorbidity index) 4 or greater, ASA-PS 3 or greater are high
risk; †, a bile culture should be performed during GB drainage; Ψ, advanced center = intensive care and advanced laparoscopic techniques are available; M, in case of serious operative diffi-
culty, bail-out procedures including conversion should be used. GB gallbladder, LC laparoscopic cholecystectomy, PS performance status [Colour figure can be viewed at wileyonlinelibrary.-
com]
Table 7 Transfer criteria for acute cholecystitis Mayo Clinic College of Medicine, Jacksonville, FL,
Severe acute cholecystitis (Grade III) USA; Itaru Endo, Department of Gastroenterological
When a patient meets certain conditions defined by the AC Surgery, Yokohama City University Graduate School
flowchart, Lap-C can be performed only by an expert of Medicine, Kanagawa, Japan; Yukio Iwashita and
laparoscopic surgeon at a specialized center that provides Masafumi Inomata, Department of Gastroenterological
intensive care. Otherwise, transfer to advanced facilities should
and Pediatric Surgery, Oita University Faculty of Medi-
be considered
cine, Oita, Japan; Taizo Hibi, Department of Surgery,
Moderate acute cholecystitis (Grade II)
Keio University School of Medicine, Tokyo, Japan;
Patients should be treated at centers that can provide emergent
drainage of the gallbladder or early Lap-C. Otherwise, Henry A. Pitt, Lewis Katz School of Medicine at Temple
transfer to advanced facilities should be considered University, Philadelphia, PA, USA; Akiko Umezawa,
Mild acute cholecystitis (Grade I) Minimally Invasive Surgery Center, Yotsuya Medical
In the case of patients whose operation is delayed because Cube, Tokyo, Japan; Koji Asai, Department of Surgery,
of existing serious comorbidity transfer to advanced facilities Toho University Ohashi Medical Center, Tokyo, Japan;
that can provide emergent drainage of the gallbladder or early
Ho-Seong Han and Yoo-Seok Yoon, Department of Sur-
Lap-C should be considered
gery, Seoul National University Bundang Hospital, Seoul
National University College of Medicine, Seoul, Korea;
Tsann-Long Hwang, Keng-Hao Liu and Miin-Fu Chen,
The Statement Division of General Surgery, Linkou Chang Gung
Memorial Hospital, Taoyuan, Taiwan; Yasuhisa Mori and
Surgical skill and experience in advanced MIS sur- Masafumi Nakamura, Department of Surgery and Oncol-
gery vary. ogy, Graduate School of Medical Sciences, Kyushu
The selection of a particular pathway of care University, Fukuoka, Japan; Wayne Shih-Wei Huang,
should take this factor into account. Department of Surgery, Show Chwan Memorial Hospital,
When skill and experience are high, early LC in Changhua, Taiwan; Giulio Belli, Department of General
AC may be appropriate in all Grade of AC as and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy;
indicated in the flowcharts. Christos Dervenis, First Department of Surgery, Agia
The application of patient selection criteria is other Olga Hospital, Athens, Greece; Masamichi Yokoe and
key factor predictive of success (predictive factor, Yoshinori Noguchi, Department of General Internal Med-
FOSF, CCI, ASA-PS etc). icine, Japanese Red Cross Nagoya Daini Hospital, Aichi,
Japan; Seiki Kiriyama, Department of Gastroenterology,
Ogaki Municipal Hospital, Gifu, Japan; Takao Itoi,
Department of Gastroenterology and Hepatology, Tokyo
Acknowledgments We would like to express our deep gratitude to
the Japanese Society for Abdominal Emergency Medicine, the Japan Medical University Hospital, Tokyo, Japan; Palepu
Biliary Association, Japan Society for Surgical Infection, and the Jagannath, Department of Surgical Oncology, Lilavati
Japanese Society of Hepato-Biliary-Pancreatic Surgery, which Hospital and Research Centre, Mumbai, India; O James
provided us with great support and guidance in the preparation of
Garden, Clinical Surgery, University of Edinburgh, Edin-
the Guidelines.
burgh, UK; Akihiko Horiguchi, Department of Gastroen-
terological Surgery, Fujita Health University School of
Conflict of interest Goro Honda has received honoraria from
Medicine, Aichi, Japan; Go Wakabayashi, Department of
Johnson and Johnson and Medtronic.
Surgery, Ageo Central General Hospital, Saitama, Japan;
Daniel Cherqui, Hepatobiliary Center, Paul Brousse
Appendix: author’s affiliations Hospital, Villejuif, France; Eduardo de Santiba~ nes,
Department of Surgery, Hospital Italiano, University of
Kohji Okamoto, Department of Surgery, Center for Gas- Buenos Aires, Buenos Aires, Argentina; Satoru Shikata,
troenterology and Liver Disease, Kitakyushu City Yahata Director, Mie Prefectural Ichishi Hospital, Mie, Japan;
Hospital, Fukuoka, Japan; Kenji Suzuki, Department of Tomohiko Ukai, Department of Family Medicine, Mie
Surgery, Fujinomiya City General Hospital, Shizuoka, Prefectural Ichishi Hospital, Mie, Japan; Ryota Higuchi
Japan; Tadahiro Takada, Fumihiko Miura and Keita and Masakazu Yamamoto, Department of Surgery, Insti-
Wada, Department of Surgery, Teikyo University School tute of Gastroenterology, Tokyo Women’s Medical
of Medicine, Tokyo, Japan; Steven M. Strasberg, Sec- University, Tokyo, Japan; Goro Honda, Department of
tion of Hepato-Pancreato-Biliary Surgery, Washington Surgery, Tokyo Metropolitan Komagome Hospital,
University School of Medicine in St. Louis, St. Louis, Tokyo, Japan; Avinash Nivritti Supe, Department of Sur-
MO, USA; Horacio J. Asbun, Department of Surgery, gical Gastroenterology, Seth G S Medical College and K
E M Hospital, Mumbai, India; Masahiro Yoshida, 3. Yokoe M, Hata J, Takada T, Strasberg SM, Asbun HJ, Wak-
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DOI: 10.1002/jhbp.512
GUIDELINE
Tokyo Guidelines 2018: diagnostic criteria and severity grading of

acute cholangitis (with videos)
Seiki Kiriyama Kazuto Kozaka Tadahiro Takada Steven M. Strasberg Henry A. Pitt Toshifumi Gabata
Jiro Hata Kui-Hin Liau Fumihiko Miura Akihiko Horiguchi Keng-Hao Liu Cheng-Hsi Su Keita Wada
Palepu Jagannath Takao Itoi Dirk J. Gouma Yasuhisa Mori Shuntaro Mukai Mariano Eduardo Gimenez
Wayne Shih-Wei Huang Myung-Hwan Kim Kohji Okamoto Giulio Belli Christos Dervenis Angus C. W.
Chan Wan Yee Lau Itaru Endo Harumi Gomi Masahiro Yoshida Toshihiko Mayumi Todd H. Baron
Eduardo de Santiba~ nes Anthony Yuen Bun Teoh Tsann-Long Hwang Chen-Guo Ker Miin-Fu Chen
Ho-Seong Han Yoo-Seok Yoon In-Seok Choi Dong-Sup Yoon Ryota Higuchi Seigo Kitano Masafumi Inomata

Daniel J. Deziel Eduard Jonas Koichi Hirata Yoshinobu Sumiyama Kazuo Inui Masakazu Yamamoto

The author’s affiliations are listed Abstract Although the diagnostic and severity grading criteria on the 2013 Tokyo
in the Appendix. Guidelines (TG13) are used worldwide as the primary standard for management of acute
Correspondence to: Tadahiro cholangitis (AC), they need to be validated through implementation and assessment in actual
Takada, Department of Surgery, clinical practice. Here, we conduct a systematic review of the literature to validate the TG13
Teikyo University School of diagnostic and severity grading criteria for AC and propose TG18 criteria. While there is little
Medicine, 2-11-1 Kaga, Itabashi-ku, evidence evaluating the TG13 criteria, they were validated through a large-scale case series
e-mail: t-takada@jshbps.jp study in Japan and Taiwan. Analyzing big data from this study confirmed that the diagnostic
rate of AC based on the TG13 diagnostic criteria was higher than that based on the TG07
DOI: 10.1002/jhbp.512 criteria, and that 30-day mortality in patients with a higher severity based on the TG13
severity grading criteria was significantly higher. Furthermore, a comparison of patients
treated with early or urgent biliary drainage versus patients not treated this way showed no
difference in 30-day mortality among patients with Grade I or Grade III AC, but significantly
lower 30-day mortality in patients with Grade II AC who were treated with early or urgent
biliary drainage. This suggests that the TG13 severity grading criteria can be used to identify
Grade II patients whose prognoses may be improved through biliary drainage. The TG13
severity grading criteria may therefore be useful as an indicator for biliary drainage as well as
a predictive factor when assessing the patient’s prognosis. The TG13 diagnostic and severity
grading criteria for AC can provide results quickly, are minimally invasive for the patients,
and are inexpensive. We recommend that the TG13 criteria be adopted in the TG18
guidelines and used as standard practice in the clinical setting. Free full articles and mobile
app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47.
Related clinical questions and references are also included.
Keywords Acute cholangitis Diagnostic criteria Diagnostic imaging Guidelines

Severity grading
Introduction
Acute cholangitis (AC) occurs when biliary stenosis, due to various benign causes (often
bile duct stones) or the presence of a tumor, results in cholestasis and biliary infection.
This biliary stenosis or blockage elevates pressure within the biliary system and flushes
the microorganisms or endotoxins from the infected bile into

systemic circulation, inducing a systemic inflammatory Charcot’s triad shows very high specificity. The
response [1, 2]. Mortality risk is high if the condition is not presence of Charcot’s triad strongly suggests
treated with antibiotic therapy and biliary pressure is not imme- the presence of acute cholangitis. However, due to
diately reduced using appropriate methods. We, therefore, need the low sensitivity, it is not applicable in using as
to be able to reliably diagnose and assess the severity of diagnosis criteria for acute cholangitis. (Level D)
cholangitis to determine whether the patient’s life is in danger.
However, very little evidence related to AC has been Acute cholangitis has long been diagnosed on the basis
collected over the years, and the evidence that does exist is of Charcot’s triad, which relies on clinical signs [8].
extremely old. No globally accepted diagnostic criteria for Although Charcot’s triad provides highly specific diagnos-
AC have existed. Although AC has long been diagnosed on tic criteria [9], studies have reported its sensitivity to be on
the basis of Charcot’s triad, as discussed in greater detail the order of 50 to 70% [9–16]. More recent multicenter case
below, this method is problematic because of its low sensi- series studies showed Charcot’s triad diagnosis rates to be
tivity (around 26%). The lack of evidence in this field has much lower (26.4% [4] and 21.2% [17]). Thus, the ability
prompted specialists to establish a consensus. Thus, the of this method to diagnose AC is severely limited.
International Consensus Meeting for the Management of To compensate for the low sensitivity of Charcot’s
Acute Cholecystitis, Cholangitis was held on 1–2 April triad, the TG07 diagnostic criteria were based on Char-
2006 in Tokyo, Japan. Based on the outcomes from this cot’s triad with the addition of blood test and imaging
meeting and a systematic review of the literature, the Tokyo findings; however, this still did not provide sufficient sen-
Guidelines for the management of AC and cholecystitis sitivity. In the updated TG13 guidelines, the Tokyo
(TG07) were published in 2007 and the first ever diagnostic Guidelines Revision Committee conducted joint research
and severity grading criteria for AC were presented [2]. at multiple sites. Initially, when the TG07 items were
However, validation of the TG07 diagnostic criteria in actual reclassified as three main clinical manifestations based on
clinical practice revealed that these guidelines were not suffi- Charcot’s triad, the method had exhibited good sensitivity
ciently sensitive to identify potentially life-threatening cases (95.1%) but poor specificity (66.3%) due to the high rate
[3, 4]. Moreover, the TG07 severity grading criteria were (38.8%) of false positives for acute cholecystitis. Exclud-
found to be of limited use due to the ambiguous definition of ing abdominal pain, one of the Charcot’s triad, gave
moderate cholangitis as “not responding to initial treatment” 91.8% sensitivity and 77.7% specificity, with a 5.9% false
and the lack of methodologies allowing clinicians to carry positive rate for acute cholecystitis; so, this was used as
out rapid assessment at the time of diagnosis [3–6]. In 2013, the updated TG13 diagnostic criteria [4, 5].
therefore, the criteria for diagnosis and severity grading of
AC were amended and reintroduced as the updated TG13
guidelines [5], based on a systematic review of the literature, Q2. Are the TG13 diagnostic criteria for acute cholan-
international consensus meetings, and multicenter study. gitis useful for clinical practice and appropriate as the
Today, it is recommended to manage AC by referring TG18 criteria? [Foreground question]
to the globally accepted diagnostic criteria and severity
grading criteria as defined in the TG13 guidelines. How-
ever, the criteria for diagnosis and severity grading The TG13 diagnostic criteria are recommended
defined in these guidelines also need to be re-examined to be used as the TG18 criteria because more
and amended after implementation and assessment in the patients with possible acute cholangitis can be
clinical setting [7]. TG13 also needs to be validated diagnosed by using these criteria. (Recommenda-
through application in clinical practice. Here, we validate tion 1, level D)
the criteria for diagnosis and severity grading of AC in
the TG13 guidelines based on a systematic review of the
literature and, in particular, a large-scale Japanese/Tai- The entire literature on TG13 diagnostic criteria for
wanese joint case series study and propose diagnostic and AC consisted of two case series studies [17, 18], indicat-
severity grading criteria for the TG18 guidelines. ing the paucity of studies in this area. Recently a large-
scale multicenter case series study to validate the TG13
diagnostic criteria for AC was conducted at sites in Japan
Diagnostic criteria for acute cholangitis and Taiwan [17]. This study enrolled patients who were
clinically diagnosed with AC and admitted for treatment
Q1. What is the role of Charcot’s triad in the diagnostic over a 2-year period between 2011 and 2013, prior to the
criteria for acute cholangitis? [Background question] publication of the TG13 guidelines. Retrospective
Table 1 Comparison of diagnostic rates of TG13 and TG07 [17] which can be life-threatening if not diagnosed rapidly and
Diagnostic status No. of patients P-value treated appropriately. Large-scale case series research
showed that the TG13 diagnostic criteria for AC are asso-
TG13 TG07
ciated with high diagnosis rates of around 90% for cases
Definite 4,430 (73.1%) 3,977 (65.6%) actually treated as AC. Moreover, when the TG13 diag-
Suspected 1,024 (16.9%) 838 (13.8%) nostic criteria are used, clinicians can make a diagnosis
Cholangitis (definite or 5,454 (90.0%) 4,815 (79.4%) <0.0001 based on clinical signs and symptoms, routine blood tests,
suspected diagnosis) and diagnostic imaging, all of which can be performed
Non-cholangitis 609 (10.0%) 1,248 (20.6%) and provide results quickly, are minimally invasive for the
Cited from Kiriyama et al. [17] patients, and are inexpensive.
We therefore recommend that the TG13 diagnostic cri-
teria for AC be adopted as TG18 diagnostic criteria and
application of the TG13 diagnostic criteria to the patients used as standard practice in the clinical setting. Table 2
suspected of AC on a clinical basis yielded definite and shows the TG18/TG13 diagnostic criteria for AC.
suspected diagnoses in 5,454 of 6,063 patients for a diag-
nosis rate of 90.0%. Application of TG07 diagnostic crite-
ria resulted in definite and suspected diagnoses in 4,815
patients for a diagnosis rate of 79.4%, confirming that Table 2 TG18/TG13 diagnostic criteria for acute cholangitis [4]
TG13 provides improved diagnostic capabilities for AC
A. Systemic inflammation
(Table 1). Systemic inflammation was not observed in A-1. Fever and/or shaking chills
511 of the 609 patients (83.9%) who did not receive a A-2. Laboratory data: evidence of inflammatory response
definite or suspected diagnosis based on the TG13 diag- B. Cholestasis
B-1. Jaundice
nostic criteria. Moreover, of the 2,523 Grade I patients,
B-2. Laboratory data: abnormal liver function tests
the diagnosis rate based on the TG13 diagnostic criteria C. Imaging
was only 83.6%; analysis by causative factor showed a C-1. Biliary dilatation
high diagnosis rate in cases where the cholangitis had a C-2. Evidence of the etiology on imaging (stricture, stone, stent etc.)
clear cause (bile duct stones, malignant tumors, and stent Suspected diagnosis: one item in A + one item in either B or C
Definite diagnosis: one item in A, one item in B and one item in C
occlusion) but a low diagnosis rate for other types of
cholangitis including cases where the cause was unknown. Note:
There are still limitations that must be overcome, includ- A-2: Abnormal white blood cell counts, increase of serum C-
ing the low diagnosis rates in patients with mild disease, reactive protein levels, and other changes indicating inflammation
patients where findings of a systemic inflammatory B-2: Increased serum ALP, r-GTP (GGT), AST, and ALT levels
Other factors which are helpful in diagnosis of acute cholangitis
response are lacking, or patients where imaging is difficult include abdominal pain (right upper quadrant or upper abdominal)
to obtain and the cause cannot be readily identified. That and a history of biliary disease such as gallstones, previous biliary
said, the diagnosis rates based on TG13 are better than procedures, and placement of a biliary stent.
those based on TG07. Limitations of this study include In acute hepatitis, marked systematic inflammatory response is
observed infrequently. Virological and serological tests are required
the fact that the decision processes used at each facility to when differential diagnosis is difficult.
diagnose and treat AC of the enrolled patient may have
differed and the fact that specificity was not assessed. Thresholds:
Note that one report showed roughly equivalent diagnosis
A-1 Fever BT >38°C
rates with TG13 and TG07 [18]; however, this study only
A-2 Evidence of WBC count (91,000/lL) <4 or >10
investigated cases with a definite diagnosis of AC with inflammatory CRP (mg/dL) ≥1
confirmed purulent bile, which is a subset of AC cases response
targeted by the diagnostic and therapeutic guidelines. This B-1 Jaundice T-Bil ≥2 (mg/dL)
may explain the high diagnosis rates in that report result- B-2 Abnormal liver ALP (IU) >1.5 9 STDa
ing from the TG07 diagnostic criteria based on Charcot’s function tests cGTP (IU) >1.5 9 STDa
triad. AST (IU) >1.5 9 STDa
The systematic review of the literature performed for ALT (IU) >1.5 9 STDa
the TG18 revision revealed that there is little evidence
validating the diagnostic capabilities of the TG13 diagnos-
ALP alkaline phosphatase, ALT alanine aminotransferase, AST aspar-
tic criteria for AC and that no studies have evaluated tate aminotransferase, CRP C-reactive protein, r-GTP (GGT) r-gluta-
specificity. However, in terms of diagnostic criteria, sensi- myltransferase, WBC white blood cell
a
tivity is more important than specificity for this disease, STD: upper limit of normal value
No 1.4% aminotransferase (AST) and

(ALT)) in the blood test results.
alanine aminotransferase
Imaging findings
Remarkable advances have been made in the equipment

and methods used for diagnostic imaging [19–21]. How-
ever, even though new technologies and knowledge are
steadily accumulating, we are still unable to directly diag-
nose AC based on imaging findings. Even in the TG13
Yes
guidelines, diagnostic imaging is considered a method to
98.6% directly identify biliary stenosis/blockage that can cause
AC or to describe cholangiectasis that can be used as an
indirect finding in support of a diagnosis [5]. Imaging
modalities capable of yielding such findings include
Fig. 1 Response to the question: “Do you agree with the suggestion abdominal ultrasound, computed tomography (CT), and
that TG13 diagnostic criteria for acute cholangitis would be adopted magnetic resonance imaging (MRI)/magnetic resonance
as the TG13/TG18 criteria without revising setting?”
cholangiopancreatography (MRCP) [5, 22], whereas sim-
At the Updating the Tokyo Guidelines Public Hearing, ple X-rays are not suited to diagnoses. Endoscopic retro-
the majority of attendees (98.6%) agreed that the TG13 grade cholangiopancreatography is performed for the
diagnostic criteria on AC should be adopted as the TG18/ purposes of treatment (drainage), but is not suitable as
TG13 diagnostic criteria on AC (Fig. 1). first choice for diagnostic purposes.
According to the TG18/TG13 diagnostic criteria, a
diagnosis of AC can be made if the patient presents with Q3. What are useful imaging methods for acute
the three pathologies of systemic inflammation (must be cholangitis?
present), cholestasis, and bile duct lesions (from imaging
findings).
Should ultrasound or CT be performed to identify
the cause of acute cholangitis and demonstrate bil-
Systemic inflammation iary stenosis? (Recommendation 1, level D)
In the TG18/TG13 diagnostic criteria for AC, a diagnosis

of AC requires findings of systemic inflammation, based The literature contains no reports on diagnosis of AC
on fever or an elevated inflammatory response (elevated using abdominal ultrasound and only reports on diagnostic
leukocytes, high C-reactive protein). Fever is defined as a capabilities for biliary stenosis/blockage that can cause
temperature of 38°C or above, but mild cases can exhibit AC. Abdominal ultrasound can readily detect abnormal
only minor increases in body temperature. With such dilation of the bile duct and, at the same time, be used to
cases, diagnosis can be made with additional blood test identify the cause (Figs 2, 4a). Bile duct stones present as
findings. However, the potential inability to diagnose mild highly echoic nodular lesions that cast an acoustic sha-
cases has been cited as one of the limitations of the dow, whereas with malignant stenosis of the bile duct, the
TG18/TG13 diagnostic criteria [17]. mass around the stenosed bile duct can be identified as a
normal, low-echo region. According to a meta-analysis by
Abboud et al., abdominal ultrasound has a sensitivity of
Cholestasis 42% (95% CI: 28 to 56%) and a specificity of 96% (95%
CI: 94 to 98%) for dilated common bile duct and a sensi-
Cholestasis is a key clinical feature of AC. Jaundice, one tivity of 38% (95% CI: 27 to 49%) and a specificity of
of the symptoms in Charcot’s triad, is only observed in 100% (95% CI: 99 to 100%) for all bile duct stones.
60 to 70% of patients with AC [9–16]. With the TG18/ These results show that abdominal ultrasound has high
TG13 diagnostic criteria for AC, a diagnosis of AC can specificity but insufficient sensitivity [23]. Another report
still be made in the absence of jaundice, based on elevated on patients with obstructive jaundice where abdominal
alkaline phosphatase (ALP), gamma-glutamyltransferase ultrasound was used to determine the cause [24] showed
(GTP), leucinaminopeptidase and transaminases (aspartate diagnostic sensitivity and specificity of 100% and 89%,
diagnosing local complications (e.g. liver abscess or portal

(a)
vein thrombosis) [27–30] (Figs 6, 7).
MRCP is a non-invasive method that can delineate the
bile duct and is a good option for identifying malignant
disease or bile duct stones causing a biliary obstruction
[31] (Figs 3f, 4d).
In the clinical setting, when a patient presents with
Panc acute abdominal pain, CT is often performed ahead of
abdominal ultrasound as it can image wide areas and is
therefore useful for excluding other diseases. Although
MRI/MRCP are objective imaging methods with sufficient
diagnostic capabilities, they are usually not the first-choice
test method for reasons of availability and convenience.
(b)
Q5. Are MRI/MRCP tests recommended in acute
cholangitis? [Foreground question]
MRI/MRCP are recommended, as they are useful

CBD tumor when diagnosing the cause of acute cholangitis
and evaluating inflammation. (Recommendation 2,
level C)
Because of limited accessibility, MRI/MRCP are gener-

ally only used for imaging when a diagnosis proves diffi-
Fig. 2 Identification of the cause of acute cholangitis by abdominal cult or uncertain with abdominal ultrasound or CT. MRI
ultrasound. (a) Stone in the common bile duct in a patient with acute provides superior contrast resolution and allows the opera-
cholangitis. The stone can be seen as hyperechoic nodule with slight tor to image any cross-section; furthermore, MRCP can
acoustic shadow in the intrapancreatic common bile duct. (b) Cholangitis
clearly delineate the bile duct without the use of a contrast
caused by cancer of the pancreatic head. The bile duct is clearly dilated
and the duct is abruptly blocked by a tumor of the pancreatic head agent. There is no question, therefore, that MRI/MRCP
are useful modalities for biliary diseases [31] (Figs 3c-f,
respectively, for bile duct stones and 98.78% and 83.33%, 4c, d). Calculi can be seen as obvious signal voids in the
respectively, for bile duct cancer. There are various disad- bile that present as a high signal on T2 weighted images
vantages relating to the accuracy of abdominal ultrasound (Figs 3d, e, 4c). Because T1 weighted images can depict
such as the greater likelihood of being affected by techni- calcium bilirubinate stones as high signal intensities, fat-
cian experience and clinical condition of the patient com- suppressed T1 weighted imaging is a useful sequence to
pared to CT scans [25], but abdominal ultrasound should detect microcalculi [32] (Fig. 3c). Research comparing the
be performed initially in patients with suspected AC given diagnostic accuracy of MRI/MRCP, CT, and abdominal
its minimal invasiveness, wide availability, convenience, ultrasound in obstructive jaundice showed MRCP to have
and cost effectiveness. the best diagnostic capabilities, with benign and malignant
Unlike abdominal ultrasound, CT imaging is not disease being identified in 98% and 98% of cases, respec-
affected by intestinal gas and thus can be used to objec- tively, with MRI/MRCP, 82.86% and 91.43% of cases with
tively identify high-attenuated nodules in the bile duct CT, and 88% and 88% of cases with abdominal ultrasound
(Fig. 3a). However, because the CT value of bile duct [33]. Imaging findings with AC include increased signal
stones depends on the amount of calcium phosphate or around the bile duct on T2-weighted images and heteroge-
calcium carbonate in the stones [26], the detection sensi- neous enhancement of the bile duct wall, abscesses, and
tivity of CT is only 25 to 90% [27] (Fig. 4b). CT imaging portal vein thrombosis on contrast enhanced T1-weighted
can clearly identify bile duct dilatation and can contribute images, underlining the utility of this method in the diagno-
to much better diagnoses of the cause of biliary stenosis sis of AC and complications [34]. MRI/MRCP tests are
(e.g. biliary carcinoma, pancreatic cancer, or sclerosing therefore recommended when abdominal ultrasound or CT
cholangitis) (Fig. 5). CT imaging is also useful for imaging do not provide a definite diagnosis.
(a) (b)
(c) (d)
(e) (f)
Fig. 3 Example of non-incarcerated common bile duct stones. (a) Precontrast CT, (b) contrast-enhanced CT, (c) T1-weighted MRI, (d) T2-
weighted MRI single shot fast spin echo (SSFSE), (e) coronal T2-weighted MRI SSFSE, and (f) 3D MRCP images. On the precontrast CT
image (a), in the common bile duct, two high-density nodules (arrow) can be seen, which can be identified as common bile duct stones. On the
contrast-enhanced CT image (b), the opacification of common bile duct stones (arrow) becomes faint due to both the effect of contrast enhance-
ment on the surrounding organs and the different setting of window width and window level. On the T1-weighted MR image (c), a clear area of
hyperintensity is evident (arrow). Because stones appear as signal void on the T2-weighted images, the stones (arrow) in image (d) are clearly
contrasted within the bile duct, which is filled with hyperintense bile. On the coronal T2-weighted MR image (e), two common bile duct stones
can be clearly identified (arrows). On the MRCP image (f), the stones appear as signal voids (arrows). In this patient, the left hepatic duct first
branches to the right of the right hepatic duct, then branches ventrally to the right hepatic duct (anatomical variation). A stone is also present in
the left hepatic duct (arrowhead), and the distal bile duct in the lateral segment is dilated. Note: the asterisk (*) indicates a hepatic cyst
Q8. Are dynamic CT and dynamic MRI imaging meth- Although methods for the direct imaging of AC have
ods useful in the diagnosis of acute cholangitis? yet to be established, research suggests that transient
[Future research question] hyperattenuation differences (THAD) in the hepatic par-
enchyma on early-phase of dynamic CT as well as tran-
sient heterogeneous enhancement in the hepatic
Research suggests that dynamic CT and dynamic parenchyma on early-phase of dynamic MRI may provide
MRI imaging might be useful test methods in the a specific imaging finding for AC [35]. Other recent stud-
diagnosis of acute cholangitis. (Level D) ies have also suggested that THAD may be useful for
severity grading [30, 36, 37].
(a) (b)
CBD
(c) (d)
Fig. 4 Example of non-incarcerated common bile duct stones. (a) Abdominal ultrasound, (b) plain CT, (c) coronal T2-weighted MRI, and (d)
MRCP images. On the B-mode ultrasound image (a), a hyperechoic structure with faint acoustic shadow can be seen (arrow) in the common
bile duct. On the plain CT image (b), any bile duct stones in the common bile duct (arrow) cannot be identified and there is no evidence of
bile duct dilatation (not shown). On the T2-weighted MRI image (c), two hypointense nodules are apparent (arrows) in the common bile duct.
The same common bile duct stones can also be identified (arrows) on the MRCP image (d). No dilation of the upstream bile duct is observed
(a) (b) (c)
Fig. 5 Example of extrahepatic bile duct cancer. (a) Precontrast CT, (b) early-phase of dynamic contrast-enhanced CT, and (c) its coronal
reconstruction images. On the precontrast CT image (a), circumferential thickening of the wall of the upper bile duct is evident (arrow). On
the contrast-enhanced CT image (b), the circumferential thickening of the wall of the upper bile duct is clearly contrasted (arrow). On the
coronal contrast-enhanced CT image (c), thickening of the wall of the upper bile duct is clearly apparent (arrows). Upstream biliary dilatation
is clearly visible (arrowheads). Heterogeneous contrast enhancement of the hepatic parenchyma is also evident (b, c), suggesting that acute
cholangitis has developed as a secondary condition
Transient hyperattenuation differences may be caused shows the transient periductal signal difference, which is
by increased arterial blood flow accompanying biliary nearly equal to THAD on early-phase of dynamic CT, in
inflammation [29]. THAD is hardly seen in healthy indi- a high percentage of patients with AC [34]. Various
viduals (1.78 to 5% of cases), but is seen in 67.9 to studies have suggested that THAD may be useful in the
85% of patients with AC [35, 38] (Figs 8, 9, and Videos diagnosis of AC and also as a predictive factor for
S1, S2). A study has also shown that dynamic MRI severity: one study reported good diagnostic capabilities
(a) (b)
* (c)
Fig. 6 Example of acute cholangitis and hepatic abscess in a patient with a surgical history of duodenal cancer and bile duct reconstruction
(choledochojejunostomy). Early-phase of dynamic CT image series (a), (b), (c) (caudal to cranial). Irregular early enhancement of the hepatic
parenchyma is apparent (arrows). Pneumobilia is evident in the bile duct (arrowheads). A multilocular cyst is in S3 and S5 (asterisks in (b)
and (c)), the walls of which are enhanced. After antibacterial treatment, this lesion disappeared, suggesting a hepatic abscess
Precontrast Early phase Equilibrium phase
(a) (b) (c)
Fig. 7 Example of acute cholangitis with portal vein thrombosis: dynamic contrast-enhanced CT. On the precontrast CT image (a), a faint hyper-
density (arrow) is seen in the umbilical portion of the portal vein. The left branch of the portal vein is not enhanced (arrows in b, c), suggesting
portal vein thrombosis. In the early phase (b), segmental early enhancement is present in the left lobe (inside of the broken lines), but in the equi-
librium phase this is unclear, which is a sign of compensatory increased arterial blood flow associated with reduced portal vein blood flow
for AC using a scoring method based on the degree of imaging analysis study on 123 patients before biliary
THAD spread, bile duct diameter, and presence of occlu- drainage was performed, divided into two groups accord-
sive lesions [36]; another study found correlation ing to whether the patients had AC, reported no relation-
between the degree of THAD spread and C-reactive pro- ship between the degree of THAD and degree of
tein, leukocyte count, and clinical symptoms like abdom- severity [40], which was inconsistent with the other
inal pain and fever [39]; another study demonstrated the reports suggesting usefulness in severity grading. THAD
utility of THAD in differentiating between acute suppu- is observed in a wide range of diseases, including acute
rative cholangitis and acute non-suppurative cholangitis pancreatitis, pyelonephritis, and pneumonia, so this
[30]; and yet another study assessed THAD in 93 AC method may not be expected to be highly specific. As
patients divided into two groups according to whether such, although research suggests that THAD may be use-
overall biliary dilatation was observed – the results ful in the diagnosis of AC, given the current paucity of
showed that the extent of THADs was significantly smal- evidence, further clinical studies are needed to determine
ler in the group without biliary dilatation than in the its usefulness (in the diagnosis and severity assessment
group with biliary dilatation [37]. However, another of AC).
(a) (b)
WW/WL: 350/30 WW/WL: 70/100

(c) (d)
WW/WL: 350/30 WW/WL: 70/100

Fig. 8 Examples of a patient with acute cholangitis (a, b) and healthy individual (c, d). This figure shows early-phase of dynamic contrast-
enhanced CT images under two display conditions. (a) Under the typical conditions, diffuse heterogeneous early enhancement of the liver is
faint. (b) When the settings are changed to lift the window level and narrow the window width, diffuse heterogeneous early enhancement of
the liver becomes clearly apparent. The diffuse heterogeneous early enhancement of the liver in this patient disappeared in the late phase (tran-
sient hepatic attenuation difference: THAD, not shown). Early enhancement of the liver is weaker in the healthy patient (c) compared to a
patient with acute cholangitis (a). Given that no abnormal liver enhancement can be identified in image (d), even at the same window width
and level settings as in (b), we can conclude that THAD is absent. WL window level, WW window width
Severity grading criteria for acute cholangitis Three of the case series studies mentioned above dis-
cuss prognostic factors in the TG13 severity grading crite-
Q9. Are the TG13 severity grading criteria for acute ria. In a large, multicenter case series study on patients
cholangitis useful for clinical practice and appropriate with AC conducted in Japan and Taiwan, application of
as the TG18 criteria? [Foreground question] the TG13 severity grading criteria to the case series
yielded 1,521 patients with Grade III (25.1%), 2,019
patients with Grade II (33.3%), and 2,523 patients with
The TG13 severity grading criteria are recom-
Grade I (41.6%). In patients with a higher severity grad-
mended to be used as the TG18 criteria because
ing, 30-day mortality was significantly higher. However,
patients whose prognosis can potentially be
no correlation between severity grading and 30-day mor-
improved by early biliary drainage can be identi-
tality was observed in patients with AC caused by malig-
fied by using these criteria. (Recommendation
nant tumors [17]. One of the problems with the TG13
1, level D)
severity grading criteria is that the Grade III prognostic
factors are all assigned the same weight, which has
The entire literature on TG13 severity grading criteria resulted in univariate analysis identifying “disturbance of
consisted of four case series studies [17, 18, 41, 42], consciousness” as the most important predictor of risk
again illustrating the paucity of research in this area. [41]. In the multicenter study in Japan and Taiwan, the
The TG13 severity grading criteria for AC are important Grade III prognostic factors (other than hepatic dysfunc-
for predicting prognosis and determining a treatment strategy, tion) shown by multivariate analysis to be significant all
especially identifying patients that require early biliary drainage. had roughly equal weights. For Grade II, white blood cell
Precontrast Early phase Late phase

Before
After
Fig. 9 Images change before and after the onset of acute cholangitis. Before (top row) and after (bottom row) the onset of acute cholangitis.
Biliary dilatation can be identified on both precontrast and contrast-enhanced CT. In early-phase of dynamic contrast-enhanced CT, heteroge-
neous enhancement of the liver is more obvious after the onset of acute cholangitis (center of the bottom row, arrows) compared with before
onset (center of the top row). This enhancement disappeared during the late phase (THAD) (Videos S1, S2)
count abnormalities and hypoalbuminemia have been Only two of the case series studies evaluated the TG13
shown to be significant prognostic factors [17]. In terms severity grading criteria as an indicator for biliary drainage
of predictors of poor outcomes, whereas univariate analy- [17, 42]. In the multicenter case series study performed in
sis has identified renal failure, hepatic dysfunction, intra- Japan and Taiwan, patients were divided into two groups –
hepatic biliary stenosis, AC caused by malignant disease, those treated with early or urgent biliary drainage and those
and hypoalbuminemia as significant predictors of 30-day that were not; the 30-day mortality of the two groups were
mortality, multivariate analysis has identified only intra- compared. No difference was observed between groups for
hepatic biliary stenosis and hypoalbuminemia [18]. As patients with Grade I or Grade III AC; however, 30-day
evidenced by the above, different studies have produced mortality was significantly lower in patients with Grade II
different results related to the weighting of each factor, AC who were treated with early or urgent biliary drainage
with one report even identifying hepatic dysfunction as a (Table 3) [17]. This suggests that the TG13 severity grad-
significant prognostic factor; these varied results have led ing criteria for AC can be used to identify Grade II patients
to inconsistent conclusions. whose prognoses may be improved through biliary
Table 3 Thirty-day mortality rate relevant to the timing of biliary drainage and severity grading by TG13 [17]
Severity grade 30-day mortality according to the timing or absence of biliary drainage
Urgent biliary drainage Urgent or early biliary drainage
Within 24 h After 24 h or P-value Within 48 h After 48 h or P-value
(n = 2,709) absence (n = 3,354) (n = 3,730) absence (n = 2,333)
Grade III (n = 1,521) 5.4% (42/781) 4.9% (36/740) 0.727 4.9% (50/1,017) 5.6% (28/504) 0.622
Grade II (n = 2,019) 1.7% (16/939) 3.4% (37/1,080) <0.05 2.0% (25/1,272) 3.7% (28/747) <0.05
Grade I (n = 2,523) 1.3% (13/989) 1.2% (18/1,534) 0.853 1.1% (16/1,441) 1.4% (15/1,082) 0.586
Total (n = 6,063) 2.6% (71/2,709) 2.7% (91/3,354) 0.873 2.4% (91/3,730) 3.0% (71/2,333) 0.164
Urgent performed on the admission day (within 24 h), early performed on the day following admission (24–48 h)
Table 4 TG18/TG13 severity assessment criteria for acute cholangitis [4]

Grade III (severe) acute cholangitis
“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 dysfunction: hypotension requiring dopamine ≥5 lg/kg per min, or any dose of norepinephrine
2. Neurological dysfunction: disturbance of consciousness
Grade II (moderate) acute cholangitis
“Grade II” acute cholangitis is associated with any two of the following conditions:
1. Abnormal WBC count (>12,000/mm3, <4,000/mm3)
2. High fever (≥39°C)
3. Age (≥75 years old)
4. Hyperbilirubinemia (total bilirubin ≥5 mg/dl)
5. Hypoalbuminemia (<STDa90.7)
Grade I (mild) acute cholangitis
“Grade I” acute cholangitis does not meet the criteria of “Grade III (severe)” or “Grade II (moderate)” acute cholangitis at initial diagnosis.
Early diagnosis, early biliary drainage and/or treatment for etiology, and antimicrobial administration are fundamental treatment for acute
cholangitis classified not only “Grade III (severe)” and “Grade II (moderate)” but also “Grade I (mild)”.
Therefore, it is recommended that patients with acute cholangitis who do not respond to the initial medical treatment (general supportive care
and antimicrobial therapy) undergo early biliary drainage or treatment for etiology (see flowchart).
a
STD: lower limit of normal value
drainage. For Grade III patients, no difference in prognosis requiring early biliary drainage were the most important
was seen even when patients were treated with early or issue discussed when revising and repackaging the TG07
urgent biliary drainage. This study defined urgent drainage guidelines as the TG13 guidelines. For diagnosis and treat-
as being performed within 24 h of admission, whereas the ment of AC patients in the clinical setting, an indicator for
two other studies defined urgent drainage as being per- biliary drainage is more meaningful than a prognostic pre-
formed within 12 h [18, 42]. Given the possibility that the diction. The TG13 severity grading criteria allow assess-
prognosis for Grade III patients may be improved if biliary ment based on clinical signs and symptoms and routine
drainage is performed at an even earlier stage, further blood tests that can be performed and provide results
research is warranted. It has also been suggested that some quickly, are minimally invasive for the patient, and are
of the patients requiring early or urgent drainage might inexpensive. As such, we recommend that the TG13 sever-
have been misclassified as Grade I patients [42]. However, ity grading criteria for AC be adopted as TG18 severity
the study consisted of only a small case series, and it is not grading criteria and used as standard practice in the clini-
clear what types of patients were misclassified in this way. cal setting. Table 4 shows the TG18/TG13 severity grad-
When establishing prognoses using the TG13 severity ing criteria for AC. At the Updating Tokyo Guidelines
grading criteria, there are problems with AC caused by Public Hearing, a majority of attendees (93.7%) agreed
malignant disease, but it can be useful to look at the corre- that the TG13 severity grading criteria should be adopted
lation between severity grading and mortality rates. How- as the TG18/TG13 severity grading criteria (Fig. 10).
ever, different studies have produced varying results in
terms of the weighting of each prognostic factor, including Q10. Is procalcitonin useful for diagnosis and severity
the predictive value of hepatic dysfunction; as such, vari- assessment for acute cholangitis? [Future research
ous issues still need to be resolved. The TG13 criteria are question]
also useful as an indicator for biliary drainage by enabling
the identification of patients requiring early biliary drai- Procalcitonin is suggested as a useful parameter
nage as Grade II. Because Grade II patients have not yet for the severity assessment of acute cholangitis.
progressed to organ dysfunction but are at risk of doing (Level D)
so, the severity grading criteria for Grade II cholangitis
No 6.3%
Hepato-Biliary-Pancreatic Surgery for the article processing
managing office of Tokyo Guidelines 18 to prepare the publication.
We appreciate all secretariats of the Japanese Society of Hepato-
Biliary-Pancreatic Surgery for their technical support.
Conflict of interest Anthony Yuen Bun Teoh has received

consultant fees from Boston Scientific Corporation, USA, Cook
Medical, USA, and Taewoong Medical, Korea.
Appendix: author’s affiliations
Seiki Kiriyama, Department of Gastroenterology, Ogaki

Yes 93.7% Municipal Hospital, Gifu, Japan; Kazuto Kozaka, Depart-
ment of Radiology, Kanazawa University Graduate School
of Medical Sciences, Ishikawa, Japan; Tadahiro Takada,
Fumihiko Miura, and Keita Wada, Department of Surgery,
Fig. 10 Response to the question: “Do you agree with the sugges- Teikyo University School of Medicine, Tokyo, Japan;
tion that TG13 severity grading criteria for acute cholangitis would Steven M. Strasberg, Section of Hepato-Pancreato-Biliary
be adopted as the TG13/TG18 criteria without revising setting?” Surgery, Washington University School of Medicine in St.
Louis, St. Louis, MO, USA; Henry A. Pitt, Lewis Katz
Acute cholangitis occurs when biliary stenosis results School of Medicine at Temple University, Philadelphia,
in bile backing up and becoming infected. This blockage PA, USA; Toshifumi Gabata, Director, Kanazawa Univer-
elevates pressure within the biliary system and results in sity Hospital, Ishikawa, Japan; Jiro Hata, Department of
the infected bile being flushed into systemic circulation, Endoscopy and Ultrasound, Kawasaki Medical School,
inducing a systemic inflammatory response. The patient Okayama, Japan; Kui-Hin Liau, Liau KH Consulting PL,
can develop septicemia if this situation continues. Severe Mt Elizabeth Novena Hospital Singapore and Yong Loo
AC can lead to organ failure due to septicemia; a recent Lin School of Medicine, National University of Singapore,
report has suggested that measurement of serum procalci- Singapore; Akihiko Horiguchi, Department of Gastroen-
tonin, a serum marker for septicemia, can provide a sim- terological Surgery, Fujita Health University School of
pler and faster method to assess the severity of AC. Medicine, Aichi, Japan; Keng-Hao Liu, Tsann-Long
Three case series studies have investigated the relation- Hwang, and Miin-Fu Chen, Division of General Surgery,
ship between serum procalcitonin levels and the severity Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan;
of AC. One study reported significantly higher levels of Cheng-Hsi Su, Department of Surgery, Cheng Hsin General
serum procalcitonin in patients assessed as having severe Hospital, Taipei, Taiwan; Palepu Jagannath, Department of
AC based on the TG07 severity grading criteria [43]. Surgical Oncology, Lilavati Hospital and Research Centre,
Another study reported significantly higher levels in Mumbai, India; Takao Itoi and Shuntaro Mukai, Depart-
patients assessed as having severe AC based on the TG13 ment of Gastroenterology and Hepatology, Tokyo Medical
severity grading criteria compared with patients assessed as University Hospital, Tokyo, Japan; Dirk J. Gouma, Depart-
mild AC [44]. Finally, the third study reported that serum ment of Surgery, Academic Medical Center, Amsterdam,
procalcitonin levels increased with severity based on the The Netherlands; Yasuhisa Mori, Department of Surgery
TG13 guidelines [45]. These results suggest that serum and Oncology, Graduate School of Medical Sciences,
procalcitonin levels are useful when assessing the severity Kyushu University, Fukuoka, Japan; Mariano Eduardo
of AC. However, as this research only includes small-scale Gimenez, Chair of General Surgery and Minimal Invasive
case series studies in single institutions and the current Surgery “Taquini”, University of Buenos Aires, DAICIM
body of evidence remains small, further clinical research is Foundation, Buenos Aires, Argentina; Wayne Shih-Wei
needed to evaluate the usefulness of this method. Huang, Department of Surgery, Show Chwan Memorial
Hospital, Changhua, Taiwan; Myung-Hwan Kim, Depart-
ment of Gastroenterology, University of Ulsan College of
Acknowledgments We express our deep gratitude to the Japanese Medicine, Seoul, Korea; Kohji Okamoto, Department of
Society of Hepato-Biliary-Pancreatic Surgery, the Japanese Society Surgery, Center for Gastroenterology and Liver Disease,
Surgical Infection, the Japan Biliary Association, for their substantial
Kitakyushu City Yahata Hospital, Fukuoka, Japan; Giulio
support and guidance in the preparation of the article. We also Belli, Department of General and HPB Surgery, Loreto
would like to express our deep gratitude to the Japanese Society of Nuovo Hospital, Naples, Italy; Christos Dervenis, First
Department of Surgery, Agia Olga Hospital, Athens, cholangitis: Tokyo Guidelines. J Hepatobiliary Pancreat Surg.
Greece; Angus C. W. Chan, Surgery Centre, Department of 2007;14:52–8.
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Health, Mito Kyodo General Hospital, University of Tsu- iary Pancreat Sci. 2012;19:548–56.
kuba, Ibaraki, Japan; Masahiro Yoshida, Department of 5. Kiriyama S, Takada T, Strasberg SM, Solomkin JS, Mayumi T,
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DOI: 10.1002/jhbp.515
GUIDELINE
Tokyo Guidelines 2018: diagnostic criteria and severity grading of

acute cholecystitis (with videos)
Masamichi Yokoe Jiro Hata Tadahiro Takada Steven M. Strasberg Horacio J. Asbun Go Wakabayashi
Kazuto Kozaka Itaru Endo Daniel J. Deziel Fumihiko Miura Kohji Okamoto Tsann-Long Hwang Wayne
Shih-Wei Huang Chen-Guo Ker Miin-Fu Chen Ho-Seong Han Yoo-Seok Yoon In-Seok Choi Dong-Sup
Yoon Yoshinori Noguchi Satoru Shikata Tomohiko Ukai Ryota Higuchi Toshifumi Gabata Yasuhisa
Mori Yukio Iwashita Taizo Hibi Palepu Jagannath Eduard Jonas Kui-Hin Liau Christos Dervenis Dirk
J. Gouma Daniel Cherqui Giulio Belli O. James Garden Mariano Eduardo Gimenez Eduardo de
Santiba~nes Kenji Suzuki Akiko Umezawa Avinash Nivritti Supe Henry A. Pitt Harjit Singh Angus C. W.
Chan Wan Yee Lau Anthony Yuen Bun Teoh Goro Honda Atsushi Sugioka Koji Asai Harumi Gomi

Takao Itoi Seiki Kiriyama Masahiro Yoshida Toshihiko Mayumi Naoki Matsumura Hiromi Tokumura
Seigo Kitano Koichi Hirata Kazuo Inui Yoshinobu Sumiyama Masakazu Yamamoto

The author’s affiliations are listed Abstract The Tokyo Guidelines 2013 (TG13) for acute cholangitis and cholecystitis
in the Appendix. were globally disseminated and various clinical studies about the management of acute
Correspondence to: Tadahiro cholecystitis were reported by many researchers and clinicians from all over the world.
Takada, Department of Surgery, The 1st edition of the Tokyo Guidelines 2007 (TG07) was revised in 2013. According
Teikyo University School of to that revision, the TG13 diagnostic criteria of acute cholecystitis provided better
Medicine, 2-11-1 Kaga, Itabashi-ku, specificity and higher diagnostic accuracy. Thorough our literature search about
e-mail: t-takada@jshbps.jp diagnostic criteria for acute cholecystitis, new and strong evidence that had been
released from 2013 to 2017 was not found with serious and important issues about
DOI: 10.1002/jhbp.515 using TG13 diagnostic criteria of acute cholecystitis. On the other hand, the TG13
severity grading for acute cholecystitis has been validated in numerous studies. As a
result of these reviews, the TG13 severity grading for acute cholecystitis was
significantly associated with parameters including 30-day overall mortality, length of
hospital stay, conversion rates to open surgery, and medical costs. In terms of severity
assessment, breakthrough and intensive literature for revising severity grading was not
reported. Consequently, TG13 diagnostic criteria and severity grading were judged
from numerous validation studies as useful indicators in clinical practice and adopted
as TG18/TG13 diagnostic criteria and severity grading of acute cholecystitis without
any modification. Free full articles and mobile app of TG18 are available at: http://
www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and
references are also included.
Keywords Acute Cholecystitis Diagnosis Diagnostic imaging Guidelines

Severity of Illness Index
Introduction
The Tokyo Guidelines 2013 (TG13) diagnostic criteria and severity grading of acute
cholecystitis [1] have become widely adopted in recent years, being used not only in
clinical practice but also in numerous research studies on this disease. These diagnostic
criteria and severity gradings of acute cholecystitis constitute the work of revising TG18 can justly be said to be proceed-
guidelines produced on the basis of the consensus achieved ing on the basis of clinical data.
during discussions by global experts at the Tokyo Consensus In the Tokyo Guidelines Revision Committee, we
Meeting held in 2007, and the first version was published as searched for evidence published since TG13, and identified
Tokyo Guidelines 2007 (TG07) [2]. Based on studies that 216 articles related to the diagnostic criteria and severity grad-
have found the lifespan of guidelines to be around 5 years ing of acute cholecystitis, including 19 randomized controlled
[3], the Tokyo Guidelines Revision Committee revised the trials (RCTs). Work on revision began in 2016. Based on
TG07 guidelines in 2013. Validation of the TG07 diagnostic these articles, we found that when considering new evidence
criteria and severity grading of acute cholecystitis had identi- gathered on the TG13 diagnostic criteria and severity grading
fied two issues with the diagnostic criteria in particular: the of acute cholecystitis, such as validation studies, there was
use of two categories for deciding a definitive diagnosis led relatively little evidence concerning diagnostic criteria, with
to ambiguity in clinical practice, and criteria for suspected most validation studies instead being concerned with severity
diagnosis were not specified [4]. That validation study found grading [9–13]. Some studies found that severity grading
that the sensitivity and specificity of a definitive diagnosis plays a useful role in predicting vital prognosis [9], and others
according to TG07 were 84.9% and 50.0%, respectively, that the length of hospitalization and the laparotomy conver-
whereas Murphy’s sign was of 20.5% sensitivity and 87.5% sion rate were significantly higher in more severe cases [10].
specificity. The diagnostic accuracy of the TG07 diagnostic Other studies, however, found that severe cholecystitis may
criteria was thus significantly greater than that of Murphy’s be amenable to surgical treatment, even if percutaneous
sign (P = 1.31 9 10 10). However, the authors pointed out cholecystostomy is not always feasible and open cholecystec-
that further improvement was required in the specificity of tomy may be required [11, 12]. Endo et al. carried out multi-
the diagnostic criteria for definitive diagnosis. Rather than variate analysis of the Japan-Taiwan multicenter cohort study
changing the factors used for assessment, further considera- data and used the results to propose a new treatment strategy
tion of new diagnostic criteria led to the decision to change for Grade III in accordance with TG13 severity grading [14].
the criteria by designating the presence of local signs of Although the prognosis for acute cholecystitis is far from
inflammation and systemic signs of inflammation as indicat- poor, survival prognosis is still determined by severity grad-
ing a suspected diagnosis, and requiring confirmation by ing, and the discussion during the 2007 Tokyo Consensus
imaging findings in addition to these two factors for a defini- Meeting in which it was decided that acute cholecystitis
tive diagnosis. These new diagnostic criteria were validated patients with organ failure affecting survival should therefore
by a multicenter joint study of 451 patients with acute chole- be graded as Grade III (severe), is still a recent memory.
cystitis [5], which found that their use improved sensitivity In these present revisions, in light of the evidence
and specificity to 91.2% and 96.9%, respectively. On the accumulated so far, we report on our investigation of
basis of this result, the diagnostic criteria of TG13 were whether the diagnostic criteria and severity grading should
revised to reflect this new designation. At that point, no be changed for TG18, and if so how. We also provide
major problems with the use of the TG07 severity assessment new information on diagnostic imaging in relation to diag-
criteria in clinical practice had been reported and no new evi- nosis and severity grading.
dence was available; therefore, the severity assessment crite-
ria were adopted unchanged in TG13. However, Takada Q1. Is TG13 diagnostic criteria of acute cholecystitis
et al. expressed concern with the lack of evidence at the time recommended to use as TG18 diagnostic criteria?
that preparations for the publication of TG13 were completed [Foreground question (clinical question)]
[6]. A large-scale epidemiological survey of acute biliary
infection was therefore launched as a Japan-Taiwan Collabo-
The TG13 diagnostic criteria for acute cholecystitis
rative project: Defining the best practice of managing Acute
have high sensitivity and specificity and good
Cholangitis and Cholecystitis since September 2012. This
diagnostic yield; therefore, their use as the TG18
study gathered “big data” from over 7,000 cases. Data from
diagnostic criteria for acute cholecystitis is recom-
over 5,000 patients with acute cholecystitis in that study were
mended. (Recommendation 1, level C)
then used to describe patient characteristics, treatment status,
and the status of use of the TG13 diagnostic criteria and
severity grading in clinical practice, and this was published To date, no diagnostic criteria for acute cholecystitis
as a descriptive study [7]. A large-scale validation of the meriting that title have been established other than TG13
TG13 severity grading of acute cholecystitis was then carried [1]. However, studies of the diagnostic yield of the TG13
out on the basis of those results [8], providing evidence for diagnostic criteria are limited [5, 15, 16].
the current revisions. The inclusion of validation by “big Studies have found that diagnostic accuracy ranges
data” in revision work on guidelines is far from common, but from 94.0% [5] to 60.4% [15] if pathological samples are
used as the gold standard. In the former study, the sensi- Although systematic reviews of the value of PCT for
tivity and specificity of the diagnostic criteria for acute the diagnosis and severity grading of sepsis have been
cholecystitis were 91.2% and 96.9%, compared with published [18, 19], a meta-analysis has found that incon-
83.1% and 37.5% in the latter study. sistencies in study design mean that it is not helpful in
However, the latter study found that neutrophil count was distinguishing between sepsis and non-sepsis [20]. There
the only independent predictor of acute cholecystitis for has been only a single clinical study limited to patients
which a significant difference was evident on the basis of with acute cholecystitis: this study found that it was corre-
multivariate analysis [15]. The use of neutrophil count alone lated with the TG13 severity grading classification [21].
for the definitive diagnosis of acute cholecystitis is unrealis- A number of studies that have collected cases of patients
tic. The World Society of Emergency Surgery guidelines for with acute cholangitis have reported that PCT is correlated
acute calculous cholecystitis, which are restricted to chole- with severity [22–24]. At this point, there is insufficient evi-
cystitis due to calculi, recommend the combined use of clini- dence to investigate the value of PCT measurement in acute
cal, laboratory, and imaging findings for diagnosis, without cholecystitis, and as more evidence must be gathered in
designating new diagnostic criteria [16]. The TG13 diagnos- order for this to be assessed, this issue is therefore desig-
tic criteria for acute cholecystitis constitute exactly this com- nated as a question for future research.
bination, and we considered that they share the same concept
for the designation of diagnostic criteria. A Japanese study of Q3. Is ultrasonography (US) recommended for diag-
the association between diagnostic criteria and factors such nosing acute cholecystitis? [Foreground question (clini-
as length of hospitalization and medical costs found statistical question)]
cally significant differences between definitive and suspected
diagnoses [17], demonstrating the effectiveness of these diag-
Although the diagnostic criteria for the diagnosis
nostic criteria. In light of the results of such validation stud-
of acute cholecystitis by US and its diagnostic yield
ies, we considered that there are no major problems with the
vary in different studies, its low invasiveness, wide-
TG13 diagnostic criteria for acute cholecystitis, and recom-
spread availability, ease of use, and cost-effective-
mend that they be used unchanged as the TG18/TG13 diag-
ness make it recommended as the first-choice
nostic criteria (Table 1).
imaging method for the morphological diagnosis of
Table 1 TG18/TG13 diagnostic criteria for acute cholecystitis acute cholecystitis. (Recommendation 1, level C)
A. Local signs of inflammation etc.
(1) Murphy’s sign, (2) RUQ mass/pain/tenderness
B. Systemic signs of inflammation etc. The use of US in acute cholecystitis has been well
(1) Fever, (2) elevated CRP, (3) elevated WBC count reported, and its ease of use and non-invasive modality
C. Imaging findings have been described in case series studies [15, 25–28].
Imaging findings characteristic of acute cholecystitis However, the diagnostic yield described in those articles
Suspected diagnosis: one item in A + one item in B varies according to the device, assessment criteria, and
Definite diagnosis: one item in A + one item in B + C diagnostic criteria used in each of the studies, all of which
Cited from Yokoe et al. [5]
were of small numbers of patients in single institutions.
The TG13 diagnostic criteria of acute cholecystitis was judged from
All studies that have compared the diagnostic yield of
numerous validation studies as useful indicators in clinical practice hepatobiliary scintigraphy (HIDA scanning) with that of
and adopted as TG18 diagnostic criteria without any modification US have found that the diagnostic yield is higher for
Acute hepatitis, other acute abdominal diseases, and chronic chole- HIDA scanning [26, 27], but diagnostic imaging with US
cystitis should be excluded is nevertheless recommended in three newly proposed
CRP C-reactive protein, RUQ right upper abdominal quadrant, WBC guidelines despite its limited diagnostic yield [16, 29, 30].
white blood cell
US is comparatively inexpensive compared with modali-
ties such as computed tomography (CT) and magnetic reso-
Q2. Is procalcitonin measurement useful for diagnos- nance imaging (MRI), and its non-invasive nature and
ing and severity grading of acute cholecystitis? [Future comparatively high diagnostic yield make it the best option
research question] for the diagnostic imaging of acute cholecystitis [31, 32]: its
rate of use in clinical practice is reported to be 61.3% [7].
Few studies have addressed procalcitonin (PCT) in A meta-analysis comparing methods of diagnostic
acute cholecystitis, and at present its value cannot imaging for acute cholecystitis reported that US has 81%
be assessed. (Level C) sensitivity (95% CI: 0.75–0.87) and 83% specificity (95%
CI: 0.74–0.89) [33] (Fig. 1).
Fig. 1 Forest plot. Paired forest plot of

summary estimates for sensitivity and
specificity. The overall summary
estimates of sensitivity and specificity
for cholescintigraphy, ultrasonography,
and magnetic resonance imaging
(MRI) are plotted in pairs. Error
bars = calculated 95% CIs. (Cited from
Kiewiet et al. [33])
Fig. 2 Typical ultrasound images of

acute cholecystitis. (a) Pericholecystic
fluid. Pericholecystic fluid is
demonstrated to the left side of the
gallbladder. Gallstones and debris are
also seen in the gallbladder. (b) An
intraluminal flap seen in a gangrenous
cholecystitis. A linear echogenic line
representing the intraluminal flap is
demonstrated
(a) (b)
According to the TG13 diagnostic criteria for acute literature relevant to the color Doppler sonography, we
cholecystitis, diagnostic imaging findings are required for were unable to identify any articles concerning the diagno-
a definitive diagnosis, and US is the recommended method sis of acute cholecystitis. None of the literature stated the
of diagnostic imaging (Fig. 2, Video S1). type of device or device settings used (Doppler gain, high-
pass filter, Doppler frequency, or speed range) or described
Q4. Is color or power Doppler sonography useful for diag- patient characteristics (such as body wall thickness), and
nosing acute cholecystitis? [Future research question] evaluation was subjective and qualitative in all cases.
Potential problems include performance bias, detection bias,
and inaccuracy. Thus, the use of color Doppler sonography
No recent studies have found that color or power
for assessment is risky. Insufficient evidence is available to
Doppler sonography is useful for diagnosing acute
consider its value as it cannot be assessed until further evi-
cholecystitis. In terms of the underlying principles,
dence has been gathered. This is regarded as a question for
the evaluation of blood flow by Doppler sonogra-
future research (Fig. 3).
phy is strongly affected by factors such as device
performance and the patient’s body type, which
Q5. Is MRI/magnetic resonance cholangiopancreato-
makes quantification difficult, and the designation
graphy (MRCP) useful for diagnosing acute cholecysti-
of standard levels for use in diagnosis is therefore
tis? [Foreground question (clinical question)]
inappropriate. (Level D)
MRI/MRCP is useful for diagnosing acute chole-

A study of the use of color Doppler sonography in acute cystitis. It is recommended if abdominal US does
cholecystitis found that although it was useful for the diag- not provide a definitive diagnosis. (Recommenda-
nosis of gallbladder adhesions, it was not predictive of the tion 2, level B)
degree of surgical difficulty [34]. In our search of the
(a) (b)
Fig. 3 Typical ultrasound images of acute cholecystitis. (a) Color Doppler images of acute cholecystitis. Increased intraluminal blood flow is
demonstrated. However, it is not always easy to estimate the intraluminal flow since the sensitivity of color Doppler imaging is influenced by
several factors such as the settings of the filter, velocity range, frequency of the ultrasound beam, the patients’ constitutions, and the limita-
tions of the equipment. (b) Superb Microvascular Imaging of acute cholecystitis. Superb Microvascular imaging, which is more sensitive than
the conventional color Doppler in the detection of blood flow, shows the increased intraluminal flow of the gallbladder in a patient with acute
cholecystitis. Still, the same problem as described in the figure legend of (a) remains so it is difficult to make use of these Doppler imagings
as an objective method for the diagnosis of acute cholecystitis
Abdominal US should be the first method of diagnostic and another study also found that abnormal signals in
imaging used for acute cholecystitis. However, as a causa- fatty tissue around the gallbladder on MRI T2-weighted
tive stone in the gallbladder or bile duct may not always imaging had higher specificity compared with CT findings
be clearly identifiable on abdominal US and the diagnosis [41] (Fig. 5). MRCP enables the anatomy of the biliary
of gangrenous cholecystitis may be difficult [35], it is also tract to be visualized without the use of a contrast agent,
recommended that contrast-enhanced CT or MRI be per- and is thus extremely useful. Although MRI/MRCP is
formed if required [36, 37]. expensive [16] compared with abdominal US, which is
The generally accepted imaging findings of acute generally the lowest-cost method of imaging, its diagnos-
cholecystitis are thickening of the gallbladder wall tic yield is somewhat better than that of abdominal US,
(≥4 mm), enlargement of the gallbladder (long axis and its use is therefore recommended when abdominal US
≥8 cm, short axis ≥4 cm), gallstones or retained debris, does not provide a definitive diagnosis. It is noteworthy
fluid accumulation around the gallbladder, and linear that the image quality of MRI/MRCP may be deteriorated
shadows in the fatty tissue around the gallbladder [38]. due to a patient with acute abdominal pain who may not
A 2012 meta-analysis of the MRI diagnosis of acute be able to hold his/her breath or keep his/her at rest.
cholecystitis indicated the value of MRI/MRCP as shown
in Figure 1, with the diagnostic yield of MRI for acute Q6. Is TG13 severity grading of acute cholecystitis rec-
cholecystitis providing 85% sensitivity (95% CI: 0.66– ommended to use as TG18 severity grading? [Fore-
0.95) and 81% specificity (95% CI: 0.69–0.90) [33]. ground question (clinical question)]
However, that meta-analysis was based on three cohort
studies and a cross-sectional study performed around the Grade III (severe) acute cholecystitis in the TG13
turn of the millennium, and the fact that contrast-enhanced severity grading of acute cholecystitis causes systemic
MRI and MRCP were not yet in use at that point must be symptoms due to organ damage and affects survival
taken into account. Even non-contrast MRI/MRCP pro- prognosis. The TG13 severity grading of acute chole-
vides good visualization of thickening of the gallbladder cystitis is recommended for use as the TG18 severity
wall, fluid retention around the gallbladder wall, and grading of acute cholecystitis as a useful indicator
enlargement of the gallbladder, and one study has found from the perspective of predicting prognosis, among
that it is not inferior to contrast-enhanced MRI [39]. The others. (Recommendation 1, level C)
anatomy of the biliary system is easy to assess on MRCP
(by the visualization of accessory hepatic ducts and the
common bile duct), making it useful for preoperative (Addendum: Although moderate acute cholecystitis does
investigation. In terms of differentiation from chronic not result in organ damage, this is still a risk, and as serious
cholecystitis, thickening of the gallbladder wall and dense local complications may also arise, assessment using this
staining of the gallbladder bed in the early phase of con- severity grading may also be used to predict this risk.
trast-enhanced MRI have been found to have 92% speci- Serum total bilirubin level is required to measure in order to
ficity for the diagnosis of acute cholecystitis [40] (Fig. 4), judge predictive factor of acute cholecystitis on flowchart.)
Fig. 4 Typical magnetic resonance

imaging (MRI) of acute cholecystitis
comparing contrast-enhanced computed
tomography (CT). Man in 40s with
acute cholecystitis due to gallstones.
Dynamic contrast-enhanced MRI and
CT are shown. Early phase (a) and
portal venous phase (b) of contrast-
enhanced MRI. Early phase (c) and
portal venous phase (d) of contrast-
enhanced CT. Numerous signal voids
are visible in the gallbladder (a,
arrowhead which indicates the
(a) (b)
gallstones). Clear contrast enhancement
of the gallbladder wall is evident (b,
arrows). This contrast enhancement of
the wall is more clearly visualized on
MRI compared with contrast-enhanced
CT, and gallstone visualization is also
better on MRI than on CT. To identify
gallstone, T2 weighted MRI is also
helpful (image is not shown)
(c) (d)
(a) (b) (c)
Fig. 5 Typical magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP) of acute cholecystitis. Man in
70s with acute cholecystitis due to gallstones. MRI T2 weighted image (ssfse: single shot fast spin echo) (a), diffusion weighted image (b),
and MRCP (c). On T2 weighted image of MRI (a), a hypointense gallstone (a, arrowhead) is visible in the gallbladder. The gallbladder is
enlarged, with thickening of the wall (a, arrow). On diffusion weighted image of MRI (b), thickening of the gallbladder wall (b, arrows) is
clearly evident. The deposition of debris is visualized as a hyperintensity (b, *) at the neck of the gallbladder. On 2D MRCP image (40 mm
slice thickness) (c), the aberrant posterior hepatic duct (c, arrow) is clearly visualize. The asterisk indicates the neck of the gallbladder
Grade III (severe) acute cholecystitis in the TG13 mortality rate for acute cholecystitis is only around 1% [7,
severity grading of acute cholecystitis is described as 42], and some studies, including case series studies, have
acute cholecystitis associated with organ system dysfunc- also failed to find any association between severity grade
tion, which in some circumstances may require treatment and prognosis [12, 43]. Nevertheless, logistic regression
in an intensive care unit [1]. Severe acute cholecystitis is analysis of the prediction of prognosis for acute cholecys-
thus a condition that affects vital prognosis. However, the titis has shown that TG13 severity grading is a factor in
predicting mortality on admission [9]. In a case series Complications are also significantly more common for
study of over 5,000 patients, the prognosis for Grade III patients at higher severity grades [44] (Table 5).
patients was also significantly worse than for Grades I A study of intraoperative bile duct injury also found
and II [8] (Table 2). that complications occurred significantly more often in
The TG13 severity grading is thus well regarded as a higher-grade cases [47]. Postoperative pathological find-
factor predicting vital prognosis. Studies have also found ings of gangrenous cholecystitis and emphysematous
that the length of hospital stay increases significantly for cholecystitis have been found to be more severe in
patients at higher grades according to the TG13 severity higher-grade cases [13]. The only study of medical costs
grading [10–13, 17, 44] (Table 3). so far performed is a Japanese study that found that medi-
Conversion from laparoscopic cholecystectomy to open cal costs are significantly higher in higher-grade cases
surgery has also been found to be significantly more [17].
likely for patients at higher TG13 severity grades [10–13, A German study has proposed a new preoperative scor-
45] (Table 4). ing system for acute cholecystitis [48]. This consists of
In a study in the USA, multivariate analysis showed eight factors identified as independent risk factors by mul-
that TG13 severity grade was an independent predictor of tivariate analysis: sex, age, body mass index (BMI), Amer-
both length of hospital stay and conversion to open sur- ican Society of Anesthesiologists (ASA) score, recurrent
gery [10]. colic, gallbladder wall thickness, white blood cell count
(WBC), and C-reactive protein (CRP) level. These factors
are scored according to a scoring system with a maximum
Table 2 Relationship between severity and 30-day overall mortal- of 9 points, with a score of 7 points or more designated as
itya severe (Grade III). This scoring system has been found to
Severity grading be correlated with operating time, ICU admission, and
length of hospital stay, but is not associated with compli-
Grade I Grade II Grade III P-value
n = 1,339 n = 1,702 n = 680
cations or conversion rate. An Italian group has also
reported diagnostic criteria for severe cholecystitis in
30-day mortality 15 (1.1%) 13 (0.8%) 37 (5.4%) <0.001 which gangrenous cholecystitis and phlegmonous chole-
a
Cited from Yokoe et al. [8] cystitis are designated as severe, consisting of four factors:
Table 3 Length of hospital stay

References Year n Grade I Grade II Grade III P-value
Cheng [44] 2014 103 7.3 3.5 9.2 3.9 15.2 8.5 <0.05
Kamalapurkara [11] 2014 84 5 (4–8) 12 (8–16) <0.001
Wrighta [10] 2015 445 3 (1–16) 4 (1–33) 7 (1–60) <0.001
Ambeb [13] 2015 138 6.0 2.7 7.8 3.3 10.4 6.1 0.02
Amirthalingamc [12] 2016 149 4.46 (2–14) 6.24 (1–41) 9.31 (3–21) <0.001
Hayasaki [17] 2016 171 4.3 2.5 11.0 11.6 20.8 13.5 <0.001
Data are presented as mean days SD
a
Median (range)
b
Postoperative length of hospital stay
c
Median (interquartile range)
Table 4 Conversion rate from laparoscopic cholecystectomy to open surgery

Asai [45] 2014 225 7/105 (6.7%) 22/119 (18.5%) 0/1 (0%) 0.0279
Kamalapurkar [11] 2014 84 1/60 (1.7%) 4/24 (16.7%) 0.006
Wright [10] 2015 445 7/92 (7.0%) 31/121 (25.6%) 9/26 (34.6%) 0.001
Ambe [13] 2015 138 5/79 (6.3%) 5/33 (15.2%) 9/26 (34.6%) 0.001
Amirthalingam [12] 2016 149 2/84 (2.4%) 6/49 (12.2%) 0/16 (0%) 0.03
Table 5 Complications (morbidities)

Cheng [44] 2014 103 3/31 (9.7%) 7/25 (28.0%) 9/20 (45.0%) <0.05
Wright [10] 2015 445 4/137 (2.9%) 6/191 (3.1%) 13/117 (11.1%) 0.003
Ambe [13] 2015 138 7/79 (8.9%) 5/33 (15.2%) 12/26 (46.2%) 0.01
Table 6 Survival analysis of 30-day mortality in patients with Grade III ACa
Survivor (n = 591) Non-survivor (n = 20) Univariate P-value Multivariate P-value Odds ratio (95% CI)
Charlson comorbidity index

0 0–5 304 7 0.148 0.380
1 ≥6 287 13
Jaundice
0 477 9 <0.01 <0.01 6.470 (2.446–17.110)
1 + 114 11
Neurological
0 518 12 <0.01 <0.01 4.346 (1.640–11.515)
1 + 73 8
Respiratory
0 528 13 <0.01 <0.01 5.843 (2.052–16.635)
1 + 63 7
a
Cited from Endo et al. [14]
fever >38°C, distention of gallbladder, wall edema, and cholecystitis on flowchart, serum total bilirubin level is
preoperative adverse events [49]. The authors found that required to measure [50].
when two or more factors were positive this system had The assessment criteria used in the TG13 severity grad-
54.9% sensitivity (95% CI: 44.1–65.2) and 81.2% speci- ing for acute cholecystitis have been validated in numer-
ficity (95% CI: 75.4–85.9), and when three or more factors ous studies, are significantly associated with parameters
were positive it had 15.9% sensitivity (95% CI: 9.5–25.3) including vital prognosis, length of hospital stay, conver-
and 98.6% specificity (95% CI: 95.9–99.5). Neither of the sion to open surgery, and medical costs, and are useful
two newly proposed guidelines indicate criteria for severity indicators in clinical practice. Their use as the TG18/
grading [16, 29]. Studies have found that surgery for TG13 severity assessment criteria is therefore recom-
patients classed as Grade III according to the TG13 sever- mended (Table 7).
ity grading is feasible even if percutaneous cholecystec-
tomy is not always performed, with conversion or subtotal Q7. What method of diagnostic imaging is recom-
cholecystectomy also possible procedures [11, 12]. The mended for diagnosing gangrenous cholecystitis?
TG13 severity grading cannot be used to assess surgical [Foreground question (clinical question)]
difficulty. If a set of severity grading criteria including
such an element of surgical difficulty were to be produced
Contrast-enhanced CT or contrast-enhanced MRI
in future, a large-scale validation study taking account of a
is recommended for diagnosing gangrenous chole-
large number of factors would be required. Rather than
cystitis. (Recommendation 2, level C)
changing the Grade III assessment criteria, it may be possi-
ble to subdivide Grade III cases to enable safe surgery and
select the appropriate treatment strategy. On this point, Gangrenous cholecystitis exhibits specific findings on
Endo et al. used multivariate analysis to investigate predic- dynamic CT, including irregular thickening of the gall-
tive factors in Grade III cases, and showed that factors bladder wall, poor contrast enhancement of the gallbladder
including jaundice, neurological dysfunction, and respira- wall (interrupted rim sign), increased density of fatty tis-
tory dysfunction were associated with vital prognosis [14] sue around the gallbladder, gas in the gallbladder lumen
(Table 6). In order to judge predictive factors of acute or wall, membranous structures within the lumen
Table 7 TG18/TG13 severity grading for acute cholecystitis

Grade III (severe) acute cholecystitis
“Grade III” acute cholecystitis is associated with dysfunction of any one of the following organs/systems:
1. Cardiovascular dysfunction: hypotension requiring treatment with dopamine ≥5 lg/kg per min, or any dose of norepinephrine
2. Neurological dysfunction: decreased level of consciousness
4. Renal dysfunction: oliguria, creatinine >2.0 mg/dl
Grade II (moderate) acute cholecystitis
“Grade II” acute cholecystitis is associated with any one of the following conditions:
1. Elevated WBC count (>18,000/mm3)
2. Palpable tender mass in the right upper abdominal quadrant
3. Duration of complaints >72 ha
4. Marked local inflammation (gangrenous cholecystitis, pericholecystic abscess, hepatic abscess, biliary peritonitis, emphysematous
cholecystitis)
Grade I (mild) acute cholecystitis
“Grade I” acute cholecystitis does not meet the criteria of “Grade III” or “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
Cited from Yokoe et al. [5]: the TG13 severity assessment criteria of acute cholecystitis was judged from numerous validation studies as use-
ful indicators in clinical practice and adopted as TG18severity assessment criteria without any modification. To judge predictive factors of
acute cholecystitis on flowchart in Grade III, serum total bilirubin level is required to measure.
a
Laparoscopic surgery should be performed within 96 h of the onset of acute cholecystitis
(a) (b) (c)
Fig. 6 Typical computed tomography (CT) images of gangrenous cholecystitis. Woman in her 70s with gangrenous cholecystitis (acute acal-
culous cholecystitis). Dynamic contrast-enhanced CT (a, plain; b, early phase; c, equilibrium phase). Enlargement of the gallbladder, thicken-
ing of the gallbladder wall, and edematous lesions beneath the gallbladder serosa are evident on plain CT (arrows). On contrast-enhanced CT
(b,c), irregularity of the gallbladder wall and the partial lack of contrast enhancement can be seen (arrows) as the characteristic appearance of
gangrenous cholecystitis. Transient early-phase staining of the hepatic parenchyma (b) and edematous changes to the hepatoduodenal ligament
(c, arrowhead) are also apparent, suggesting the spread of inflammation
(intraluminal flap or intraluminal membrane), and peri- yield of abdominal US. A retrospective image analysis
gallbladder abscess [51] (Fig. 6). These signs of irregular- study of patients diagnosed with acute cholecystitis also
ity or rupture of the gallbladder wall are often underesti- found that a combination of the perfusion defect of the
mated on abdominal US [35], and studies have found that gallbladder wall and no identifiable calculi had 92% diag-
the presence of the interrupted rim sign on contrast- nostic accuracy, 88.2% sensitivity, and 100% specificity
enhanced CT has 73% sensitivity and 95% negative pre- for the diagnosis of acute gangrenous cholecystitis [52].
dictive value [38] and that the appearance of intraluminal Gangrenous cholecystitis is classed as moderate (Grade
membranous structures on contrast-enhanced MRI has II) acute cholecystitis according to the TG13 severity
80% diagnostic accuracy [52], exceeding the diagnostic grading, and is a serious condition that may cause organ
(ai)
(a)
(b) (c) (d)
Fig. 7 Typical computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI) findings of gangrenous cholecystitis. Man in
his 80s with emphysematous cholecystitis. Chest X-ray (a, inset picture is a magnification of the squared area), plain CT (b), dynamic con-
trast-enhanced CT: early phase (c), equilibrium phase (d). On chest X-ray, abnormal gas is apparent in the right upper abdomen. Gas is pre-
sent both within the gallbladder lumen (ai, *) and the gallbladder wall (ai, arrows). On plain CT, gas is evident both within the gallbladder
wall and the gallbladder lumen. Contrast enhancement is apparent in the wall at the neck of the gallbladder (arrowhead). Inflammation has
spread beneath the duodenal mucosa, and an abscess is also present (*)
damage if its diagnosis is delayed. Abdominal US is gen-

erally the lowest-cost method of imaging, and contrast- CT is recommended for diagnosing emphysema-
enhanced CT and contrast-enhanced MRI are expensive tous cholecystitis. (Recommendation 2, level D)
tests [53]. However, the diagnostic yield of contrast-
enhanced CT and contrast-enhanced MRI is better than Emphysematous cholecystitis is an inflammation
that of abdominal US for gangrenous cholecystitis, and caused by aerogenic bacteria, and has a high perforation
the use of one of these methods is particularly recom- rate. It causes potentially fatal complications including
mended for patients with suspected gangrenous cholecysti- intra-abdominal abscess, generalized peritonitis, gas gan-
tis (Videos S2, S3). grene of the abdominal wall, and sepsis; its clinical
course is often extremely rapid. In TG13 it is classed as
Q8. What method of diagnostic imaging is recom- moderate acute cholecystitis (so-called “marked local
mended for diagnosing emphysematous cholecystitis? inflammation”) [1]. An accurate assessment of the pres-
[Foreground question (clinical question)] ence of gas within the gallbladder wall is important for
the diagnosis of emphysematous cholecystitis, but in We also would like to express our deep gratitude to the Japanese
abdominal US it is very often difficult to distinguish Society of Hepato-Biliary-Pancreatic Surgery for the Article
Processing Managing Office of the Tokyo Guidelines 2018 for
between intramural gas, which appears hyperechoic, and preparing this publication. We appreciate all secretariats of the
porcelain gallbladder. As gas is sometimes found to be Japanese Society of Hepato-Biliary-Pancreatic Surgery for their
present within the gallbladder lumen after biliary surgery technical support.
or sphincterotomy, distinguishing between intraluminal
and intramural gas is important, but this may be diffi- Conflict of interest Anthony Yuen Bun Teoh has received
cult to diagnose correctly on abdominal US. Gas consultant fees from Boston Scientific Corporation, USA, Cook
appears clearly hypodense on CT (usually near the Medical, USA, and Taewoong Medical, Korea. Goro Honda has
1,000 HU), making detection extremely easy [36, 51]. received honoraria from Johnson and Johnson and Medtronic.
Intramural gas is often present also in gangrenous chole-
cystitis [38, 52].
Contrast-enhanced CT should be considered for the Appendix: author’s affiliations
evaluation of complications such as intraperitoneal abscess
and peritonitis. Gas appears as a signal void on MRI [54], Masamichi Yokoe and Yoshinori Noguchi, Department of
however this modality is inferior to CT in terms of spatial General Internal Medicine, Japanese Red Cross Nagoya
resolution for the detection of minute amounts of gas. Daini Hospital, Aichi, Japan; Jiro Hata, Department of
Plain CT is thus the most useful method for diagnosing Endoscopy and Ultrasound, Kawasaki Medical School,
emphysematous cholecystitis (Fig. 7). Okayama, Japan; Tadahiro Takada and Fumihiko Miura,
Department of Surgery, Teikyo University School of Med-
icine, Tokyo, Japan; Steven M. Strasberg, Section of
Results of discussion about the diagnostic criteria and Hepato-Pancreato-Biliary Surgery, Washington University
severity grading for acute cholecystitis at the public School of Medicine in St. Louis, St. Louis, MO, USA;
hearing Horacio J. Asbun, Department of Surgery, Mayo Clinic
College of Medicine, Jacksonville, FL, USA; Go Wak-
In A-PHPBA at Yokohama Congress Center on 9 June abayashi, Department of Surgery, Ageo Central General
2017, a public hearing was held and various opinions Hospital, Saitama, Japan; Kazuto Kozaka, Department of
were gathered about this topic. It was decided that TG13 Radiology, Kanazawa University Graduate School of
diagnostic criteria and severity grading would be adopted Medical Sciences, Ishikawa, Japan; Itaru Endo, Depart-
to TG18 without any modification by final vote (Fig. 8). ment of Gastroenterological Surgery, Yokohama City
University Graduate School of Medicine, Kanagawa,
Japan; Daniel J. Deziel, Department of Surgery, Rush
University Medical Center, Chicago, IL, USA; Kohji Oka-
moto, Department of Surgery, Center for Gastroenterology
10.7% and Liver Disease, Kitakyushu City Yahata Hospital,
Fukuoka, Japan; Tsann-Long Hwang and Miin-Fu Chen,
Division of General Surgery, Linkou Chang Gung Memo-
Yes rial Hospital, Taoyuan, Taiwan; Wayne Shih-Wei Huang,
Department of Surgery, Show Chwan Memorial Hospital,
Changhua, Taiwan; Chen-Guo Ker, Department of Sur-
89.3% No gery, Yuan’s General Hospital, Kaohsiung, Taiwan; Ho-
Seong Han and Yoo-Seok Yoon, Department of Surgery,
Seoul National University Bundang Hospital, Seoul
National University College of Medicine, Seoul, Korea;
In-Seok Choi, Department of Surgery, Konyang Univer-
sity Hospital, Daejeon, Korea; Dong-Sup Yoon, Depart-
Fig. 8 Public hearing final voting outcome
ment of Surgery, Yonsei University Gangnam Severance
Hospital, Seoul, Korea; Satoru Shikata, Director, Mie Pre-
fectural Ichishi Hospital, Mie, Japan; Tomohiko Ukai,
Acknowledgments We express our deep gratitude to the Japanese Department of Family Medicine, Mie Prefectural Ichishi
Society of Hepato-Biliary-Pancreatic Surgery, the Japanese Society
Hospital, Mie, Japan; Ryota Higuchi and Masakazu
Surgical Infection, and the Japan Biliary Association, for their Yamamoto, Department of Surgery, Institute of Gastroen-
substantial support and guidance in the preparation of this article. terology, Tokyo Women’s Medical University, Tokyo,
Japan; Toshifumi Gabata, Director, Kanazawa University Kiriyama, Department of Gastroenterology, Ogaki Munici-
Hospital, Ishikawa, Japan; Yasuhisa Mori, Department of pal Hospital, Gifu, Japan; Masahiro Yoshida, Department
Surgery and Oncology, Graduate School of Medical of Hemodialysis and Surgery, Ichikawa Hospital, Interna-
Sciences, Kyushu University, Fukuoka, Japan; Yukio Iwa- tional University of Health and Welfare, Chiba and
shita, Department of Gastroenterological and Pediatric Department of EBM and Guidelines, Japan Council for
Surgery, Oita University Faculty of Medicine, Oita, Japan; Quality Health Care, Tokyo, Japan; Toshihiko Mayumi,
Taizo Hibi, Department of Surgery, Keio University Department of Emergency Medicine, School of Medicine,
School of Medicine, Tokyo, Japan; Palepu Jagannath, University of Occupational and Environmental Health,
Department of Surgical Oncology, Lilavati Hospital and Fukuoka, Japan; Naoki Matsumura and Hiromi Tokumura,
Research Centre, Mumbai, India; Eduard Jonas, Surgical Department of Surgery, Tohoku Rosai Hospital, Miyagi,
Gastroenterology/Hepatopancreatobiliary Unit, University Japan; Seigo Kitano, President, Oita University, Oita,
of Cape Town and Groote Schuur Hospital, Cape Town, Japan; Koichi Hirata, Department of Surgery, JR Sapporo
South Africa; Kui-Hin Liau, Liau KH Consulting PL, Mt Hospital, Hokkaido, Japan; Kazuo Inui, Department of
Elizabeth Novena Hospital, Singapore and Yong Loo Lin Gastroenterology, Second Teaching Hospital, Fujita
School of Medicine, National University of Singapore, Health University, Aichi, Japan; Yoshinobu Sumiyama,
Singapore; Christos Dervenis, First Department of Sur- Director, Toho University, Tokyo, Japan.
gery, Agia Olga Hospital, Athens, Greece; Dirk J. Gouma,
Department of Surgery, Academic Medical Center, Ams-
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Guideline
Accepted Article
Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and
cholecystitis
Harumi Gomi, Joseph S. Solomkin, David Schlossberg, Kohji Okamoto, Tadahiro Takada, Steven M.
Strasberg, Tomohiko Ukai, Itaru Endo, Yukio Iwashita, Taizo Hibi, Henry A. Pitt, Naohisa Matsunaga,
Yoriyuki Takamori, Akiko Umezawa, Koji Asai, Kenji Suzuki, Ho-Seong Han, Tsann-Long Hwang,
Yasuhisa Mori, Yoo-Seok Yoon, Wayne Shih-Wei Huang, Giulio Belli, Christos Dervenis, Masamichi
Yokoe, Seiki Kiriyama, Takao Itoi, Palepu Jagannath, O. James Garden, Fumihiko Miura, Eduardo de
Santibañes, Satoru Shikata, Yoshinori Noguchi, Keita Wada, Goro Honda, Avinash Nivritti Supe, Masahiro
Yoshida, Toshihiko Mayumi, Dirk J. Gouma, Daniel J. Deziel, Kui-Hin Liau, Miin-Fu Chen, Keng-Hao
Liu, Cheng-Hsi Su, Angus C. W. Chan, Dong-Sup Yoon, In-Seok Choi, Eduard Jonas, Xiao-Ping Chen,
Sheung Tat Fan, Chen-Guo Ker, Mariano Eduardo Giménez, Seigo Kitano, Masafumi Inomata, Shuntaro
Mukai, Ryota Higuchi, Koichi Hirata, Kazuo Inui, Yoshinobu Sumiyama, Masakazu Yamamoto
Tadahiro Takada, M.D., Ph.D., Department of Surgery, Teikyo University School of Medicine, 2-11-1
Kaga, Itabashi-ku, Tokyo 173-8605, Japan
Email: t-takada@jshbps.jp
Keywords: Acute cholangitis, acute cholecystitis, biliary tract infection, antimicrobial therapy, treatment
guidelines
Abstract
Antimicrobial therapy is a mainstay of the management for patients with acute cholangitis and/or
cholecystitis. Tokyo Guidelines 2018 (TG 18) provides recommendations for the appropriate for use of
antimicrobials for community-acquired and healthcare-associated infections. The listed agents are for
empirical therapy) provided before the infecting isolates are identified. Antimicrobial agents are listed by
class-definitions and TG 18 Severity Grade I, II, and III subcategorized by clinical settings. In the era of
emerging and increasing antimicrobial resistance, monitoring and updating local antibiograms is
underscored. Prudent antimicrobial usage and early de-escalation or termination of antimicrobial therapy
are now important parts of decision-making. What is new in TG 18 is that the duration of antimicrobial
therapy for both acute cholangitis and cholecystitis is systematically reviewed. Prophylactic antimicrobial
usage for elective endoscopic retrograde cholangiopancreatography (ERCP) is no more recommended and
the section was deleted in TG 18.
doi: 10.1002/jhbp.518
Introduction
TG 13 Antimicrobial therapy for acute cholangitis and cholecystitis, International practice guidelines for
Accepted Article
the management of patients with acute cholangitis and cholecystitis (Tokyo Guidelines 2013) [1] have been
reviewed and revised along with other parts of the therapy for the patients with acute cholangitis and
cholecystitis [2-6]. This paper provides Tokyo Guidelines 2018 (TG 18) Antimicrobial therapy for acute
cholangitis and cholecystitis.
In the TG 18 guidelines, empiric therapy is defined as antimicrobial therapy until the cultures
and susceptibility testing results are available. Once causative microorganisms and the susceptibility
testing results are available, antimicrobial therapy should be adjusted to specific antimicrobial agents
targeting the organisms. This process is defined as de-escalation of antimicrobial therapy in the TG 18
guidelines [7].
Role of antimicrobial therapy
Acute cholangitis and cholecystitis are still fatal diseases if not appropriately treated in a timely fashion. In
previous guidelines (TG13), we defined a severity grading system. A recent large scale study indicated the
morality rate (30-day all-cause mortality rate) of 2.4%, 4.7%, 8.4% by TG 13 Severity Grade I, II, and, III,
respectively [8]. For patients with septic shock, appropriate antimicrobial therapy should be administered
within an hour [7]. For other, less acutely ill patients, therapy should be administered within six hours of
diagnosis. The primary goal of antimicrobial therapy in acute cholangitis and cholecystitis is to limit both
the systemic septic response and local inflammation, to prevent surgical site infections in the superficial
wound, fascia, or organ space, and to prevent intrahepatic abscess formation [9].
While drainage of the obstructed biliary trees (termed source control) has been recognized as the
mainstay of the therapy for patients with acute cholangitis [9], the roles of antimicrobial therapy for acute
cholangitis is to allow patients to have elective drainage procedures other than emergency [10]. Boey and
Way retrospectively reviewed 99 consecutive patients with acute cholangitis, and reported that 53% of
their patients who responded well to antimicrobial therapy were therefore provided elective instead of
emergency operation [9-10].

For acute cholecystitis, the role of antimicrobial therapy varies depending on the severity and
pathology. In early and non-severe cases (or patients with acute cholecystitis of TG 18 Severity Grade I
Accepted Article
[11]), it is not obvious that bacteria play a significant role in the pathology encountered. In these patients,
antimicrobial therapy is at best prophylactic, preventing progression to infection. In more progressed,
moderately severe or severe cases, with clinical findings of a systemic inflammatory response,
antimicrobial therapy is therapeutic, and antimicrobial therapy may be required until the gallbladder is
removed [12].
Decision process
A systematic literature review was performed using PubMed and Cochrane Clinical Controlled Trials
(CCT) and Cochrane Database of Systematic Reviews (CDSR) from January 1, 2010 to December 16,
2016. All references were searched with the keywords “Acute cholangitis” AND “Antibiotics OR
Antimicrobial therapy,” and “Acute cholecystitis” AND “Antibiotics OR Antimicrobial therapy” among
human studies. These references were further narrowed using “Clinical trials” and “Randomized trials.”
Literature cited in the TG 07 [13, 14] and TG 13 [1] was also reviewed and integrated for revision. In
making recommendations, a consensus process utilizing the GRADE systems [15, 16] was used by the
members of the Tokyo Guidelines Revision Committee. GRADE stands for Grades of Recommendation
Assessment, Development, and Evaluation. In the TG 18 guidelines, the strength of the recommendation
was graded as 1(strong) or 2(weak). The quality of the evidence was graded as high (level A), moderate
(level B), low (level C), and very low (level D). Newly identified literatures cited in the TG 18 were
mentioned in the clinical question sections.
Microbiology of acute cholangitis and cholecystitis
The bacteria commonly found in biliary tract infections are well known, and are presented in Tables 1 and
2 [8, 13, 14, 17-29], A large scale multicenter international observational study was conducted and
published in 2017 on epidemiology and microbiology among patients with acute cholangitis [8] . In this
study, the most frequently isolated organisms were Escherichia coli across the Severity Grades of Tokyo
Guidelines 2013 (TG 13) [30].

Local prevalence of extended-spectrum beta-lactamase and carbapenemase producing Gram negative
bacilli
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Antimicrobial therapy largely depends on local antimicrobial susceptibility data. The emergence
of antimicrobial resistance among clinical isolates of Enterobacteriaceae from patients with
community-acquired intra-abdominal infections has been widely reported [29, 31-37]. Especially,
Extended-spectrum beta-lactamases (ESBL) and carbapenemases (i.e., metallo-beta-lactamase and
non-metallo beta-lactamase) producing bacilli reported [38-42] have been significantly affecting the
selection of empirical therapy for patients with intra-abdominal infections, including acute cholangitis and
cholecystitis [43].
In selecting empirical antimicrobial therapy, special attention should be paid to the incidence of
extended spectrum beta-lactamase (ESBL) and carbapenemase-producing bacteria in non-urinary tract
isolates. A prospective cohort study in patients with acute cholecystitis involving 116 institutions
worldwide showed that among 96 isolated E. coli, 16 (16.7%) were producing ESBL [44]. However, the
proportion of ESBL producing E. coli varies widely region to region: 31.2 % in two German university
hospitals [45], 70.0 % in Korean university medical center [46] and 66% in Indian medical college hospital
[47]. There are few reports about the prevalence of Carbapenem resistant bacteria specifically among
patients with acute cholangitis and cholecystitis. One from Korea reported 13 out of 376 (3.5%) isolates in
bile were Carbapenemase producing [48].
In Tokyo Guideline 2018, the international practice guidelines for acute cholangitis and
cholecystitis (TG 18), agents appropriate for use are provide in the Table 3 by antimicrobial class-based
definitions. Table 3 has been re-evaluated with systematic literature review and Tokyo Guidelines Revision
Committee. There was no new significant evidence to modify the list of the agents. Therefore, Table 3 has
been endorsed from TG 13, Table 3 [1]. Table 3 lists antimicrobial agents appropriate for use for the
treatment of patients with both community-acquired and healthcare-associated cholangitis and
cholecystitis.

Monitoring and updating local antibiograms are critical to provide effective therapy in a timely
fashion in the clinical setting. We recommend that microbiology laboratories report resistance data by site
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of infection, and include biliary infections with other intra-abdominal infections. We also recommend
empiric therapy for resistant isolates if they occur in more than 20% of patients [49].
In particular, ampicillin/sulbactam can be used as initial therapy if the susceptibility remains over
80% in the local area. However, in many places of the world, its susceptibility has been reported
decreasing. Ampicililn/sulbactam can be used once its susceptibility is known as definitive or targeted
therapy.
Clinical questions
Clinically relevant questions are provided with brief answers and explanations below.
Questions 1 and 2, and their answers and explanations have been endorsed from TG 13 Q1 and Q2 [1].
Q1. What specimen should be sent for culture to identify the causative organisms in acute cholangitis
and cholecystitis?
(Bile cultures)
Bile cultures should be obtained at the beginning of any procedure performed. Gallbladder bile should be
sent for culture in all cases of acute cholecystitis excepting those with grade I severity （recommendation 1,
level C）.
We suggest cultures of bile and tissue when perforation, emphysematous changes, or necrosis of
gallbladder are noted during cholecystectomy (recommendation 2, level D).
(Blood cultures)
Blood cultures are not routinely recommended for grade I community-acquired acute cholecystitis
(recommendation 2, level D).
Identifying the causative organism(s) is an essential step for the management of acute biliary infections.
Positive rates of bile cultures range from 28 to 93% for acute cholangitis [8, 13-24] and positive rates of
either bile or gallbladder cultures range from 29 to 54% for acute cholecystitis [13-24]. In a recent study,
which utilized the TG 07 diagnostic classification, positive rates of bile cultures among patients with

cholangitis were 67% (66 of 98 patients) and 33% (32 of 98) without[24]. Table 1 demonstrates common
microbial isolates from bile cultures among patients with acute biliary infections [8, 13-24].Common duct
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bile should be sent in all cases of suspected cholangitis.
On the other hand, previous studies indicated that positive rates of blood cultures among patients
with acute cholangitis ranged from 21 to 71% [13]. A recent multicenter study of patients with acute
cholangitis showed the proportions of positive blood cultures were 15.2%, 21%, and 25.7% by TG 13
Severity Grade I, II, III, respectively [7]. For acute cholecystitis, the prevalence of positive blood cultures
is less than acute cholangitis, and in the last two decades it has been reported ranging from 7.7% to
15.8%.[25,28] Table 2 demonstrates the most recently reported microbial isolates from patients with
bacteremic biliary tract infections [8, 25-27, 29].
There is a lack of clinical trials examining the benefit of blood cultures in patients with acute
biliary tract infections. On the other hand, there is an argument that every opportunity should be utilized to
identify microorganisms and susceptibility testing in the era of antimicrobial resistance [45].
Most of the bacteremic isolates reported (Table 2) are organisms that do not form vegetations on
normal cardiac valves nor military abscesses [8]. Their intravascular presence does not lead to an extension
of therapy or selection of multi-drug regimens. We therefore recommend such cultures be taken only in
high severity infections when such results might mandate changes in therapy [3-4, 7]. Blood cultures are
not routinely recommended for grade I community-acquired acute cholecystitis.
The SIS-NA/IDSA 2010 guidelines recommended against routine blood cultures for community
acquired intra-abdominal infections since the results do not change the management and outcomes [49].
This recommendation is carried forward in recent guidelines [43]. This is in part driven by a study of the
clinical impact of blood cultures taken in the emergency department [51]. In this retrospective study, 1,062
blood cultures were obtained during the study period. Among them, 92 (9%) were positive. Of the positive
blood cultures, 52 (5%) were true positive, and only 18 (1.6%) resulted in altered management.

Q2. What considerations should be taken when selecting antimicrobial agents for the treatment of
acute cholangitis and cholecystitis?

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When selecting antimicrobial agents, targeted organisms, pharmacokinetics and
pharmacodynamics, local antibiogram, a history of antimicrobial usage, renal and hepatic
function, and a history of allergies and other adverse events should be considered
(recommendation 1, level D). We suggest anaerobic therapy if a biliary-enteric anastomosis is
present (recommendation 2, level C).
There are multiple factors to consider in selecting empiric antimicrobial agents. These include targeted
organisms, local epidemiology and susceptibility data (antibiogram), alignment of in-vitro activity (or
spectrum) of the agents with these local data, characteristics of the agents such as pharmacokinetics and
pharmacodynamics, and toxicities, renal and hepatic function, and any history of allergies and other
adverse events with antimicrobial agents[13-14, 17-24]. A history of antimicrobial usage is important
because recent (< 6 months) antimicrobial therapy greatly increases the risk of resistance among isolated
organisms.
Renal function should be estimated before dosing antimicrobial agents with the commonly used
equation: Serum creatinine = (140-age) (optimum body weight (kg))/72 x serum creatinine (mg/dl) [13-14,
52] Individual dosage adjustments for altered renal and hepatic function is available in several recent
publications [53-54]. Consultation with a clinical pharmacist is recommended if there are concerns.
Regarding the timing of therapy, therapy should be initiated as soon as the diagnosis of biliary
infection is suspected. For patients in septic shock, antimicrobials should be administered within one hour
of recognition [7]. For other patients, as long as six hours may be spent obtaining definitive diagnostic
studies prior to beginning antimicrobial therapy. Antimicrobial therapy should definitely be started before
any procedure, either percutaneous, endoscopic, or operative, is performed. In addition, anaerobic therapy
is appropriate if a biliary-enteric anastomosis is present [49].

Antimicrobial agents appropriate for use in the management of community-acquired acute
cholangitis and cholecystitis

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Table 3 summarizes antimicrobial recommendations [1]. It should be kept in mind that in the treatment of
cholangitis, source control, (i.e., drainage) is an essential part of management. The indications and timing
for drainage are provided in the severity and flowchart of the management sections regarding acute
cholangitis [2-6]. There have been multiple reports on clinical isolates with multiple drug resistance from
intra-abdominal infections worldwide, and biliary infections in particular [29, 31-37, 55] .
Recommendations for antimicrobial therapy are based primarily upon extrapolations of
microbiologic efficacy and behavior of these agents against the more susceptible isolates treated in the
cited clinical trials [56-66]. Some concerns about this approach to defining efficacy against resistant
isolates has been raised [67].
The use of severity of illness as a guide to antimicrobial agent selection has been questioned in
the face of the increasing numbers of ESBL-producing E. coli and Klebsiella in the community. These
organisms are not reliably susceptible to cephalosporins, penicillin derivatives, or fluoroquinolones.
Previous guidelines have recommended that if more than 10-20% of community isolates of E. coli are so
resistant, than empiric coverage should be provided for these organisms until susceptibility data
demonstrates sensitivity to narrower spectrum agents [49]. Carbapenems, piperacillin/tazobactam,
tigecycline, amikacin, and other newer agents such as ceftazidime/avibactum and ceftolozane/tazobactam
may also be used to treat these isolates.
For grade III community-acquired acute cholangitis and cholecystitis, as initial therapy
(empirical therapy), agents with anti-pseudomonal activities are recommended until causative organisms
are identified. Pseudomonas aeruginosa is present in approximately 20% of previous series [24, 29].
However, recent large scale data showed very few ranging from 1.1% to 3.1% among isolates from blood
cultures and 2.5% to 3.6% from bile cultures obtained from patients with acute cholangitis, respectively [8].
P. aeruginosa is a known virulent pathogen and failure to empirically cover this organism in critically ill
patients may result in excess mortality.

Enterococcus spp. is another important pathogen for consideration in patients with grade III
community-acquired acute cholangitis and cholecystitis. Vancomycin is recommended to cover

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Enterococcus spp. for patients with grade III community-acquired acute cholangitis and/or cholecystitis,
until the results of cultures are available. Ampicillin can be used if isolated strains of Enterococcus spp. are
susceptible to ampicillin. Ampicillin covers most of the strains of Enterococcus faecalis from
community-acquired infections in general. For Enterococcus faecium, vancomycin is the drug of choice for
empirical therapy. However, in many hospitals, vancomycin-resistant Enterococcus spp., both E. faecium
and E. faecalis, have emerged as important causes of infection. Treatment for these organisms requires
either linezolid or daptomycin. Surgeons and other physicians making treatment decisions for patients with
healthcare-associated infections should be aware of the frequency of these isolates in their hospital and unit.
Then regarding infrequently isolated anaerobes such as Bacteroides fragilis group, we suggest to cover
these organisms empirically when a biliary-enteric anastomosis is present [49].
For grade I and II community-acquired cholangitis and cholecystitis, Table 3 provide the agents
appropriate for use. Clindamycin resistance among Bacteroides spp. is significant and the use of
clindamycin is no longer recommended in other intra-abdominal infections [49]. Cefoxitin, cefmetazole,
flomoxef, and cefoperazone/sulbactam are the agents in cephalosporins that have activities against
Bacteroides spp. Cefoxitin is no longer recommended by the SIS-NA/IDSA 2010 guidelines due to high
prevalence of resistance among Bacteroides spp.[49]. Local availability of agents as well as local
susceptibility results are emphasized when choosing empirical therapy.
Table 4 summarizes antimicrobial agents with high prevalence of resistance among
Enterobacteriaceae [29, 31-37]. Ampicillin/sulbactam is one of the most frequently used agents for
intra-abdominal infections. Nonetheless, the activity of ampicillin/sulbactam against E. coli, with or
without ESBLs, has fallen to levels that prevent a recommendation for its use.
In the TG 18, ampicillin/sulbactam is not recommended as empirical therapy if the local
susceptibility is <80%. It is reasonable to use ampicillin/sulbactam as definitive therapy when the
susceptibility of this agent is proven. Ampicillin/sulbactam may be used if susceptibility testing results are
available.

Fluoroquinolone use is only recommended if the susceptibility of cultured isolates is known
since antimicrobial resistance has been increasing significantly [29, 31-37]. This agent can also be used as
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an alternative agent for patients with -lactam allergies.
Antimicrobial agents appropriate for use in the management of healthcare-associated acute
cholangitis and cholecystitis
Since 2010, there have been very few clinical studies on antimicrobial therapy for patients with
healthcare-associated acute cholangitis and cholecystitis.
There is no evidence to support any agent as optimal treatment of healthcare-associated acute cholangitis
and cholecystitis. The principles of empirical therapy of healthcare-associated infections include using
agents with anti-pseudomonal activity until definitive causative organisms are found.
The local prevalence of ESBL and/or carbapenemase producing Enterobacteriacea is critical information in
selecting empirical agents. Optimal agents vary from institution to institution. Therefore it is underscored
that local susceptibility should be monitored strictly and periodically.
Multi-disciplinary approach would be beneficial to provide and discuss appropriate antimicrobial agents in
the institution, region, and country.
Table 3 provides empirical agents (presumptive therapy) for healthcare-associated acute
cholangitis and cholecystitis. Vancomycin is recommended when patients are colonized with resistant gram
positive bacteria such as methicillin-resistant Staphylococcus aureus and/or Enterococcus spp. or these
multi-drug resistant gram positives are of concern. Staphylococcus aureus is not as a common isolate for
acute biliary infections as Enterococcus spp. In recent study, Staphylococcus aureus was isolated less than
1% both from blood and bile for patients with acute cholangitis [8].
Vancomycin resistant Enterococcus (VRE) should be covered empirically with linezolid or
daptomycin if this organism is known to be colonizing the patient, if previous treatment included
vancomycin, and/or if the organism is common in the community.
Isolation of Bacteroides fragilis group was 1.1% from blood cultures, and 1.6% from bile
cultures among patients with acute cholangitis [8]. For empirical therapy for anaerobes such as Bacteroides
fragilis group, we suggest to cover these organisms empirically in the presence of a biliary-enteric
anastomosis [49].

Is it necessary for agents used in acute biliary infections to be concentrated in bile?
Historically, biliary penetration of agents has been considered in the selection of antimicrobial agents.
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However, there is considerable laboratory and clinical evidence that as obstruction occurs, secretion of
antimicrobial agents into bile stops [10]. Recent international guidelines for acute calculous cholecystitis
summarized the bile to serum concentration ratio and recommend to select agents with good infected sites
penetration [50]. Well-designed randomized clinical trials comparing agents with or without good biliary
penetration are needed to determine the clinical relevance and significance of biliary penetration in treating
acute biliary infections.
How should highly resistant causative organisms be managed in treating acute cholangitis and
cholecystitis?
ESBL-producing E. coli is highly susceptible to carbapenems and to tigecycline. In multiple areas of the
world, highly resistant Klebsiella spp. and E. coli with carbapenemases are seen [67-70]. The widely
accepted rule for empirical therapy is that resistant organisms occurring in more than 10-20% of patients
should be treated. Colistin is the salvage agent for the above multi-drug resistant gram negative bacilli
epidemic strains [55, 70]. This agent is toxic, dosing is uncertain, and its use should involve consultation
with infectious disease specialists [55]. Newer agents such as ceftazidime/avibactam and
ceftolozane/tazobactam has limited evidence for use among patients with acute cholangitis and
cholecystitis.
In TG 18, endorsed from TG 13 [1], carbapenems, piperacillin/tazobactam, and ceftazidime or
cefepime, each combined with metronidazole have been recommended when the prevalence of resistant
Pseudomonas aeruginosa, ESBL-producing Enterobacteriaceae, Acinetobacter or other multidrug-resistant
gram negative bacilli is less than 20% [49]. For ESBL-producing Enterobacteriaceae, carbapenems,
piperacillin/tazobactam, and aminoglycosides are recommended. For Pseudomonas aeruginosa, if the
prevalence of resistance to ceftazidime is more than 20%, carbapenems, piperacillin/tazobactam, and
aminoglycosides are empirically recommended until culture and susceptibility testing results are available.

Q 3. What is the optimal duration and route of antimicrobial therapy for patients with acute
cholangitis?
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・Once the source of infection is controlled, antimicrobial therapy for patients with acute
cholangitis is recommended for the duration of 4 to 7 days. (recommendation 1, level C).
Listerature was searched using PubMed an Cochrane library using the key words of (acute cholangitis* OR
acute biliary tract infections*) AND (antimicrobial therapy* OR antibiotics*) AND duration of therapy.*
Mesh was also used for each word. There were a total of 151
There were a total of 151 articles by PubMed, 16 by Cochrane Controlled Clinical Trials (CCT), and 1 by
Cochrane Clinical Database of Systematic Reviews (CDSR). Among them, selection criteria were either
randomized studies or observational studies. The articles met the selection criteria were screened initially
by title, then if it was difficult to judge it, the abstract was also reviewed. As a result, there were four
relevant articles found.
Uno et al. [71] compared retrospectively the outcomes among patients with bacteremic acute cholangitis
due to Gram negative bacilli who received antimicrobial therapy either 14 or 10 days. There were no
differences between the two groups in 30-day mortality and recurrence rate within three months. There
were statistically significant differences in the lengths of stay (17.5 days vs. 14 days, p < 0.01). van Lent et

al. [72] reported that in their single institution, there were no difference in the recurrence rate for acute
cholangitis between the patients who received less than three-day therapy vs. more than five-day therapy
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once the source of infection was controlled among patients with acute cholangitis. Kogure et al.[73]
conducted a prospective observational study to investigate how long antimicrobial therapy should be
administered for patients with acute cholangitis after successful biliary drainage. In this study, 18 patients
were analyzed for recurrent cholangitis within 3 days after discontinuing antimicrobial therapy. There were
no recurrence noted. Park et al. [74] conducted a randomized study to compare the recurrence rate and
30-day mortality among patients with bacteremic cholangitis due to ciprofloxacin-susceptible
Enterobacteriacae who underwent successful biliary drainage and received either conventional intravenous
therapy or 6 day intravenous antimicrobial therapy followed by oral therapy. In this study, there were no
differences between the two groups in the recurrence of cholangitis and 30-day mortality. In the TG 18, the
duration of therapy for patients with acute cholangitis is for 4 to 7 days once the source of infection is
controlled by integrating the above studies and expert opinion (Table 5). When bacteremia with gram
positive bacteria such as Enterococcus spp. and Streptococcus spp. is present, it is prudent to offer
antimicrobial therapy for two weeks since these organisms are well-known to cause infective endocarditis.
The incidence of endocarditis among patients with acute cholangitis has been reported 17 (0.3%) out of
6,147 patients with acute cholangitis [8].
In June 2017, the 6th Asian Pacific Hepatobiliary Pancreatic Surgery Conference was held and a clinical
question was asked among the expert panel, with successful biliary drainage, how long would you
administer antimicrobial therapy for patients with bacteremic acute cholangitis due to Gram positive cocci?
Five answers were provided, such as A: 14 days, B: 10 days, C: 7 days, D: 4-5 days, and E: 3 days or less.
The answers were as follows. A 9%, B 3.8%, C 26.9%, D 32.1%, and E 26.9%.

Q4. What is the optimal duration of antimicrobial therapy for patients with acute cholecystitis?
・Antimicrobial therapy for patients with Grade I and II acute cholecystitis is recommended only
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before and at the time of surgery. (recommendation 1, level B).
・Once the source of infection is controlled, antimicrobial therapy for patients with Grade III acute
cholecystitis is recommended for the duration of 4 to 7 days.
Listerature was searched using PubMed an Cochrane library using the key words of (acute cholecystitis*
OR acute biliary tract infections*) AND (antimicrobial therapy* OR antibiotics*) AND duration of
therapy.* Mesh was also used for each word. There were a total of 83
There were a total of 51 articles by PubMed, 21 by Cochrane Controlled Clinical Trials (CCT), and 1 by
Cochrane Clinical Database of Systematic Reviews (CDSR). Among them, selection criteria were either
randomized studies or observational studies. The articles met the selection criteria were screened initially
by title, then if it was difficult to judge it, the abstract was also reviewed. As a
result, there were four relevant articles found such as three randomized controlled studies (RCT) [75-77]
and one observational study [78].
TG 13 [1] and SIS-IDSA 2010 [49] recommended postoperative antimicrobial therapy for
different durations, ranging from 24 hours to 7 days depending on the severity of cholecystitis given the
lack of high-quality evidence. Recently, two RCTs assessing the non-inferiority of no postoperative
antimicrobial therapy with postoperative antimicrobial therapy for patients with mild or moderate acute
cholecystitis who underwent early cholecystectomy were conducted [75-76]. Although non-inferiority was
not proven in both RCTs, there was not clinically significant difference. The results of the two RCTs were

integrated and the risk difference for postoperative infection was 0.01 (95% CI, -0.04 – 0.06) (Figure 1).
Considering the disadvantages of extended antimicrobial therapy, including increased medical costs,
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prolonged hospital stay, and increased bacterial resistance, the antimicrobial therapy should be limited to
before and at the time of surgery for Grade I and II acute cholecystitis. Some patients would need extended
postoperative antibiotics depending on their condition.
For Grade III acute cholecystitis, there are scarce data available. Hence, we suggest the expert
opinion of continuing antimicrobial therapy for 4 -7 days after the source of infection is controlled (Table
5). When bacteremia with Gram-positive bacteria is present, administering antimicrobial therapy for two
weeks is prudent and recommended to decrease the risk of infective endocarditis.
In the consensus meeting, there was a statement by the member that there were no sufficient data
to support this duration of therapy for patients with Grade III acute cholecystitis, and that it would be
difficult to recommend this.
(Antimicrobial therapy for special conditions)
・In patients with pericholecystic abscesses or perforation of the gallbladder, treatment with
an antimicrobial regimen as listed in Tables 3 is recommended. Therapy should be continued
until the patient is afebrile, with a normalized white count, and without abdominal findings
In most cases, cholecystectomy removes the infection, and little if any infected tissue remains. Under these
circumstances, there is no benefit to antimicrobial therapy extending beyond 24 hours [75-76].

Randomized clinical trials for antimicrobial therapy of acute cholecystitis are limited [60, 62-65].
In these randomized studies, comparisons were made such as ampicillin plus tobramycin vs. piperacillin or
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cefoperazone, pefloxacin vs. ampicillin and gentamicin, cefepime vs. mezlocillin plus gentamicin [14, 60,
63, 65].There were no significant differences between the agents compared. In the TG 18, the agents
considered as appropriate therapy, and listed in Table 3, have all been utilized in randomized controlled
trials of intra-abdominal infections. These studies included patients with pathologically advanced
cholecystitis (abscess or perforation). Table 3 is provided for both community acquired-and
healthcare-associated acute cholecystitis.
Antimicrobial therapy after susceptibility testing results are available
Once susceptibility testing results of causative microorganisms are available, specific therapy (or definitive
therapy) should be offered. This process is called de-escalation [7]. Agents in Table 4 can be used safely
once the susceptibility is proven.
Conversion to oral antimicrobial agents
Patients with acute cholangitis and cholecystitis who can tolerate oral feeding may be treated with oral
therapy [79]. Depending on the susceptibility patterns of the organisms identified, oral antimicrobial agents
such as fluoroquinolones (ciprofloxacin, levofloxacin, or moxifloxacin), amoxicillin/clavulanic acid, or
cephalosporins may also be used. Table 6 lists commonly used oral antimicrobial agents with good
bioavailabilities.
Use of antibiotic irrigation
There has been continuing interest in irrigation of surgical fields with antimicrobial agents, and the subject
has recently been reviewed [80]. The authors concluded that topical antimicrobial agents are clearly
effective in reducing wound infections and may be as effective as the use of systemic antimicrobial agents.
The combined use of systemic and topical antimicrobial agents may have additive effects, but this is
lessened if the same agent is used for both topical and systemic administration.

Conclusions
In TG 18, antimicrobial agents appropriate for use as empirical therapy for community-acquired and
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healthcare-associated infections are provided. Globally increasing and spreading antimicrobial resistance,
antimicrobial stewardship should be underscored and implemented for prudent antimicrobial usage in each
institution. Local, national, and international continuous monitoring of antibiogram would provide safe and
appropriate therapy for patients with acute cholangitis and cholecystitis in a timely fashion. More
definitive studies to indicate the appropriate duration of antimicrobial therapy for patients with bacteremic
cholangitis and cholecystitis should be warranted.
Acknowledgements
We express our deep gratitude to the Japanese Society of Hepato-Biliary-Pancreatic Surgery, the Japanese
Society of Abdominal Emergency Medicine, the Japanese Society of Surgical Infection, the Japan Biliary
Association, for their substantial support and guidance in the preparation of the article. We also would like
to express our deep gratitude to the Japanese Society of Hepato-Biliary-Pancreatic Surgery for the article
processing managing office of Tokyo Guidelines 18 to prepare the publication. We appreciate all
secretariats of the Japanese Society of Hepato-Bilialy-Pancreatic Surgery for their technical support.
Goro Honda has received honoraria from Johnson and Johnson and Medtronic.
Appendix
Harumi Gomi, Center for Global Health, Mito Kyodo General Hospital, University of Tsukuba, Ibaraki,
Japan; Joseph S Solomkin, Department of Surgery, University of Cincinnati College of Medicine,
Cincinnati, OH, USA; David Schlossberg, Professor of Medicine, Lewis Katz School of Medicine at
Temple University, Philadelphia, PA, Medical Director, TB Control Program, Philadelphia, PA,
Department of Public Health, Philadelphia, PA, USA; Kohji Okamoto, Department of Surgery, Center for
Gastroenterology and Liver Disease, Kitakyushu City Yahata Hospital, Fukuoka, Japan; Tadahiro Takada,
Fumihiko Miura, and Keita Wada, Department of Surgery, Teikyo University, School of Medicine, Tokyo,
Japan; Steven M. Strasberg, Section of HPB Surgery, Washington University in St.Louis, St. Louis, MO,

USA; Tomohiko Ukai, Department of Family Medicine, Mie Prefectural Ichishi Hospital, Mie, Japan; Itaru
Endo, Department of Gastroenterological Surgery, Yokohama City University Graduate School of

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Medicine, Kanagawa, Japan; Yukio Iwashita and Masafumi Inomata, Department of Gastroenterological
and Pediatric Surgery, Oita University Faculty of Medicine, Oita, Japan; Taizo Hibi, Department of
Surgery, Keio University School of Medicine, Tokyo, Japan; Henry A. Pitt, Lewis Katz School of
Medicine at Temple University, Philadelphia, PA, USA; Naohisa Matsunaga, Department of Infection
Control and Prevention, Teikyo University, Tokyo, Japan; Yoriyuki Takamori, Department of Internal
Medicine, Teikyo University School of Medicine, Tokyo, Japan; Akiko Umezawa, Minimally Invasive
Surgery Center, Yotsuya Medical Cube, Tokyo, Japan; Koji Asai, Department of Surgery, Toho University
Ohashi Medical Center, Tokyo, Japan; Kenji Suzuki, Department of Surgery, Fujinomiya City General
Hospital, Shizuoka, Japan; Ho-Seong Han and Yoo-Seok Yoon, Department of Surgery, Seoul National
University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea; Tsann-Long
Hwang, Miin-Fu Chen, and Keng-Hao Liu, Division of General Surgery, Linkou Chang Gung Memorial
Hospital, Tauyuan, Taiwan; Yasuhisa Mori, Department of Surgery and Oncology, Graduate School of
Medical Sciences, Kyushu University, Fukuoka, Japan; Wayne Shih-Wei Huang, Department of Surgery,
Show Chwan Memorial Hospital, Changhua, Taiwan; Giulio Belli, Department of General and HPB
Surgery, Loreto Nuovo Hospital, Naples Italy; Christos Dervenis, First Department of Surgery, Agia Olga
Hospital, Athens, Greece; Masamichi Yokoe and Yoshinori Noguchi, Department of General Internal
Medicine, Japanese Red Cross Nagoya Daini Hospital, Aichi, Japan; Seiki Kiriyama, Department of
Gastroenterology, Ogaki Municipal Hospital, Gifu, Japan; Takao Itoi and Shuntaro Mukai, Department of
Gastroenterology and Hepatology, Tokyo Medical University Hospital, Tokyo, Japan; Palepu Jagannath,
Department of Surgical Oncology, Lilavati Hospital and Research Centre, Mumbai, India; O James Garden,
Clinical Surgery, University of Edinburgh, Edinburgh, UK; Eduardo de Santibañes, Department of Surgery,
Hospital Italiano, University of Buenos Aires, Buenos Aires, Argentina; Satoru Shikata, Director, Mie
Prefectural Ichishi Hospital, Mie, Japan; Goro Honda, Department of Surgery, Tokyo Metropolitan
Komagome Hospital, Tokyo, Japan; Avinash Nivritti Supe, Department of Surgical Gastroenterology, Seth
G S Medical College and K E M Hospital, Mumbai, India; Masahiro Yoshida, Department of Hemodialysis
and Surgery, Ichikawa Hospital, International University of Health and Welfare, Chiba, Department of
EBM and Guidelines, Japan Council for Quality Health Care, Tokyo, Japan; Toshihiko Mayumi,

Department of Emergency Medicine, School of Medicine University of Occupational and Environmental
Health, Fukuoka, Japan; Dirk J. Gouma, Department of Surgery, Academic Medical Center, Amsterdam,
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The Netherlands; Daniel J. Deziel, Department of Surgery, Rush University Medical Center, Chicago, IL,
USA; Kui-Hin Liau, Liau KH Consulting PL, Mt Elizabeth Novena Hospital, Singapore, Yong Loo Lin
School of Medicine, National University of Singapore, Singapore; Cheng-Hsi Su, Department of Surgery,
Cheng Hsin General Hospital, Taipei, Taiwan; Angus C.W. Chan, Surgery Centre, Department of Surgery,
Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong; Dong-Sup Yoon, Department of Surgery,
Yonsei University Gangnam Severance Hospital, Seoul, Korea; In-Seok Choi, Department of Surgery,
Konyang University Hospital, Daejeon, Korea; Eduard Jonas, Surgical
Gastroenterology/Hepatopancreatobiliary Unit, University of Cape Town and Groote Schuur Hospital,
Cape Town, South Africa; Xiao-Ping Chen, Hepatic Surgery Centre, Department of Surgery, Tongji
Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
Sheung Tat Fan, Director, Liver Surgery Centre, Hong Kong Sanatorium & Hospital, Hong Kong, Hong
Kong; Chen-Guo Ker, Department of Surgery, Yuan’s General Hospital, Kaohsiung, Taiwan; Mariano
Eduardo Giménez, Chair of General Surgery and Minimal Invasive Surgery “Taquini”, University of
Buenos Aires, Argentina DAICIM Foundation, Buenos Aires, Argentina; Seigo Kitano, President, Oita
University, Oita, Japan; Ryota Higuchi and Masakazu Yamamoto, Department of Surgery, Institute of
Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan; Koichi Hirata, Department of
Surgery, JR Sapporo Hospital, Hokkaido, Japan; Kazuo Inui, Department of Gastroenterology, Second
Teaching Hospital, Fujita Health University, Aichi, Japan; Yoshinobu Sumiyama, Director, Toho University,
Tokyo, Japan.

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Accepted Article
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Accepted Article
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Table 1: Common microorganisms isolated from bile cultures among patients with acute
biliary infections
(Endorsed from Tokyo Guidelines 2013 [1], Table 1)
Accepted Article
Isolated microorganisms Proportions of
from bile cultures isolated organisms (%)
Gram negative organisms
Escherichia coli 31-44
Klebsiella spp. 9-20
Pseudomonas spp. 0.5-19
Enterobacter spp. 5-9
Acinetobacter spp. -
Citrobacter spp. -
Gram positive organisms
Enterococcus spp. 3-34
Streptococcus spp. 2-10
Staphylococcus spp. 0*
Anaerobes 4-20
Others -
Legends:
Table 1 is cited from Tokyo Guidelines 2013 (TG 13) [1]. Data from Reference 7 was integrated for Tokyo
Guidelines 2018 (TG 18).
The data are from references 8, 13-14,17-24, 27.
* A recent study by Salvador et al.[24] reported none from bile cultures, while a study by Sung et al.[29]
reported 3.6% from blood cultures among community-acquired (2%) and healthcare-associated (4%)
bacteremic acute biliary infections.
Table 2: Common isolates from patients with bacteremic biliary tract infections
Bacteremic biliary tract infections
Isolated microorganisms Community-acquired Healthcare-associated
from blood cultures infections* infections**
Gram negative organisms Proportions of isolates (%) Proportions of isolates (%)
Escherichia coli 35-62 23
Klebsiella spp. 12-28 16
Pseudomonas spp. 4-14 17
Enterobacter spp. 2-7 7
Acinetobacter spp. 3 7
Citrobacter spp. 2-6 5
Gram positive organisms
Enterococcus spp. 10-23 20
Streptococcus spp. 6-9 5
Staphylococcus spp. 2 4
Anaerobes 1 2
Others 17 11
Legends:
Table 2 is cited from Tokyo Guidelines 2013 (TG 13)[1]. Data from Reference 8 was integrated for Tokyo
Guidelines 2018 (TG 18).
*The data are from references 8, 25-27, 29.
** The data are from reference 29.

ccepted Articl
Table 3: Antimicrobial recommendations for acute biliary infections
Community-acquired biliary infections
Healthcare-associated
biliary infections (4)
Severity Grade I Grade II Grade III (4)
Antimicrobial Cholangitis and Cholangitis and cholecystitis Cholangitis and Healthcare-associated
agents cholecystitis cholecystitis cholangitis and cholecystitis
Penicillin-based therapy Ampicillin/sulbactam (1) is not Piperacillin/tazobactam Piperacillin/tazobactam Piperacillin/tazobactam

recommended if > 20% resistance
rate.
Cephalosporin-based Cefazolin,* Ceftriaxone, Cefepime, Cefepime,
therapy or Cefotiam,* or Cefotaxime, or Ceftazidime, or Ceftazidime,
or Cefuroxime,* or Cefepime, or Cefozopran or Cefozopran
or Ceftriaxone, or Cefozopran, + Metronidazole(3) + Metronidazole(3)
or Cefotaxime or Ceftazidime
+ Metronidazole(3) + Metronidazole(3)
Cefoperazone/sulbactam
Cefmetazole,* Cefoxitin,*
Flomoxef,*
Cefoperazone/sulbactam
Carbapenem-based Ertapenem Ertapenem Imipenem/cilastatin, Imipenem/cilastatin,

therapy Meropenem, Meropenem, Doripenem,
Doripenem, Ertapenem Ertapenem
Monobactam-based - - Aztreonam Aztreonam

therapy + Metronidazole(3) + Metronidazole(3)
Fluoroquinolone-based Ciprofloxacin, Levofloxacin, Ciprofloxacin, Levofloxacin, Pazufloxacin - -

therapy(2) Pazufloxacin + Metronidazole(3)
+ Metronidazole(3) Moxifloxacin
Moxifloxacin
Table 3 Legends:

ccepted Articl
Table 3 is modified and cited from Tokyo Guidelines 2013 (TG 13) [1]
Footnotes:
＊ Local antimicrobial susceptibility patterns (antibiogram) should be considered for use.
1. Amp/sulbactam has little activity left against Escherichia coli. It is removed from the North American guidelines [43, 49]
2. Fluoroquinolones use is recommended if the susceptibility of cultured isolates is known or for patients with -lactam allergies. Many extended-spectrum
-lactamase (ESBL)-producing gram negative isolates are fluoroquinolone resistant.
3. Anti-anaerobic therapy, including use of metronidazole, tinidazole, or clindamycin, is warranted if a biliary-enteric anastomosis is present. The carbapenems,
piperacillin/tazobactam, ampicillin/sulbactam, cefmetazole, cefoxitin, flomoxef, and cefoperazone/sulbactam have sufficient anti-anaerobic activity for this situation.
4. Vancomycin is recommended to cover Enterococcus spp. for grade III community-acquired acute cholangitis and cholecystitis, and healthcare-associated acute
biliary infections. Linezolid or daptomycin is recommended if vancomycin-resistant Enterococcus (VRE) is known to be colonizing the patient, if previous treatment
included vancomycin, and/or if the organism is common in the community.

Table 4: Antimicrobial agents with high prevalence of resistance among
Enterobacteriaceae
Accepted Article
Antimicrobial class Antimicrobial agents

Penicillin Ampicillin/sulbactam
Cephalosporins Cefazolin
Cefuroxime
Cefotiam
Cefoxitin
Cefmetazole
Flomoxef
Ceftriaxone* or Cefotaxime*
Fluoroquinolones Ciprofloxacin
Levofloxacin
Moxifloxacin
Legends:
Table 4 is cited from Tokyo Guidelines 2013 (TG 13)[1].
References 14, 31-35.
* This resistance indicates global spread of extended-spectrum -lactamase (ESBL)-producing
Enterobacteriaceae.

ccepted Articl
Table 5: Recommended duration of antimicrobial therapy
Healthcare-associated
Community-acquired biliary infections
biliary infections
Severity Grade III Grade I, II, III
Diagnosis Grade I and II Cholecystitis Grade I Grade II Cholangitis and Healthcare-associated
Cholangitis Cholangitis cholecystitis cholangitis and
cholecystitis
Duration of therapy Antimicrobial therapy can be Once source of infection is controlled, duration of 4-7 If bacteremia with gram
discontinued within 24 hours days is recommended. positive cocci such as
after cholecystectomy is Enterococcus spp.,
performed. If bacteremia with gram positive cocci such as Streptococcus spp. is
Enterococcus spp., Streptococcus spp. is present, duration present, duration of
of minimum 2 weeks is recommended. minimum 2 weeks is
recommended.
Specific conditions Perforation, emphysematous ・Residual stones or obstruction of the bile tract are present, treatment should be
for extended therapy changes, and necrosis of continued until these anatomic problems are resolved.
gallbladder are noted during ・If liver abscess is present, treatment should be continued until clinical, biochemical
cholecystectomy, duration of and radiological follow-up demonstrates complete resolution of the abscess.
4-7 days is recommended.

Table 6: Representative oral antimicrobial agents for community-acquired and
healthcare-associated acute cholangitis and cholecystitis with susceptible isolates
Accepted Article
Antimicrobial class Antimicrobial agents
Penicillins Amoxicillin/clavulanic acid
Cephalosporins Cephalexin
+ Metronidazole(1)
Fluoroquinolones Ciprofloxacin
or Levofloxacin
+ Metronidazole(1)
Moxifloxacin
Footnotes:
1. Anti-anaerobic therapy, including use of metronidazole, tinidazole, or clindamycin, is warranted if a
biliary-enteric anastomosis is present.
Figure 1 legends
This meta-analysis was performed by integrating two randomized studies, references 75 and 76.

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Batu Empedu Tokyo Guidelines 2018

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Batu Empedu Tokyo Guidelines 2018

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Article Type: Guideline

The author’s affiliations are listed in the Appendix.

Keywords: Laparoscopic cholecystectomy, acute cholecystitis, safety, difficult, critical view

Besides preoperative factors and severity of AC, intraoperative findings are

Surgeons should choose bail-out procedures to prevent BDI according to the

In TG13, conversion to open cholecystectomy was the only recommendation in cases of AC

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Fundus first technique

Delphi consensus on bail-out procedures in difficult situations

Standardized safe steps are recommended in difficult LC according to the

Step 1: If a distended GB interferes with the field of view, it should be decompressed by

If there is a risk of BDI, intraoperative cholangiography, intraoperative ultrasound,

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Either approach is acceptable. (level B)

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Figure 1. Detailed bail-out procedures for difficult laparoscopic cholecystectomy: a, Subtotal

Figure 2. Standardized safe steps in laparoscopic cholecystectomy. a: Decompression of a

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2. NIH consensus conference. gallstones and laparoscopic cholecystectomy. JAMA. 1993;

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Gallbladder wall>4-5 mm on preoperative

Incarcerated stones in the gallbladder neck Age > 60 or 65

Duration of elevated CRP Male gender

Roheena Z Panni+ and Steven M Strasberg