Optimal treatment strategy for acute cholecystitis based on predictive factors

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Original article
Optimal treatment strategy for acute cholecystitis based on predictive factors:
Japan-Taiwan multicenter cohort study
Itaru Endo, Tadahiro Takada, Tsann-Long Hwang, Kohei Akazawa, Rintaro Mori,
Fumihiko Miura, Masamichi Yokoe, Takao Itoi, Harumi Gomi, Miin-Fu Chen, Yi-Yin
Jan, Chen-Guo Ker, Hsiu-Po Wang, Seiki Kiriyama, Keita Wada, Hiroki Yamaue,
Masaru Miyazaki, Masakazu Yamamoto
Affiliation: The author's affiliations are listed in the Appendix.
KEY WORDS: acute cholecystitis, cholecystectomy, cholecystostomy, comorbidity,
laparoscopic cholecystectomy
CORRESPONDENCE TO:
Corresponding author: Tadahiro Takada, Department of Surgery, Teikyo University
School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
Email: t-takada@jshbps.jp
RUNNING HEAD: Optimal treatment strategy for acute cholecystitis

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Abstract
Background: Although early laparoscopic cholecystectomy is widely performed for acute
cholecystitis, the optimal timing of a cholecystectomy in clinically ill patients remains
controversial. This study aims to determine the best practice for the patients presenting
with acute cholecystitis focused on disease severity and co-morbidities.
Patients and Methods: An international multicentric retrospective observational study
was conducted over a 2-year period. Patients were divided into four groups, Group A:
primary cholecystectomy, Group B: cholecystectomy after gallbladder drainage, Group C:
gallbladder drainage alone, and Group D: medical treatment alone.
Results: The subjects of analyses were 5329 patients. There were statistically significant
differences in mortality rates between patients with Charlson co-mobidity index ( CCI)
scores below and above 6 (p<0.001). The shortest operative time was observed in Group A
patients who underwent surgery 0-3 days after admission (p<0.01). Multiple regression
analysis revealed CCI and low BMI <20 as predictive factors of 30-day mortality in Grade
I+II subjects. Also, jaundice, neurological dysfunction, and respiratory dysfunction were
predictive factors of 30-day mortality in Grade III patients. In Grade III patients without
predictive factors, there were no difference in mortality between Group A and Group B
(0% vs 0%)、whereas Group A patients had higher mortality rates than that of Group B
patients (9.3% vs 0.0%) in cases with at least one predictive factors.
Conclusion: Even patients with Grade III severity, primary cholecystectomy can be
performed safely if they have no predictive factors of mortality. Gallbladder drainage may
have a therapeutic role in subgroups with higher CCI or higher disease severity.
Introduction
Individuals with gallstones often develop acute cholecystitis (AC) (10-20%)(1)(2), which
is one of the most frequent abdominal emergencies. About 70 to 80 % of patients with AC
proceed to surgery, while the remaining are treated with medical therapy, including
several types of gallbladder drainage such as percutaneous transhepatic gallbladder

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drainage (PTGBD), percutaneous transhepatic gallbladder aspiration (PTGBA),
endoscopic naso-gallbladder drainage/ stenting (ENGBD), endoscopic ultrasound-guided
gallbladder drainage, and operative cholecystostomy. Although open cholecystectomy was
preferred by surgeons in the early 2000s (3), currently, laparoscopic cholecystectomy is
accepted as the gold standard treatment for AC. However, the optimal timing of
cholecystectomy in patients with AC remains controversial, especially in elderly patients
with medical co-morbidities (4).
Tokyo Guidelines 2013 (TG13) suggest that an early laparoscopic cholecystectomy
(ELC) is preferable for patients with mild cholecystitis, whereas delayed laparoscopic
cholecystectomy (DLC) can be performed in patients with moderate or severe cholecystitis
(5). However, in daily practice, treatment strategies are determined not only based on
disease severity, but also on the patients’ condition, including age, co-morbidities and
performance status. American Society of Anesthesiologist (ASA) classification of fitness
for surgery (6), POSSUM (Physiological and Operative severity Score for the enumeration
of Mortality and Morbidity) (7) score, and Charlson co-morbidity index (CCI)(8), which
influence surgical outcomes, have been used in several reports to evaluate patients
status. Donati et al. reported that modified ASA classification is related to postoperative
mortality in acute cholecystitis (9). The Portsmouth-POSSUM equation produced better
fit with the observed in-hospital mortality than POSSUM (10). Pasquer et al. reported
that patients with a high CCI should be treated at high volume centers, because the
postoperative morbidity and mortality rates is lower in high volume centers than in low
volume centers (11). Since the number of elderly patients is currently increasing,
patients’ general status must be evaluated using objective scores to reduce operative
morbidity and mortality.
Several authors prefer to perform gallbladder drainage to decrease local inflammation,
and to avoid emergency operation and instead, perform delayed cholecystectomy for
complicated acute cholecystectomy (12)(13)(14)(15). However, the clinical significance of
gallbladder drainage has not been fully elucidated. Recently, some surgeons argued that
PTGBD has no clinical benefits even in severely ill patients (16)(17). As seen above,
treatment strategies are affected by severity grade and patient factors, including age,
performance status, co-morbidities etc. Therefore, there are multiple factors to be

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considered in decision-making regarding the optimal treatment strategy for AC,
including gallbladder drainage.
The results of small studies are not likely to accurately reflect clinical practice, making
it difficult to explore the best practice for each subgroup, such as the patients with
co-morbidities and severe cholecystitis. Randomized control studies (RCTs) is generally
provide the highest quality of evidence. However, RCTs also sometimes do not reflect true
practice because RCTs usually focus on a single variable. Recently, several multi-center
cohort studies consisting of over four thousands of patients have been published
(18)(19)(20)(21). According to these large-database studies, early cholecystectomy is
reportedly superior to delayed cholecystectomy. On the other hand, these
population-based studies generally lack the data concerning disease severity, since the
severity grading was first established only in 2007 (22).
To address these issues, we conducted a retrospective cohort study consisting of over
5000 cases, including not only surgical but also non-surgical cases who underwent
gallbladder drainage or medical treatment alone, to clarify the optimal treatment
strategies in each subgroup of acute cholecystitis.
Patients and methods
Study design
An international multicentric retrospective observational study was conducted over a
2-year period (Jan 2011- Dec 2012). Data was retrospectively collected at Board certified
training institutions from board certified expert surgeons in the Japanese Society of
Hepatobiliry Pancreatic Surgery, or other institutes of gastroenterology, endoscopy and
infectious disease medicine in Japan. Furthermore, this study was performed in
cooperation with hepatobiliary surgeons, gastroenterologists and infectious disease
physicians in Taiwan. A total of 155 hospitals were involved. A detailed database was
created based on a questionnaire for each patients. Anonymous data inclusion was
guaranteed by the study protocol. This study was approved by the institutional review
board of Yokohama City University (B140109040).

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Inclusion and exclusion criteria
This study included patients who met the following criteria: 1) Aged 18 years and over,
who were hospitalized within the study period after being diagnosed with cholecystitis, or
were being treated for cholecystitis: 2) Acute cholecystitis was diagnosed by clinicians
using imaging modalities and pathological diagnosis. Patients who were younger than 18
years of age on admission were excluded from the study.
Data collection
The patient-related variables assessed included age, sex, co-morbidity according to CCI
score, and previous history of biliary surgery, while disease-related variables included
medical treatment before admission, presence of jaundice, need for endoscopic
sphincterotomy, biological parameters (e.g., WBC count, CRP, Procalcitonin),
pathological parameters, and bacterial cultures. Surgical procedure-related variables
included primary intention of open cholecystectomy, interval between admission and
operation, performance of intraoperative cholangiography, and need for conversion from
laparoscopic to open cholecystectomy. Disease severity was classified according to Tokyo
Guidelines 2013.
Endpoints
The clinical endpoints of this study that were recorded included the rates of
post-operative bile leakage, major bile duct injury (BDI), conversion to open surgery,
overall morbidity, operative time, total duration of hospital stay, and postoperative
complications. The total duration of hospital stay was defined as the total number of
in-hospital days, which included two hospitalizations for patients who underwent delayed
cholecystectomy. BDI was defined as any injury to the main biliary tree. Bile leakage was
defined as the presence of bile in the drainage fluid or intra-abdominal fluid collection, as
determined by postoperative ultrasonography or computed tomography. General
complications included urinary tract infection, cardiac complications, pulmonary
complications, deep venous thrombosis, cerebrovascular complications, renal
insufficiency, upper gastrointestinal hemorrhage, etc.

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Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics for Windows version
20.0 (IBM Corp.) and Cytel Studio version 11.0.0 (Cytel Inc.). Pearson’s chi-squared test
or Fisher’s exact test was conducted to test the equality of proportions among groups.
One-way ANOVA was performed to test the equality of mean value among A, B, C, D groups for
continuous variables such as Age, BMI, etc in Table 1. On the other hand, for categorical variables,
Chi-sqaured test was done to test the homogeneity of proportions among four groups. Furthermore,
the Cochran-Armitage trend test was used to test an increasing or decreasing trend in
proportions among groups in Table 2. We also did Chi-squared analysis to test the homogeneity
of 30th and 90th mortalities among 4 groups consisting of categories of index. Multiple logistic
regression analyses were used to explore the factors significantly associated with
mortality on the 30th day. The candidate independent factors are shown in Table 5. For
the multiple logistic regression analysis, the null hypothesis for Wald test determined
that the independent variable do not affect the probability of observing the value of 0
(absence) or 1 (presence) for mortality on the 30th day, or that the odds ratio is equal to
one. All statistical tests were two-tailed, and statistical significance was defined as
P < 0.05. All P-values used in the results were nominal values, that is, they were not
adjusted for multiple comparisons.
Results
Overall, 5459 patients diagnosed as having acute cholecystitis took part in the present
study. Mean age at the time point of admission was 66.0±15.3 (range 19 to 99) years with
63.0% of all patients being male. Median postoperative hospital stay was 7 (range 1 to
780) days. The subjects of analyses were 5329 patients with complete data on diagnostic
criteria and severity assessment. Twenty-eight percent of the patients had a history of
biliary disease, and 626 patients (11.7%) had undergone previous biliary interventions.
According to TG13 guidelines, approximately 80% of the patients fulfilled the definition of
AC (Definite n=4063 (76.2％)、Suspected n=291 (5.5％)). The severity grade of AC was

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Grade I in 2106 cases (39.5%), Grade II in 2292 cases (43.0%), and Grade III in 933 cases
(17.5%). Positive bile culture rates for each severity grade were 58.9%, 61.5%, and 68.9％
, respectively, indicating an increase in culture rates as severity grade increased,
although the differences were not statistically significant (p=0.693).
Most patients had primary cholecystectomy (GroupA: n=2947; 55.3%)(Fig 1). The
initial intervention was gallbladder drainage in 1770 patients (33.2%). Subsequent
cholecystectomy was performed in 1239 of the 1770 (70.0%) patients (Group B; 23.6% of
the whole cohort), at a median interval of 22 days (range 1 to 802 days). Five hundred
thirty-one of the patients did not undergo subsequent cholecystectomy (Group C; 10.0% of
the whole cohort). Six hundred twelve patients were treated with antibiotics and fluid
resuscitation alone (Group D; 11.5%). When each treatment group was compared
separately (Table1), Group A patients were significantly younger, and consisted of
patients with better PS. The percentage of males was higher in Groups B and C. Group
A patients had a lower comorbidity burden, ie lower CCI. In terms of patient’s status,
patients on anticancer drug therapy were frequently observed in Group C (7.6%).
Patients who received anticoagulant therapy were less frequent in Group A (14.0%) than
in Group B, C, and D (23.0%, 24.8% and 26.0%, respectively)(p<0.01). CRP levels were
higher in Groups B and C than Groups A and D. Bacterial culture was significantly
frequently positive in Group D (83.3%)(p<0.01). Group C patients were likely to have
more organ dysfunction other than hematological dysfunction. Therefore, the prevalence
of Grade III severity AC was highest in Group C (29.4%) and lowest in Group A patients
(13.1%)(p<0.01). Group C had the worst mortality for all severity grades. Grade III
patients who underwent subsequent cholecystectomy (Group B) had the lowest mortality
rate (p<0.01).
Charlson co-morbidity index score
Five thousand forty-two patients had at least one co-morbidity (94.6 %). Median CCI
score was 4.0 (range 0 to 18). When the mortality rates of each group were compared
according to the CCI score, 30-day and 90-day mortality rates were increased with the
increasing CCI in all group (Cochran-Armitage)(Table 2). In the patients who underwent
cholecystectomy (GroupA and B), there are statistical significant step-up of the mortality

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rates between below 6 and 6 or higher (P<0.01). Approximately half of the patients with
GroupC had 6 or higher CCI. Among the patients with 6 or higher CCI, mortality rate of
Group B was statistically significantly lower than that of other groups (p<0.01).
Timing of cholecystectomy
A total of 4186 patients underwent cholecystectomy (Group A and B). Laparoscopic
cholecystectomy was planned in 2929 cases（71.9％）, whereas 271 patients had
conversion of laparoscopic to open cholecystectomy (9.3%). A primary open approach
was performed in 26.6% patients (25.0% and 31.0% in Groups A and B, respectively)
(Table 3). Primary open cholecystectomy was planned more frequently in Group B
patients (<0.01). In Group A, the primary open approach was planned more frequently by
day 7 (p<0.01). The conversion rate was significantly higher in Group B than Group A
(6.1% vs. 8.5%) (p=0.028).
In Group A, the median interval between admission and cholecystectomy was 3 days
(range 1 to 1129). Most of patients underwent cholecystectomy by day3 (70.3％). In
Group B, the median interval between admission and gallbladder drainage was 2 days
(range 1 to 1097). Subsequent cholecystectomy was performed 39.9±76.4 days (mean)
after gallbladder drainage. Most patients underwent cholecystectomy after day 8 of
admission (77.4%)(Table 3).
Bile duct injury occurred at a similar frequency in Group A and B (1.2 and 1.3%,
respectively) (Table 3). There were no statistically significant differences in the incidence
of BDI in terms of timing after admission when the surgery was performed.
Intraoperative blood loss tended to be higher in Group B than in Group A (p=0.069),
although the difference was not statistically significant. Intraoperative blood loss was
highest among Group A patients who underwent surgery 0 to 3 days after admission.
Median operation time was 124 min in the entire cohort. It was statistically significantly
longer in Group B than Group A (134 min. vs 120 min., respectively). The shortest
operative time was observed in Group A patients who underwent surgery 0-3 days after
admission (p<0.01). The morbidity rate was significantly higher in Group B (p<0.01).

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Operative outcomes according to severity grades
Laparoscopic cholecystectomy was executed more frequently in Group A than Group B
(67.2% vs 58.9%, respectively) (Table 4). The conversion rate in Group A was significantly
lower than that in Group B (5.9% vs 8.3%, respectively), and it tended to increase with
increasing severity grade in Group A (p=0.025). However, there was no such tendency in
Group B. Primary open cholecystectomy was more often planned in Group A (p<0.01), and
it tended to increase with increasing severity grade in Group A (p<0.01). The amount of
blood loss increased as severity grade increased in Group A, possibly due to many cases of
open cholecystectomy among Grade III patients. Morbidity rates increased along with
severity grade increasing in Group A, although there was no such tendency in Group B
patients. Thirty day and 90-day mortality was highest in Grade III patients in Group A
(4.13% and 3.62%, respectively). There were, however, no statistically significant
differences in mortality rate between Grade I and Grade II patients in Group A. In Group
B, there was no relationship between mortality and severity grades.
Logistic analysis of 30-day mortality
Univariate analysis indicated that predictive factors for 30-day mortality in Grade I+II
severity AC were age, BMI, PS, and CCI (Table 5), while multivariate analysis indicated
BMI and CCI as predictive factors of 30-day mortality. The predictive factors of 30-day
mortality in patients with Grade III severity were PS, jaundice, neurological dysfunction,
and respiratory dysfunction on univariate analysis (Table 6), while jaundice, neurological
dysfunction, and respiratory dysfunction were the predictive factors on multivariate
analysis.
Mortality according to predictive factors
When the patients were divided into two groups according to the positivity for the above
mentioned predictive factors, there was no statistically significant difference in 30-day
mortality between Groups A and B with Grade I+II severity, regardless of the predictive
factors (Table 7). In cases with any positive predictive factors, there was no statistically
significant difference in mortality between Groups A and B (0.61% vs. 0.86%,

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respectively). Also, there were no significant differences between the two groups with no
positive predictive factors (0.26% vs 0%). However, 30-day mortality in Group B+C
(initially treated by gallbladder drainage) was significantly higher than that in Group A,
suggesting no clinical benefit of initial gallbladder drainage in Grade I+II severity AC.
In Grade III patients, there was no statistically significant difference in 30-day
mortality between Groups A and B patients with no positive predictive factors (Table 8).
In cases with positive predictive factors, 30-day mortality in Group A was 9.3%. This was
significantly higher than that in Group B (0.0%). However, the 30-day mortality of Group
A was not significantly different from that of Group B+C (9.3% vs. 6.1%, respectively).
Discussion
The present study found that both disease severity and patient condition should be
evaluated before decision-making regarding the treatment course for AC since there are
many confounding factors to be considered. In the present study, we were able to perform
subgroup comparisons owing to the huge patient database of over 5000 subjects.
According to subgroup analysis, Charlson co-morbidity index is a useful patient-factor
related to treatment choice. Further, TG13 severity grade, including neurological and
respiratory dysfunction plus jaundice at the initial presentation, is a reliable disease
–related factor that should be considered during the preoperative evaluation to determine
an appropriate therapeutic algorithm for AC.
Generally, a randomized control trials (RCT) provide superior quality evidence than
retrospective cohort studies. Indeed, RCTs are useful for single factor evaluations, such
as laparoscopic vs. open surgeries, early vs. delayed procedures, and primary
cholecystectomy vs. subsequent cholecystectomy after gallbladder drainage. However, in
actual clinical practice, there is a great degree of divergence in clinical presentation and
course. In the field of cholecystectomy, most RCTs have included relatively fewer
numbers of patients. Therefore, it is difficult to make a comprehensive analysis regarding
which therapeutic modality is superior. Since previous retrospective studies showed
significant differences in patients’ clinical backgrounds due to selection bias by

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physicians, simple inter-group comparison does not seem appropriate. For example,
GradeI+II and Grade III cholecystitis cases in this study had a 2- to 10- fold difference in
conversion and mortality rates. Recently, several population-based studies including over
10,000 patients were conducted. Some of them adopted propensity score matching to
resolve background differences (16). Another large population-based cohort study
adopted a subset analysis restricted to the patients with severe sepsis and septic shock to
adjust for patient demographics (15). The current study is the largest database from Asia
including over 5,000 acute cholecystitis patients with a range of disease severities and
backgrounds. Thus, subgroup analysis of sufficient numbers of patients could be
performed. Another feature of this study was that the data were collected from not only
hepatobiliary pancreatic (HBP) surgeons, but also gastroenterologists, endoscopists, and
infectious disease physicians in Japan and Taiwan. This allowed us to compare surgical
management with non-surgical management.
Although there are significant differences in treatment outcomes according to disease
severity, studies focusing on the disease severity are surprisingly scarce. For example, it
is well-known that patients with acute perforated cholecystitis and acalculus cholecystitis
have poor poor outcomes regardless of the therapeutic modalities used. (16)(17).
Anderson assessed 43,341 patients with acalculous cholecystitis using a population based
database in California, and presented a surprisingly high mortality rate of 30% (17). This
is much higher than the mortality of 0 to 4% in previous studies including all grades of
severity. Indeed, many studies have not been concerned with the heterogeneity of the
cohort in terms of disease severity. Since disease severity was not considered in previous
population-based databases, they could not analyze patient outcomes stratified by
disease severity. Furthermore, even meta-analyses could not analyze the data according
to disease severity since there were no world-wide accepted guidelines before the Tokyo
Guidelines 2007 (20). In the present study, we adopted TG13 severity grades for the
objective evaluation of disease severity (5). Surgical outcomes clearly depended on TG13
severity grade in the subgroup in which cholecystectomy was performed without
preceding gallbladder drainage. Conversely, surgical outcomes were not related to
disease severity in the group that underwent cholecystectomy after gallbladder drainage,
suggesting the beneficial effect of a reduction in inflammation due to decompression of
the gallbladder by gallbladder drainage. Thus, subgroup analysis according to disease
severity is mandatory in future studies.

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With the current increase in the elderly population, patients with AC have a tendency
of increased medical co-morbidities, such as coronary stents, cerebral infarction and
diabetes mellitus. Since these patients have decreased physiological functional reserve,
careful patient selection is necessary before performing this potentially morbid procedure
under general anesthesia. Although the terms ‘extremely ill’ and ‘high-risk’ have been
commonly used in previous papers, the definition of clinically ill is somewhat vague. It
often includes not only poor patients with poor general condition, but also those with
greater disease severity, such as septic shock, positive blood culture, etc. In some articles,
clinically ill is defined as higher ASA (American Society of Anesthesiologists) class of III
or IV. ASA is a simple and useful method for quick preoperative evaluation of the
patient’s condition. Indeed, some authors adopted ASA classification in their own
treatment algorithms (21) (23). Yun et al. reported that patients with acute cholecystitis
and ASA grade III or greater can be well managed by PTGBD (23). Brooks et al used an
ASA grade of IV or greater as one of the definitions of high-risk patients (21). Banz et al
used ASA classification for risk-adjustment in population based analysis to define the
optimal timing for laparoscopic cholecystectomy for AC (20). Although the
Portsmouth-POSSUM scoring system can, reportedly, well predict mortality following
hepatobiliary pancreatic surgery and emergency laparotomy, it has a tendency to
overestimate postoperative mortality (24)(25). Recently, Gonzalez-Munoz et al reported
that the Portsmouth POSSUM system is useful in the selection of primary treatment for
AC and can be a strong predictor of surgical mortality in severe acute cholecystitis (26).
The Charlson co-morbidity index was developed to predict 1-year mortality for
surgically treated patients and is frequently used to estimate the patient’s general
condition (8). Anderson et al adopted the CCI to evaluate patient’s general status and
reported that mean CCI was significantly higher in the gallbladder drainage group than
those in the primary cholecystectomy group. Gonzalez-Munoz reported that mean CCI in
non-operative patients were 8.6, which is significantly higher than that of patients who
underwent cholecystectomy (4.8-5.4)(26). These evidences may indicate that CCI is
potentially a useful factor in treatment algorithms. In the present study, as CCI
increased, mortality rates also increased in all subgroups. Future studies should consider
the use of these factors as risk-adjustment factors for comparison of potential
confounding factors.

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Traditionally, cholecystectomy for cholecystitis is performed within 3 days of the onset
of symptoms or after 5 weeks, allowing for resolution of the inflammatory response.
During the late 1990’s to early 2000’s, early laparoscopic cholecystectomy was not yet
adopted by a majority of surgeons (3). Only a minority of surgeons offered patients
presenting with acute cholecystitis the benefits of early laparoscopic cholecystectomy （
27）. The definition of early cholecystectomy is controversial (28). Different authors
variously consider early cholecystectomy as that performed within the first 2 days (29), 72
hours (30), or up to 7 days (16) after admission. Since the period between the onset of
symptoms and the day of admission is variable, Gonzales-Munoz advocated a maximum
of 6 days from the onset of the symptoms and 3 days after admission as the time limit for
considering surgery as early (26). Many RCTs have been conducted to elucidate the
superiority of early cholecystectomy (29). Most of these studies concluded that early
cholecystectomy should be recommended due to the clinical benefits of shorter hospital
stay, and lower morbidity rates. Furthermore, several meta-analysis concerning this
issue have concluded that early laparoscopic cholecystectomy might be associated with
lower hospital costs, fewer work days lost, and greater patient satisfaction (31) (32)
(33)(34).
Recently several population-based large scale studies also showed similar results, that
early laparoscopic cholecystectomy is associated with the lowest rates of complications
and mortality, and the shortest duration of hospital stay. (19). Brooks et al. showed a
lower mortality (2.5%) in association with early cholecystectomy within 3 days of
admission as compared to delayed cholecystectomy (7.5%), using the ACSNSQIP
(American College of Surgeons National Surgical Quality Improvement Program)
database (21). However it should be noted that the delayed cholecystectomy group in
their study included a larger number of ASA class>4 patients（early vs delayed; 2.9% vs
19.6%）. In the present study, primary cholecystectomy was performed within 3 days of
admission in 70.0% of the patients (2032 of 2902). Although a relatively small subgroup of
patients underwent primary cholecystectomy from day 4 to 7, the disproportionately high
conversion rate from laparoscopic to open cholecystectomy in these patients and incidence
of bile duct injury is noteworthy. Conversion rates of patients who underwent
cholecystectomy after day 8 were not show statistically significantly different from those
who underwent early cholecystectomy within 3 days (5.6-8.8% vs 8.5%). There was no

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difference in 30-day mortality as well. These findings indicate that if the patient’s
condition permits, early cholecystectomy within 3 days is most preferable.
Conversion rates reported in randomized clinical trials vary considerably among series,
from 11% to 34% (32). Recently, Cao et al. collected 77 case-control studies for
meta-analysis, 8.8% of early LC were converted to open procedure (1844/20931), while
10.9% (1427/13045) were converted to open procedure in the delayed group (28).
Conversion rate in the present study was very close to this results (8% in straight
forward, 12% in subsequent cholecystectomy after gallbladder drainage). However, in the
present study, conversion rates for early and delayed cholecystectomy were almost
similar regardless of the timing of surgery (Table 3). On the other hand, conversion rates
are increased as disease severity increased in primary cholecystectomy group. Thus,
conversion rate may be a surrogate marker of surgical difficulty. It is interesting that the
conversion rate of subsequent cholecystectomy after gallbladder drainage was nearly half
that of primary cholecystectomy in Grade III patients. This result suggests that
gallbladder drainage can reduce the amount of inflammation and fibrosis around the
gallbladder and Calot’s triangle, leading to decreased surgical difficulty in selected
patients. Indeed, some surgeons argue that gallbladder drainage allows to resolve the
inflammatory responses, therefore, it may facilitate laparoscopic cholecystectomy by
reduced technical difficulty (35)(36). On the other hand, in both Grade I and II severity
cases, subsequent cholecystectomy after gallbladder drainage was associated with a
much higher conversion rate than that in primary cholecystectomy group. These results
may suggest that gallbladder drainage offers no clinical benefits in Grade I and II
cholecystitis patients. Therefore, early primary cholecystectomy is recommended for
Grade I and II cholecystitis, if the patients’ condition permits general anesthesia.
Gallbladder drainage is expected to play a bridging role before surgery in patients with
poor general condition and complicated co-morbidities who are not amenable to
immediate surgery or are vulnerable to general anesthesia. Winbladh et al. performed a
systematic review regarding to cholecystostomy for AC in patients aged >65 years, and
reported a mortality rate after PTGBD was 15.4% (288/1925). On the other hand, a mean
mortality rate after primary cholecystectomy was 4.5% (160/3565)(37). They noted that
the material gathered in the review suggested that cholecystectomy was superior to
PTGBD, even in elderly and critically ill patients. In a recently published nationwide

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review, Anderson reported that PTGBD does not offer a survival benefit compared with
cholecystectomy or no surgical interventions in patients with acute acalculous
cholecystitis (17). Among all patients and even among subsets of patients with severe
sepsis and shock, either primary or interval cholecystectomy was associated with a lower
mortality than PTGBD alone. They noted that ‘In the era of modern medicine and
advances in surgery, anesthesiology, and intensive care, cholecystectomy (regardless
whether early or delayed) might still be a good option in some of these patients’. In this
study, the mortality rate of the patients with Grade III severity who underwent
cholecystectomy after gallbladder drainage was 0.8％. This was significantly lower than
that of primary cholecystectomy (4.0％). On the other hand, mortality rates in patients
who did not undergo subsequent cholecystectomy (16.5％) was comparable to that in
previous studies. These findings indicate that Group B patients must be selected
patients.
In terms of treatment strategy, TG13 guidelines recommend gallbladder drainage for
Grade III AC. Some authors argued that this might lower the threshold for PTGBD, even
though a great number of patients with Grade III AC might be good candidates for
primary cholecystectomy (16). In the present study, primary cholecystectomy was
performed in 41.4% (388/938) of patients with Grade III cholecystitis. The mortality rates
of this group were surprisingly low, at 4%. This results suggest that a few selected
patients are able to undergo cholecystectomy as the procedure of choice, including
patients with Grade III severity, and will likely be able to tolerate general anesthesia (
17) (38). This low incidence of mortality rate might be due to two reasons. One reason
might be a severity-grade migration. TG13 severity grade includes six factors, such as
cardiovascular, central nervous system, respiratory, renal, hepatic and coagulation
disorders. Among them, liver hepatic dysfunction is defined as PT-INR>1.5. Prolonged PT
can be induced by not only liver dysfunction but also disseminated intravascular
coagulopathy accompanying severe sepsis. Also, in TG13 guidelines, coagulation
dysfunction is defined as a platelet count of <10x106. Low platelet counts might also be
due to septic coagulopathy. These might have induced grade migration from Grade II to
Grade III in this study. Another possibility is the heterogeneity of TG13 Grade III
patients. When we compare the six factors of Grade III severity with SOFA scores
(Sepsis-Related Organ Failure Assessment; SOFA)(39), there are some variabilities
between the factors. For example, the range of SOFA scores, such as cardiovascular

AcceptedArticle
dysfunction=SOFA 3-4, neurorogical dysfunction=SOFA could not correspond because
Glasgow Come Scale (GCS) was adopted in SOFA score, respiratory dysfunction=SOFA
2-4, renal dysfunction= SOFA 2-4, hepatic dysfunction=SOFA not corresponding since
bilirubin is adopted in SOFA score, hematological dysfunction=SOFA 2-4. Due to these
ranges, TG13 Grade III might include patients with a variety of SOFA scores ranging
from 2 points up to 24 points. In our study, six determinant factors for Grade III has
different significance for mortality, in other words, patients without factors predictive of
mortality (jaundice, neurological and respiratory dysfunction) showed a very low
mortality rate (0%). Although the definition of tolerance for general anesthesia is still
undetermined (high ASA score, higher APACHE II score or high Charlson Index etc.),
surgeons should keep seeking opportunities for early laparoscopic cholecystectomy in
relatively stable Grade III patients without these predictive factors. On the other hand,
patients with any positive predictive factors should first be treated with gallbladder
drainage. Cholecystectomy can be subsequently performed in two-thirds of the patients
with zero mortality.
Consideration of technical difficulties is important for the safe conduct of surgeries,
including avoidance of conversion to open cholecystectomy and intraoperative bile duct
injuries. Sakuramoto et al. advocated that their judgment score was satisfactory in terms
of the simplicity of evaluating the technical difficulties (40). Quantification of technical
difficulty using scoring systems seems useful for preoperative prediction of which
patients will have difficulties in gallbladder dissection. Further, it might also help
surgeons to make an appropriate decision in order to avoid bile duct injuries. Creation of
an objective scoring system for surgical difficulty would also help determine whether or
not gallbladder drainage has anti-inflammatory effects. Recently we reported that
intraoperative findings are objective and could be used as appropriate indicators of
surgical difficulty during laparoscopic cholecystectomy (41). However, even among
experts, surgeons' perceptions during laparoscopic cholecystectomy depend on their
experience, hospital volume, and education (42). Further study is needed to establish a
novel grading system for evaluation of surgical difficulty and standardized laparoscopic
cholecystectomy procedures (43).
We recognize that there are several limitations to our study due to its retrospective
nature. There is probably some selection bias that could not be excluded by subgroup

AcceptedArticle
analysis based on confounding factors. However, we divided the entire cohort into
homogenous subgroups as possible because of the large number of patients. Another
limitation is the possible heterogeneity of operative technique, education and hospital
volume at each institution. Further, we did not include information about medical costs.
Several reports describe the superiority of early cholecystectomy in terms of lowered
medical costs. In this study, we could not compare medical costs in the two groups
because of the issues related to financial support in medical care in Japan, and also the
different calculation system for medical costs in Taiwan.
For patients with acute cholecystitis, all efforts should be made to perform laparoscopic
cholecystectomy within 3 days after hospital admission, according to treatment
algorithms based on both TG13 severity and patient condition. Gallbladder drainage
seems less beneficial in patients with TG13 Grade I+II severity AC, except for patients
with high CCI or low BMI. In patients with TG13 Grade III severity, primary
cholecystectomy can be performed safely if the patients has no predictive factors of
increased mortality, such as jaundice, neurological dysfunction, and respiratory
dysfunction. Gallbladder drainage may play a role in subgroups with greatest disease
severity (positive for jaundice, neurological dysfunction, or respiratory dysfunction), since
subsequent cholecystectomy can usually be performed with acceptably low mortality after
the acute inflammation has subsided.
Conflict of interest
None to declared
Financial Support
This study was supported by the Japanese Society of Hepato-Biliary-Pancreatic Surgery.

AcceptedArticle
Acknowledgement
This survey was conducted as a part of a Japan-Taiwan Collaborative Project: Defining
the best practice of managing Acute Cholangitis and Cholecystitis.
All authors express our sincere gratitude to all respondents of this study for active
participation (information about the respondents in Suppl. Fig.). We also thank Ms. Kaori
Tani and Ms. Mari Watanabe for their enormous work on data analysis.
Appendix
Itaru Endo, Department of Gastroenterological Surgery, Yokohama City University
Graduate School of Medicine, Kanagawa, Japan; Tadahiro Takada, Department of
Surgery, Teikyo University School of Medicine, Tokyo, Japan; Tsann-Long Hwang,
Division of General Surgery, Lin-Kou Chang Gung Memorial Hospital, Tauyuan, Taiwan;
Kohei Akazawa, Department of medical informatics, Niigata University, Niigata, Japan;
Rintaro Mori, Department of Health Policy at National Center for Child Health and
Development - National Center for Child Health and Development, Tokyo, Japan;
Fumihiko Miura, Department of Surgery, Teikyo University School of Medicine, Tokyo,
Japan; Masamichi Yokoe, Department of General Internal Medicine, Japanese Red Cross
Nagoya Daini Hospital, Aichi, Japan; Takao Itoi, Department of Gastroenterology and
Hepatology, Tokyo Medical University Hospital, Tokyo, Japan; Harumi Gomi, Center for
Global Health Mito Kyodo General Hospital University of Tsukuba, Ibaraki, Japan;
Miin-Fu Chen, Division of General Surgery, Lin-Kou Chang Gung Memorial Hospital,
Tauyuan, Taiwan; Yi-Yin Jan, Division of General Surgery, Lin-Kou Chang Gung
Memorial Hospital, Tauyuan, Taiwan; Chen-Guo Ker, Department of Surgery, Yuan’s
General Hospital, Kaohsiung, Taiwan; Hsiu-Po Wang, Department of Internal Medicine,
National Taiwan University Hospital, National Taiwan University College of Medicine,
Taipei, Taiwan; Seiki Kiriyama, Department of Gastroenterology, Ogaki Municipal
Hospital, Gifu, Japan; Keita Wada, Department of Surgery, Teikyo University School of
Medicine, Tokyo, Japan; Hiroki Yamaue, Second Department of Surgery, Wakayama
Medical University School of Medicine, Wakayama, Japan; Masaru Miyazaki, Emeritus
Professor, Graduate School of Medicine, Chiba University, Chiba, Japan; Masakazu

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Yamamoto, Department of Surgery, Institute of Gastroenterology, Tokyo Women’s
Medical University, Tokyo, Japan
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Figure Legends
Fig 1 Study design and patient flow across the study from initial treatment selection.
Most patients had primary cholecystectomy (GroupA: n=2947; 55.3%). The initial
intervention was several types of biliary drainage such as percutaneous transhepatic
gallbladder drainage (PTGBD), percutaneous transhepatic gallbladder aspiration
(PTGBA), endoscopic naso-gallbladder drainage (ENGBD), endoscopic ultrasound-guided
gallbladder drainage, and operative cholecystostomy in 1770 patients (33.2%).
Subsequent cholecystectomy was performed in 1239 of the 1770 (70.0%) patients (Group
B; 23.6% of the whole cohort). Five hundred thirty-one of the patients did not undergo
subsequent cholecystectomy (Group C; 10.0% of the whole cohort). Six hundred twelve
patients were treated with antibiotics and fluid resuscitation alone (Group D; 11.5%).
*Supporting Information
Additional Supporting Information may be found in the online version of this article at the publisher’s
web-site:
Supplement Figure 1. Charlson comorbidity index
Supplement Figure 2. The names of all collaborators and their work places.

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Table 1 Patient’s characteristics in each treatment group
Group A Group B Group C Group D p value
Number of patients 2947 1239 531 612
Age 64.8±14.9 68.9±12.7 73.4±12.6 69.1±15.9 p<0.01
Sex M 1811 834 354 355 p<0.01
F 1133 404 176 256
Unknown 3 1 1 1
Body weight 62.9±13.0 61.1±12.5 56.9±12.6 59.9±14.1 p<0.01
BMI 24.2±4.0 23.7±3.8 22.5±4.1 23.5±4.6 p<0.01
PS 0/1/2 95.1% 93.9% 85.7% 91.2% p<0.01
3/4 4.9% 6.1% 14.3% 8.8%
Anticoagulation + 14.0% 23.0% 24.8% 26.0% p<0.01
Immunosupp + 1.8% 2.8% 5.1% 3.3% p<0.01
Anticancer med. + 1.4% 2.6% 7.6% 3.5% p<0.01
MI + 5.1% 8.9% 10.0% 9.9% p<0.01
CHF + 3.5% 6.5% 10.1% 10.2% p<0.01
PVD + 2.0% 3.3% 3.2% 2.4% p<0.01
CVD + 8.3% 12.9% 16.2% 14.4% p<0.01
Dementia + 3.4% 4.6% 10.5% 8.4% p<0.01
COPD + 2.0% 2.6% 4.5% 3.6% p<0.01
Peptic Ulcer + 5.2% 3.9% 7.1% 6.7% 0.039
CTD + 1.3% 1.2% 3.2% 3.3% p<0.01
DM Uncomplicated 15.6% 21.8% 19.0% 19.3% p<0.01
end-organ damage 1.1% 2.5% 2.3% 2.8%

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CKD + 3.1% 4.6% 8.6% 5.0% p<0.01
Hemiplegia + 1.6% 2.0% 2.7% 3.4% p<0.01
Solid Tumor + 5.3% 7.4% 16.9% 9.7% p<0.01
Liver Disease mild 3.2% 3.1% 2.1% 5.2% p<0.01
moderate to severe 1.1% 0.6% 1.7% 5.1%
Hypertention + 39.2% 46.1% 47.6% 44.7% p<0.01
Liver cirrhosis + 1.7% 2.2% 4.0% 7.0% p<0.01
CCI 3.9±2.2 4.5±2.1 5.5±2.3 4.9±2.6 p<0.01
Gallbladder stones + 22.1% 15.6% 12.8% 13.4% p<0.01
Jaundice + 6.8% 16.1% 18.5% 15.1% p<0.01
Biliary stents + 0.47% 1.8% 5.9% 2.1% p<0.01
ALB 3.8±0.7 3.7±0.7 3.4±0.8 3.7±0.6 p<0.01
CRP 9.2±10.9 12.6±11.1 13.2±21.1 8.3±11.0 p<0.01
Positive bile culture 47.55% 30.58% 32.32% 83.33% p<0.01
Cardiovascular dysfunction 2.78% 5.15% 7.49% 5.20% p<0.01
Neurological dysfunction 1.90% 3.47% 5.44% 2.77% p<0.01
Respiratory dysfunction 1.85% 1.78% 4.88% 2.93% p<0.01
Renal dysfunction 4.15% 7.98% 12.71% 7.27% p<0.01
Hepatic dysfunction 3.85% 5.82% 12.03% 10.82% p<0.01
Hematological dysfunction (PLT<100000)
3.00% 5.43% 4.87% 5.52% p<0.01
WBC>18000 + 10.3% 18.8% 15.9% 9.4% p<0.01
Palpable tender mass in RUQ

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+ 23.7% 29.8% 26.3% 21.6% p<0.01
Duration of complaints > 72hrs
+ 26.7% 31.6% 25.9% 22.9% p<0.01
Marked local inflammation
+ 26.8% 32.8% 19.5% 10.2% p<0.01
Severity (TG13)
Grade 1 1219(57.9%) 400(19.1%) 189(9.0%) 298(14.2%) p<0.01
Grade 2 1341(58.5%) 586(25.6%) 186(8.1%) 179(7.8%)
Grade 3 389(41.6%) 253(27.2%) 156(16.8%) 135(14.5%)
% Grade 3 13.1% 20.4% 29.4% 22.1% p<0.01
30day Mortality
Grade 1 3/1219: 0.25% 2/400: 0.50% 9/189: 4.76% 4/298: 1.34% p<0.01
Grade 2 5/1341: 0.37% 0/586: 0.00% 8/186: 4.30% 3/179: 1.68%
Grade 3 16/387: 4.13% 2/253: 0.79% 21/156: 13.46% 8/135: 5.93%
Overall 90-day 23 (0.8%) 8 (0.6%) 52 (9.8%) 21 (3.4%) p<0.01
PS; performance status, CCI; Charlson Comorbidity Index, CKD; Chronic Kidney Disease, DM; Diabetes
Mellitus, CVD; Cerebrovascular Disease, MI; Myocardial infarction, CHF; Congestive heart failure, PVD;
Peripheral Vascular Disease, CTD; Connective Tissue Disease.

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Table 2 Charlson comorbidity index score and mortality rates in each group
Index Group A Group B Group C Group D
mortality mortality mortality mortality
N 30-d 90-d N 30-d 90-d N 30-d 90-d N 30-d 90-d
0～2 962 1 (0.1) 0 187 0 0 27 1 (3.4) 1 (3.4) 110 1 (0.9) 0
3～5 1453 5 (0.3) 8 (0.5) 702 0 1 (0.1) 237 12 (5.0) 15 (6.2) 266 5 (1.9) 8 (3.0%)
6～8 465 15 (3.2) 12 (2.6) 304 4 (1.3) 6 (2.0) 222 18 (8.1) 25 (11.3) 189 3 (1.6) 6 (3.2%)
>9 65 3 (4.6) 3 (4.6) 46 0 1 (2.2) 45 7(15.6) 11 (24.4) 47 6 (12.2) 7 (14.3%)
unknown 2 0 0 0
Total 2947 1239 531 612
>6 (%) 18.0 28.3 50.3 38.6

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(%)
Cochran- <0.001 <0.001 0.054 0.003 0.019 <0.001 0.004 <0.001
Armitage
chi-square <0.001 <0.001 0.012 0.009 0.064 0.002 <0.001 <0.001

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Table 3 Comparison of straight forward and subsequent cholecystectomy after gallbladder drainage in surgical outcomes according to
interval between admission and cholecystectomy
Primary cholecystectomy (Group A) Subsequent cholecystectomy after gallbladder drainage (GroupB)
d0-3 d4-7 d8-30 >d31 total p value d0-3 d4-7 d8-30 >d31 total p value p value
(A vs B)
All Grades
Total number 2035 179 342 294 2850 - 153 125 482 439 1211 - -
LapC 1334 116 248 223 1921 0.001 *** 92 76 288 263 726 0.977 <0.001
(67.4%) (60.6%)
Conversion (%) 6.1 7.3 4.4 7.5 6.1 0.368 9.8 6.4 8.1 8.0 8.5 0.779 0.028
Primary open 26.9 27.9 21.6 14.3 25.0 <0.001 ***,††
28.8 30.4 30.9 30.3 31.0 0.968 0.001
cholecystectomy (%)
BDI rate (%) 1.1 2.8 1.5 0.7 1.2 0.199 1.3 0.8 0.8 2.1 1.3 0.405 0.878
Blood loss (ml) 40 20 10 10 23 <0.001 **,*** 100 50 45 31 50 0.001 **,*** 0.069
Length ope (min) 122.0 125.5 127.0 141.5 120.0 <0.001 **,*** 127.0 140.0 139.0 134 133.5 0.665 <0.001

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Morbidity rate 9.0 7.3 6.4 7.5 8.6 0.353 14.4 12.8 12.2 10.3 12.2 0.534 0.001
30d mortality 0.74 0.00 1.17 1.02 0.84 0.500 0.65 0.80 0.21 0.23 0.33 0.644 0.133
90d mortality 0.79 0.00 0.58 0.68 0.81 0.672 1.31 0.80 0.62 0.46 0.67 0.732 1.000
Number of patients in 97 of GroupA and 40 of GroupB were excluded because of missing data.
Statistical significance 0.01 *:d0-3 vs d4-7, **:d0-3 vs d8-30, ***:d0-3 vs >d31, †
:d4-7 vs d8-30, ††
:d4-7 vs >d31, §
:d8-30 vs >d31

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Table 4 Comparison of surgical outcomes in straight forward and subsequent cholecystectomy after gallbladder drainage according to
severity grade
Primary cholecystectomy (Group A) Subsequent cholecystectomy after gallbladder drainage (GroupB)
Grade 1 Grade 2 Grade 3 Total p value Grade 1 Grade 2 Grade 3 Total p value p value
(A vs B)
Number of pts 1219 1341 387 2947 - 400 586 253 1239 -
LapC 924 868 189 1981 <0.001 *,**,†
253 325 152 730 0.047 <0.001
(%LapC) (67.2%) (58.9%) <0.01
Conversion (%) 4.5 6.8 7.2 5.9 0.025 7.8 10.4 4.3 8.3 0.012 0.005
Primary open 16.8 27.4 41.6 24.9 <0.001 *,**,†
26.5 31.4 33.6 30.3 0.112 <0.001
cholecystectomy (%)
BDI rate (%) 1.2 1.0 1.6 1.2 0.709 2.3 0.7 1.2 1.3 0.100 0.759
Blood loss (ml) 10 50 100 22 <0.001 *,**,†
27 50 65 50 0.003 ** <0.01
Length ope (min) 120 127 132 120 0.001 ** 133 137 140 135 0.467 0.058

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Morbidity rate 4.2 9.4 17.3 8.3 <0.001 *,**,†
9.5 12.1 15.0 11.9 0.101 <0.001
30d mortality 0.25 0.37 4.13 0.81 <0.001 **,†
0.50 0.00 0.79 0.32 0.135 0.095
90d mortality 0.25 0.45 3.62 0.78 <0.001 **,†
0.75 0.51 0.79 0.65 0.855 0.844
Statistical significance <0.01 *:Grade1 vs Grade2, **:Grade1 vs Grade3, †
:Grade2 vs Grade3

AcceptedArticle
Table 5 Survival analysis of 30-day mortality in patients with Grade1 and Grade2 AC
Survivor Non-survivor Univariate Multivariate odds 95%CI
(N=2677) (N=21) p-value p-value ratio
Age 0 ≦70 1584 6 <0.01 0.302
1 70＜ 1093 15
Sex 0 M 1712 12 0.518 0.518
1 F 965 9
BMI 0 ＜20 349 9 <0.01 0.011
1 20≦,＜25 1360 7 <0.01 0.241 (0.088 - 0.659)
2 25≦ 968 5 0.032 0.290 (0.094 - 0.898)
PS 0 0,1,2 2571 17 <0.01 0.054
1 3,4 106 4
Anticoagulation
0 - 2256 15 0.108 0.719
1 + 421 6
Charlson Comorbidity Index
0 0～5 2140 9 <0.01 <0.01 4.433 (1.816 - 10.822)
1 6≦ 537 12
Jaundice 0 - 2414 18 0.495 0.721
1 + 263 3
CRP 0 ＜10 1651 14 0.639 0.447
1 10≦ 1026 7
WBC>18000
0 - 2356 19 0.729 0.757

AcceptedArticle
1 + 321 2
Palpable tender mass in RUQ
0 - 2022 18 0.279 0.213
1 + 655 3
Duration of complaints > 72hrs
0 - 1998 17 0.507 0.569
1 + 679 4
Marked local inflammation
0 - 2014 17 0.545 0.446
1 + 663 4

AcceptedArticle
Table 6 Survival analysis of 30-day mortality in patients with Grade III AC
Survivor Non-survivor Univariate Multivariate odds 95%CI
(N=591) (N=20) p-value p-value ratio
Age 0 ≦70 244 6 0.313 0.815
1 70＜ 347 14
Sex 0 M 403 14 0.864 0.730
1 F 188 6
BMI 0 ＜20 96 7 0.072 0.265
1 20≦,＜25 294 9
2 25≦ 201 4
PS 0 0,1,2 532 14 <0.01 0.156
1 3,4 59 6
Anticoagulation 0 - 367 16 0.104 0.057
1 + 224 4
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
CRP 0 ＜10 266 6 0.184 0.371
1 10≦ 325 14
Categories of organ dysfuntion
0 - 457 13 0.198 0.493

AcceptedArticle
1 + 134 7
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
Renal 0 - 385 10 0.164 0.073
1 + 206 10
Hepatic 0 - 371 14 0.510 0.360
1 + 220 6
Hematological 0 - 459 17 0.437 0.513
1 + 132 3

AcceptedArticle
Table 7 Mortality rate in each therapeutic groups of Grade I and II AC according to
prognostic factors
30day-mortality
GroupA GroupB GroupC GroupB+C p-value
(N=1469) (N=734) (N=225) (N=959)
No positive 3 0 3 3 0.558 (A vs B)
PF 0.26 0.00 3.03 0.50 0.008 (A vs C)
0.421 (A vs B+C)
Any positive 2 2 7 9 1.000 (A vs B)
PFs 0.61 0.86 5.56 2.51 0.002 (A vs C)
0.066 (A vs B+C)
90day-mortality
(N=1265) (N=640) (N=202) (N=842)

AcceptedArticle
PF 0.31 0.23 4.65 0.97 0.001 (A vs C)
0.134 (A vs B+C)
PFs 0.69 2.38 7.76 4.29 <0.001 (A vs C)
0.005 (A vs B+C)
PFs; Charlson Index ≧6, BMI<20

AcceptedArticle
Table 8 Mortality rate in each therapeutic groups of Grade III AC according to
prognostic factors
30day-mortality
(N=260) (N=180) (N=93) (N=273)
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)
PFs 9.30 0.00 14.29 6.09 0.403 (A vs C)
0.426 (A vs B+C)
90day-mortality
(N=219) (N=168) (N=74) (N=242)

AcceptedArticle
PF 1.31 0.00 16.22 4.14 0.001 (A vs C)
0.164 (A vs B+C)
PFs 10.61 0.00 24.32 9.28 0.089 (A vs C)
0.794 (A vs B+C)
N A; Statistical value could not analyzed
PF; jaundice, neurological dysfunction, respiratory dysfunction

AcceptedArticle
Whole cohort
N=5459
Fig1
Incomplete data collection
in diagnostic criteria
N=98
(Tentative) analysis cohort
N=5329
Primary
cholecystectomy
n=2947 (55.3%)
Gallbladder drainage alone
n=531 (10.0%)
Cholecystectomy
following gallbladder drainage
n=1239 (23.3%)
Medical therapy
n=612 (11.5%)
GroupA GroupB GroupC GroupD
Gallbladder drainage
in severity assessment
N=23
in Treatment for acute cholecystitis
N=9

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