Results of the Tokyo Consensus Meeting Tokyo Guidelines



# Introduction
Guidelines should not only be based on evidence but should also meet the needs of current medical practice. We thought that adequate discussion, to receive feed-Offprint requests to: T. Mayumi and how they are refl ected in fi nal version of the Guidelines.

## Changes made in the guidelines at the international consensus meeting for the management of acute cholangitis and cholecystitis (tokyo, april 1-2, 2006)
In order to prepare international guidelines based on the "Evidence-Based Practice Guidelines for the Management of Acute Cholangitis and Cholecystitis", draft guidelines were modifi ed several times by the Organizing Committee, and discussion was carried out, via email, with worldwide experts on acute cholangitis and acute cholecystitis before the International Consensus Meeting.
The discussions were followed by the 2-day International Consensus Meeting, held in Tokyo on April 1-2, 2006, with the attendance of about 300 world experts specializing in acute cholangitis and acute cholecystitis, in order to prepare evidence-based guidelines. Attendees from abroad are listed (Page 8-10). Discussions at the Meeting are outlined below.

## Diagnostic criteria for acute cholangitis
Some panelists proposed that "History of biliary disease" should be included in the diagnostic criteria for acute cholangitis [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref]. A history of biliary disease, such as gallstones, a history of previous biliary surgery, and having an indwelling biliary stent play an important role in making the diagnosis, as agreed upon by many participants at the Consensus Meeting. But other panelists disagreed and proposed different criteria [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref].
Because not only an increase but also a decrease in the WBC count indicates infl ammation, "leukocytosis" was changed to "abnormal WBC count". Because Creactive protein (CRP) is sometimes not elevated, "or other evidence of infl ammatory response" was added. "WBC count" and "elevation of CRP level or other evidence of infl ammatory response" are separate items.
As aspartate aminotransferase (AST) and alanine aminotransferase (ALT) sometimes increase in acute cholangitis, "abnormal liver function tests, alkaline phosphatase (ALP), -GTP, AST, ALT)" was added.
Imaging fi ndings of infl ammatory changes in acute cholangitis are also useful for diagnosis. "Biliary dilatation or etiology (stricture, tumor, stones)" [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref] was changed to "biliary dilatation, infl ammatory fi ndings, or etiology (stricture, tumor, stones)" [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref].
Two ways of making a defi nite diagnosis were proposed; in revision 1 [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref] , these were: (1) three or four items in A (Charcot's triad) and (2) any item in A + two items in B + C, and in Revision 2 [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref] , these were: Any item in A + two items in B + C.
As more than 90% of the participants at the Tokyo Consensus Meeting agreed on four criteria in revision 1 [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref] , a history of biliary disease was included, and abnormal WBC count and elevation of CRP or other evidence of infl ammatory response were included in the fi nal version of the diagnostic criteria for acute cholangitis [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref].
In [fig_ref] Table 1: Diagnostic criteria for acute cholangitis [/fig_ref] , two or more items in A were defi ned as a suspected diagnosis, and either: (1) Charcot's triad (items 2 + 3 + 4 in A) or (2) two or more items in A plus both items in B + C, were defi ned as a defi nite diagnosis of acute cholangitis. [fig_ref] Table 2: Severity assess ment criteria for acute cholangitis [/fig_ref] More than 70% of the participants at the Tokyo Consensus Meeting agreed that the severity of acute cholangitis should be divided into three grades, severe (grade III), moderate (grade II), and mild (grade I). To stratify acute cholangitis into three grades, two different criteria were necessary, and it was decided to use "onset of organ dysfunction" and "response to the initial medical treatment" as criteria for the severity assessment of acute cholangitis.

## Severity assessment criteria for acute cholangitis
"Severe (grade III)" acute cholangitis was defi ned as that associated with any one of the categories of organ/ system dysfunction or severe local infl ammation listed in [fig_ref] Table 2: Severity assess ment criteria for acute cholangitis [/fig_ref]. This was supported by more than 90% of the panelists at the International Consensus Meeting. But the thresholds of these categories were not discussed at the Summary session.
There was some argument about whether the score on an acute physiology scoring system, such as acute physiology and chronic health evaluation (APACHE) II, or a multiple organ dysfunction scoring system, such as Marshall's system or the sepsis-related organ failure assessment (SOFA) system should be used as a criterion for severe (grade III) acute cholangitis. The principal advantage of these scoring systems is that they provide gradations of severity. The APACHE II system has been validated, especially for critical care patients, including patients with sepsis, and acute cholangitis can be interpreted as a subset of sepsis. The disadvantage of these scoring systems is that the scores are sometimes troublesome to calculate, and critically speaking, they have not been satisfactory validated in patients with acute cholangitis. The vote on this argument showed that 37.8% of the panelists supported the use of APACHE II and 62.2% did not. As a result of this vote, the chairmen of this session, Drs. Yoshifumi Kawarada (Japan) and Henry Pitt (United States), had proposed to remit the fi nal decision of whether or
[formula] ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- Defi nite diagnosis [/formula]
(1) All items in A (Charcot's triad) (2) One or two items in A + all items in B + C
[formula] ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- Defi nite diagnosis [/formula]
(1) Three or 4 items in A (Charcot's triad)
(2) Any item in A + 2 items in B + C Note: acute hepatitis and other causes of acute abdomen should be excluded (C) Proposed revision 2 at International Meeting A. Clinical context and manifestations 1. Fever and/or chills 2. Jaundice 3. Abd. pain (RUQ, epigastric) B. Laboratory data 4. Abnormal WBC count 5. Elevation of CRP level or other evidence of infl ammatory response 6. Abnormal liver function tests (ALP, -GTP, AST, ALT) C. Imaging fi ndings 7. Biliary dilatation, infl ammatory fi ndings, or etiology (stricture, tumor, stones)
[formula] ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- Defi nite diagnosis [/formula]
(1) Any item in A + 2 items in B + C
[formula] ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- Suspected diagnosis [/formula]
Two or more items in A Defi nite diagnosis
(1) Charcot's triad (2 + 3 + 4) (2) Two or more items in A + both items in B + C a Abnormal WBC count, increased serum CRP level, and other changes indicating infl ammation b Increased serum ALP, -GTP (GGT), AST, and ALT levels not APACHE II should be included as a criterion for severe (grade III) acute cholangitis to the Organizing Committee, and this proposal was approved by the audience.
Neither "recurrent symptom" nor "malignancy as etiology" always shows moderate (grade II) acute cholan-gitis. Therefore, both of these were deleted from the criteria for "moderate (grade II)" acute cholangitis. The thresholds of high fever and WBC counts were not decided.
After the International Meeting, all the criteria and thresholds of severity of acute cholangitis were dis- "Moderate (grade II)" acute cholangitis is defi ned as acute cholangitis that does not respond to the initial medical treatment a and is not associated with organ dysfunction Severe (grade III) acute cholangitis "Severe (grade III)" acute cholangitis is defi ned as acute cholangitis that is associated with the onset of dysfunction at least in any one of the following organs/systems: 1. Cardiovascular system Hypotension requiring dopamine 5 g/kg per min, or any dose of dobutamine 2. Nervous system Disturbance of consciousness 3. Respiratory system PaO 2 /FiO 2 ratio <300 4. Kidney Serum creatinine >2.0 mg/dl 5. Liver PT-INR > 1.5 6. Hematological system Platelet count <100 000/l Note: compromised patients, e.g., elderly (>75 years old) and patients with medical comorbidities, should be closely monitored a General supportive care and antibiotics cussed and decided or by the Organizing Committee [fig_ref] Table 2: Severity assess ment criteria for acute cholangitis [/fig_ref]. The defi nition of moderate (grade II) acute cholangitis was changed to: "acute cholangitis that does not respond to the initial medical treatment and is not associated with organ dysfunction [fig_ref] Table 2: Severity assess ment criteria for acute cholangitis [/fig_ref]. [fig_ref] Table 3: Diagnostic criteria for acute cholecystitis [/fig_ref] After the discussion during the Tokyo International Consensus Meeting, almost unanimous agreement was achieved [fig_ref] Table 3: Diagnostic criteria for acute cholecystitis [/fig_ref]. However, 19% of the panelists from abroad expressed the necessity for minor modifi cations, because the diagnostic criteria did not include technetium hepatobiliary iminodiacetic acid (Tc-HIDA) scans as an item in the provisional version. Some panelists insisted that "suspected diagnosis" was not necessary, and that only "defi nite diagnosis" should be included in the diagnostic criteria for acute cholecystitis. There was no discussion on whether, if "suspected diagnosis" was deleted, how the defi nition of defi nite diagnosis should be modifi ed.

## Diagnostic criteria for acute cholecystitis
After the International Meeting, "A. Local signs of infl ammation"; "B. Systemic signs of infl ammation" and "C. Imaging fi ndings" were clearly specifi ed in the diagnostic criteria for acute cholecystitis [fig_ref] Table 3: Diagnostic criteria for acute cholecystitis [/fig_ref]. Tc-HIDA scan was included in "C. Imaging fi ndings". "Suspected diagnosis" was deleted from the criteria. [fig_ref] Table 4: Severity assessment criteria for acute cholecystitis [/fig_ref] Before the International Meeting, "Severe (grade III)" acute cholecystitis was defi ned as that associated with dysfunction in any one of the organs/systems or any one of the severe local infl ammation categories listed in [fig_ref] Table 4: Severity assessment criteria for acute cholecystitis [/fig_ref]. At the Meeting, concepts of the severity of acute cholecystitis were discussed and changed as shown below. The concept of the fi nal version of the severity assessment of acute cholecystitis, "severe (grade III)" acute cholecystitis was defi ned as that associated with organ dysfunction, "moderate (grade II)" acute cholecystitis was defi ned as that associated with diffi culty to perform cholecystectomy due to local infl ammation, and "mild (grade I)" acute cholecystitis was defi ned as that which does not meet the criteria of "severe" or "moderate" acute cholecystitis.

## Severity assessment criteria for acute cholecystitis

## . imaging fi ndings characteristic of acute cholecystitis ----------------------------------------------------------------------------------------------------------------------------------------------------------------------
In the severity assessment initially proposed at the Meeting "moderate (grade II)" acute cholecystitis was associated with any of the following conditions: (1) abnormal WBC (>15 000, >18 000? threshold was not decided), (2) palpable infl ammatory mass, (3) onset more than 72-96 h and (4) Serious wall thickening and fl uid collection around the gallbladder.
Some panelists insisted that "serious" should be changed to "thickening" or deleted. Whether threshold of wall thickening should be included was not discussed.
If included, the extent of the thickness, whether 6-7 mm or 8 mm, or twice that of the normal gallbladder wall, also remained as questions. Also, it was queried whether both the thickness of the gallbladder wall and fl uid collection around the gallbladder were necessary for the diagnosis of moderate acute cholecystitis?
Panelists suggested that liver cirrhosis should be described in a Note.
After the International Meeting, each item and its threshold were discussed and decided on by the Organizing Committee. "Severe local infl ammation" was deleted from the criteria for severe (grade III) acute cholecystitis [fig_ref] Table 4: Severity assessment criteria for acute cholecystitis [/fig_ref]. "Onset more than 72-96 h" was changed to "prolonged local signs of infl ammation" in the criteria for moderate (grade II) acute cholangitis.

## Flowcharts
Flow charts for the management of acute cholangitis and acute cholecystitis according to severity were also discussed and modifi ed at the Meeting. Severe (grade III) acute cholecystitis "Severe" acute cholecystitis is associated with dysfunction of any one of the following organs/systems 1. Cardiovascular dysfunction (hypotension requiring treatment with dopamine 5 g/kg per min, or any dose of dobutamine) 2. Neurological dysfunction (decreased level of consciousness) 3. Respiratory dysfunction (PaO 2 /FiO 2 ratio <300) 4. Renal dysfunction (oliguria, creatinine >2.0 mg/dl) 5. Hepatic dysfunction (PT-INR > 1.5) 6. Hematological dysfunction (platelet count <100 000/mm 3 ) Almost all panelists agreed with the fl owchart for "General guidance for the management of acute biliary infection" . But in the fl owchart for the management of acute cholangitis , panelists suggested that medical treatment should be begun before assessment of the severity of acute cholangitis. Therefore, the fl owchart was changed, as shown in .
In the fl owchart for the management of acute cholecystitis , because the concept of severity of cholecystitis was changed, this fl owchart was also modifi ed . As "severe (grade III)" acute cholecystitis is associated with organ dysfunction, urgent/early drain-age was preferred to urgent/early cholecystectomy for "severe (grade III)" cholecystitis. Similarly, as "moderate (grade II)" acute cholecystitis is associated with diffi culty to perform cholecystectomy due to local infl ammation, urgent/early drainage was preferred to early/elective cholecystectomy for "moderate (grade II)" cholecystitis also.

## Defi nitions of severity: mild to severe (grades i-iii)
Before the Meeting, the severity of both acute cholangitis and acute cholecystitis was classifi ed as mild, moderate, and severe. But, with these criteria, even "moderate" acute cholangitis and "moderate" acute cholecystitis sometimes cause organ failure and even death. This defi nition could have confused users of these Guidelines, as "moderate" diseases are usually regarded as those having a good course without high morbidity or mortality. Therefore, instead of using the categories "mild", "moderate", and "severe", the categories "grades I, II, and III" were used as the severity classifi cations for both acute cholangitis and acute cholecystitis.

# Conclusion
In the preparation of the Guidelines for Acute Biliary Tract Infections (Acute Cholangitis and Cholecystitis), we found that there was not a suffi cient volume of highquality research. In this article, we have reported the process of developing the Guidelines, ranging from the identifi cation of current clinical practice for acute biliary tract infection, to the proposals for the Guidelines and the improvements based on consensus. The Guidelines are the world's fi rst international guidelines for the clinical management of acute biliary tract infections (acute cholangitis and cholecystitis), and it is strongly expected that they may be used broadly in everyday medical practice throughout the world as Guidelines that fully refl ect local and regional conditions.
[fig] Fig: 2a,b. Flowcharts for the management of acute cholangitis. a Original; b modifi ed at the Meeting a b [/fig]
[table] Table 1: Diagnostic criteria for acute cholangitis [/table]
[table] Table 2: Severity assess ment criteria for acute cholangitis (A) Proposed severity assessment criteria at International Meeting "Severe (grade III)" acute cholangitis "Severe (grade III)" acute cholangitis is that associated with dysfunctions of at least one of the following organs/systems Mild (grade I)" acute cholangitis is defi ned as acute cholangitis that responds to the initial medical treatment a Moderate (grade II) acute cholangitis [/table]
[table] Table 3: Diagnostic criteria for acute cholecystitis (A) Proposed at International Meeting 1.(1) Murphy's sign, (2) RUQ, mass/pain/tenderness, (3) rigidity/muscle guarding, (4) rebound tenderness 2. (1) Fever, (2) abnormal WBC count, (3) elevated CRP 3 [/table]
[table] Table 4: Severity assessment criteria for acute cholecystitis [/table]