Flowcharts for the diagnosis and treatment of acute cholangitis and cholecystitis: Tokyo Guidelines

with severe (grade III) acute cholecystitis, multiorgan support is a critical part of management. Biliary peritonitis due to perforation of the gallbladder is an indication for urgent cholecystectomy and/or drainage. Delayed elective cholecystectomy may be performed after initial treatment with gallbladder drainage and improvement of the patient's general medical condition.

# Introduction
Acute biliary infl ammation/infection is classifi ed as either acute cholangitis or acute cholecystitis, and ranges from mild forms that improve with medical treatment to severe forms that require intensive care and urgent intervention. The medical condition of a patient with biliary infl ammation/infection is likely to deteriorate rapidly and the condition can become life-threatening. Early diagnosis should be made based on clinical signs/ symptoms and laboratory fi ndings. The type and timing of treatment should be based on the grade of severity of the disease.

# Abstract
Diagnostic and therapeutic strategies for acute biliary infl ammation/infection (acute cholangitis and acute cholecystitis), according to severity grade, have not yet been established in the world. Therefore we formulated fl owcharts for the management of acute biliary infl ammation/infection in accordance with severity grade. For mild (grade I) acute cholangitis, medical treatment may be suffi cient/appropriate. For moderate (grade II) acute cholangitis, early biliary drainage should be performed. For severe (grade III) acute cholangitis, appropriate organ support such as ventilatory/circulatory management is required. After hemodynamic stabilization is achieved, urgent endoscopic or percutaneous transhepatic biliary drainage should be performed. For patients with acute cholangitis of any grade of severity, treatment for the underlying etiology, including endoscopic, percutaneous, or surgical treatment should be performed after the patient's general condition has improved. For patients with mild Although endoscopic and laparoscopic techniques have advanced recently (level 1b-2b), 1,2 the treatment of severe acute biliary infl ammation/infection still results in fatalities and increased hospital costs. To our knowledge, there are no defi nite diagnostic and therapeutic guidelines for acute biliary infl ammation/infection according to the grade of severity of the disease. This article describes the management strategy for biliary infl ammation/infection in accordance with the severity of the biliary disease. Guidelines were developed, based on best clinical evidence and discussions at the International Consensus Meeting held in Tokyo on April 1-2, 2006.

## General guidance for the management of acute biliary infl ammation/infection
A fl owchart showing general guidance for the management of acute biliary infl ammation/infection is presented in .

## Clinical presentation
Clinical fi ndings associated with acute cholangitis include abdominal pain, jaundice, fever (Charcot's triad), and rigor. The triad was already reported as an indicator of hepatic fever by Charcot in 1877, [bib_ref] De la fi evre hepatique symptomatique Comparison avec la fi evre uroseptique, Charcot [/bib_ref] and has been, historically, used as the generally accepted clinical fi ndings of acute cholangitis. About 50%-70% of patients with acute cholangitis develop all three symptoms (level 2b-4). 4-7 Reynolds' pentad (Charcot's triad plus shock and a decreased level of consciousness) was presented in 1959, when Reynolds and Dargan 8 defi ned acute obstructive cholangitis. The pentad is often used to indicate severe (grade III) cholangitis, but shock and a decreased level of consciousness are observed in only 30% or fewer patients with acute cholangitis (level 2b-4). 4-7 A history of biliary disease, such as gallstones, previous biliary procedures, or the placement of a biliary stent are factors that are very helpful to suggest a diagnosis of acute cholangitis.
Clinical symptoms of acute cholecystitis include abdominal pain (right upper abdominal pain), nausea, vomiting, and fever (level 2b-4). [bib_ref] Diagnostic approaches in acute cholecystitis; a prospective study of 1333 patients with..., Eskelinen [/bib_ref] [bib_ref] Clinical presentation of acute abdomen: study of 600 patients, Staniland [/bib_ref] [bib_ref] Does this patient have acute cholecystitis?, Trowbridge [/bib_ref] The most typical symptom is right epigastric pain. Tenderness in the right upper abdomen, a palpable gallbladder, and Murphy's sign are the characteristic fi ndings of acute cholecystitis. A positive Murphy's sign has a specifi city of 79%-96% (level 2b-3b) 9,11 for acute cholecystitis.

## Blood tests
The diagnosis of acute cholangitis requires a white blood cell count; measurement of the C-reactive protein level; and liver function tests, including alkaline phosphatase, gamma-glutamyltranspeptidase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin. Assessment of the severity of the illness requires knowledge of the platelet count, blood urea nitrogen, creatinine, and prothrombin time (PT). Blood cultures are also helpful for severity assessment, as well as for the selection of antimicrobial drugs. Hyperamylasemia is a useful parameter to identify complications such as choledocholithiasis causing biliary pancreatitis (level 1a). [bib_ref] Predictors of common bile duct stones prior to cholecystectomy: a meta-analysis, Abboud [/bib_ref] There is no specifi c blood test for acute cholecystitis; however, the white blood cell count and the measurement of C-reactive protein is very useful in confi rming an infl ammatory process. Bilirubin, blood urea nitrogen, creatinine, and PT are very useful in assessing the disease severity status of the patient.

## Diagnostic imaging
Abdominal ultrasound (US) and abdominal computerized tomography (CT) with intravenous contrast are very helpful studies in evaluating patients with acute [bib_ref] Ultrasonography by emergency physicians in patients with suspected cholecystitis, Rosen [/bib_ref] [bib_ref] Performance and interpretation of focused right upper quadrant ultrasound by emergency physicians, Kendall [/bib_ref] The role of diagnostic imaging in acute cholangitis is to determine the presence/absence of biliary obstruction, the level of the obstruction, and the cause of the obstruction, such as gallstones and/or biliary strictures. Assessment should include both US and CT. These studies complement each other and CT may better demonstrate dilatation of the bile duct and pneumobilia.
Some of the characteristic fi nding of acute cholecystitis include an enlarged gallbladder, thickened gallbladder wall, gallbladder stones and/or debris in the gallbladder, sonographic Murphy's sign, pericholecystic fl uid, and pericholecystic abscess. Sonographic Murphy's sign is a very reliable fi nding of acute cholecystitis, with a specifi city exceeding 90% (level 3b,4). 15,16 CT scan or even plain X-ray may demonstrate free air, pneumobilia, and ileus.

## Differential diagnosis
Diseases which should be differentiated from acute cholangitis are acute cholecystitis, gastric and duodenal ulcer, acute pancreatitis, acute hepatitis, and septicemia of other origins. Diseases which should be differentiated from acute cholecystitis are gastric and duodenal ulcer, hepatitis, pancreatitis, gallbladder cancer, hepatic abscess, Fitz-Hugh-Curtis syndrome, right lower lobar pneumonia, angina pectoris, myocardial infarction, and urinary infection.

## Flowchart for the management of acute cholangitis
A fl owchart for the management of acute cholangitis is shown in [fig_ref] Figure 2: Flowchart for the management of acute cholangitis drainage should be considered [/fig_ref]. The treatment of acute cholangitis should be guided by the grade of severity of the disease. Biliary drainage and antibiotics are the two most important elements of treatment. When a diagnosis of acute cholangitis is suspected, medical treatment, including nil per os (NPO) and the use of intravenous fl uids, antibiotics, and analgesia, together with close monitoring of blood pressure, pulse, and urinary output should be initiated. Simultaneously, a severity assessment of the cholangitis should be documented, even if it is mild. Frequent reassessment is important, and patients may need to be reclassifi ed as having mild (grade I), moderate (grade II), or severe (grade III) disease, based on the response to medical treatment. Appropriate treatment should be performed in accordance with the severity grade. Patients with concomitant diseases such as acute pancreatitis or malignant tumor, and elderly patients are likely to progress to a severe level; therefore, such patients should be monitored frequently.

## Mild (grade i) acute cholangitis
Medical treatment may be suffi cient. Biliary drainage is not required in most cases. However, for nonresponders to medical treatment, the necessity of biliary

## Moderate (grade ii) acute cholangitis
Patients with acute cholangitis who do not respond to medical treatment have moderate (grade II) acute cholangitis. In these patients, early endoscopic or percutaneous drainage or even emergent operative drain-age with a T-tube should be performed. A defi nitive procedure should be performed to remove the cause of the obstruction once the patient is in a stable condition.

## Severe (grade iii) acute cholangitis
Patients with acute cholangitis and organ failure are classifi ed as having severe (grade III) acute cholangitis. These patients require organ support, such as ventilatory/circulatory management (e.g., endotracheal intubation, artifi cial respiration management, and the use of vasopressin), and treatment for disseminated

## Results of the tokyo international consensus meeting
At the International Consensus Meeting, responses to the fl owcharts for the management of the different grades of acute cholangitis were elicited and a consensus was reached .

## Flowchart for the management of acute cholecystitis
A fl owchart for the management of acute cholecystitis is shown in . Early cholecystectomy is recommended for most patients, with laparoscopic cholecystectomy as the preferred method. Among high-risk patients, percutaneous gallbladder drainage is an alternative therapy for those patients who cannot safely undergo urgent/ early cholecystectomy (level 4). [bib_ref] Is percutaneous cholecystostomy the optimal treatment for acute cholecystitis in the very..., Sugiyama [/bib_ref] [bib_ref] Treatment of acute cholecystitis in non-critically ill patients at high surgical risk:..., Chopra [/bib_ref] When a diagnosis of acute cholecystitis is suspected, medical treatment, including NPO, intravenous fl uids, antibiotics, and analgesia, together with close monitoring of blood pressure, pulse, and urinary output should be initiated. Simultaneously, the grade of severity needs to be established. Appropriate treatment should be performed in accordance with the severity grade. The assessment of operative risk should also be evaluated based on the severity grade.
After the acute infl ammation has been resolved by medical treatment and gallbladder drainage, it is desirable to perform a cholecystectomy to prevent recurrence. In surgically high-risk patients with cholecystolithasis, medical support after percutaneous cholecystolithotomy should be considered (level 4). [bib_ref] Nonsurgical treatment of cholecystolithiasis with percutaneous transhepatic cholecystoscopy, Inui [/bib_ref] [bib_ref] Gallstones in critically ill patients with acute calculous cholecystitis treated by percutaneous..., Boland [/bib_ref] [bib_ref] Gallstone removal with a modifi ed cholecystoscope: an alternative to cholecystectomy in..., Majeed [/bib_ref] For patients with acalculous cholecystitis, cholecystectomy is not required, because recurrence of acute acalculous cholecystitis after gallbladder drainage is rare (level 4). [bib_ref] Is percutaneous cholecystostomy the optimal treatment for acute cholecystitis in the very..., Sugiyama [/bib_ref] [bib_ref] Percutaneous transhepatic cholecystostomy for acute acalculous cholecystitis, Shirai [/bib_ref] 

## Mild (grade i) acute cholecystitis
Early laparoscopic cholecystectomy is the preferred treatment. Elective cholecystectomy may be selected (if early cholecystectomy is not performed) in order to improve other medical problems.

## Moderate (grade ii) acute cholecystitis
Early laparoscopic or open cholecystectomy is preferred. If a patient has serious local infl ammation making early cholecystectomy diffi cult, then percutaneous or operative drainage of the gallbladder is recommended. Elective cholecystectomy can be performed after improvement of the acute infl ammatory process.

## Severe (grade iii) acute cholecystitis
Severe (grade III) acute cholecystitis is accompanied by organ dysfunction and/or severe local infl ammation. Appropriate organ support in addition to medical treatment is necessary for patients with organ dysfunction. Management of severe local infl ammation by percutaneous gallbladder drainage and/or cholecystectomy is needed. Biliary peritonitis due to perforation of the gallbladder is an indication for urgent cholecystectomy

## Results of the tokyo international consensus meeting
At the International Consensus Meeting, fl owcharts for the management of mild (grade I) and severe (grade III) acute cholecystitis were agreed upon by almost all of the participants; however, the fl owchart for moderate (grade II) acute cholecystitis was agreed upon by fewer than 90% of the participants .
We also truly appreciate the panelists who cooperated with and contributed signifi cantly to the International Consensus Meeting held in Tokyo on April 1 and 2, 2006.
repeated after the initiation of treatment for acute cholangitis.

## Flowchart for the management of acute cholecystitis
There were several controversies over the treatment of acute cholecystitis. Early cholecystectomy is indicated for most patients with acute cholecystitis, and laparoscopic cholecystectomy is preferred for experienced surgeons. Several randomized controlled trials comparing early and delayed operation conducted in the 1970s to 1980s found that early surgery had the advantages of less blood loss, shorter operation time, a lower complication rate, and a shorter hospital stay. Some Japanese doctors advocated that early cholecystectomy should not be recommended because early cholecystectomy was not prevalent in Japan. Steven M. Strasberg mentioned: "We have to be willing to accept the fact that we may need to change our practice based upon the evidence". Results of randomized controlled trials comparing early laparoscopic cholecystectomy with delayed laparoscopic cholecystectomy have also shown that early laparoscopic surgery is superior to delayed surgery in terms of the conversion rate to open surgery, complication rate, and total hospital stay. Toshihiko Mayumi (Japan) mentioned that because laparoscopic cholecystectomy by inexperienced surgeons resulted in more frequent intraoperative complications than open cholecystectomy, the laparoscopic procedure should not be overemphasized.
There was more discussion to determine the treatment strategy for acute moderate (grade II) cholecysti-tis. Before the start of the international symposium it was considered that urgent/early cholecystectomy should be performed for these patients. Steven M. Strasberg mentioned: "For patients with acute moderate cholecystitis (patients who have a white [cell] count over 18 000; patients who have cholecystitis for more than 72 h; patients who have a palpable infl ammatory mass), early cholecystectomy is going to be maybe very diffi cult. Therefore do we really want to say to the general surgeon in a small hospital that we recommend that when the white [cell] count is over 18 000 that he takes the patient to the operating room? I do not think so." After the statement of his opinion, delayed elective cholecystectomy was recommended for acute moderate (grade II) cholecystitis with severe local infl ammation. On the other hand, Eduardo de Santibanes (Argentina) advocated that early laparoscopic cholecystectomy could be performed for patients with acute moderate cholecystitis.
The treatment courses for mild (grade I) and severe (grade III) cholecystitis were accepted without major adverse opinions. The recommendation of early laparoscopic cholecystectomy for mild (grade I) cases and gallbladder drainage for severe (grade III) cases obtained consensus. Some Japanese doctors suggested that endoscopic gallbladder drainage as well as per cutaneous gallbladder drainage should be recommended. However, Jacques Belghiti rejected this suggestion, because there was poor evidence for effi cacy, and because endoscopic gallbladder drainage needed a special technique. Thomas R. Gadacz added surgical cholecystostomy to one of the methods for gallbladder drainage.
[fig] Figure 2: Flowchart for the management of acute cholangitis drainage should be considered. Treatment options such as endoscopic, percutaneous, or operative intervention may be required, depending on the etiology. Some patients, such as those who develop postoperative cholangitis, may only require antibiotics and generally do not require intervention. [/fig]