JPN Guidelines for the management of acute pancreatitis: treatment of gallstone-induced acute pancreatitis

Clinical questionsCQ1. Is an emergency endoscopy approach beneficial in the treatment of gallstoneinduced acute pancreatitis? CQ2. Is one-stage cholecystectomy followed by common bile duct (CBD) clearance safer and more effective than endoscopic procedures? CQ3. When should laparoscopic cholecystectomy be undertaken in patients with gallstone pancreatitis?

# Introduction
Research on the pathophysiology of acute pancreatitis has advanced dramatically during the past 20 years, and, as the number of randomized controlled studies (RCTs) of severe acute pancreatitis has steadily increased, mainly in the United States and Europe, evidencebased management has come to be demanded for acute pancreatitis. In Japan, three institutions -the Japanese Society for Abdominal Emergency Medicine, the Japan Pancreas Society, and the Research Group for Intractable Diseases and Refractory Pancreatic Diseases, which is sponsored by the Japanese Ministry of Health, Labour, and Welfare -collaborated to publish "Evidence-based clinical practice guidelines for acute pancreatitis: proposals." 1 This article incorporates the latest evidence in relation to gallstone pancreatitis and Abstract Gallstones, along with alcohol, are one of the primary etiological factors of acute pancreatitis, and knowledge of the etiology as well as the diagnosis and management of gallstones, is crucial for managing acute pancreatitis. Because of this, evidence regarding the management of gallstone-induced pancreatitis in Japan was collected, and recommendation levels were established by comparing current clinical practices with optimal clinical practices. The JPN Guidelines for managing gallstone-induced acute pancreatitis recommend two procedures: (1) an urgent endoscopic procedure should be performed in patients in whom biliary duct obstruction is suspected and in patients complicated by cholangitis (Recommendation A); and (2) after the attack of gallstone pancreatitis has subsided, a laparoscopic cholecystectomy should be performed during the same hospital stay (Recommendation B).

## Key words gallstone pancreatitis  emergency endoscopy  laparoscopic cholecystectomy
Offprint requests to: Y. Kimura * President, Japanese Society of Emergency Abdominal Medicine; President, Japanese Society of Hepato-Biliary-Pancreatic Surgery; President, Asian-Pacific Hepato-Pancreato-Biliary Association ** Chairman, Intractable Pancreatic Disease Investigation and Research Group of the Japanese Ministry of Health, Labour, and Welfare *** President, Japan Pancreas Society presents these guidelines (the JPN Guidelines) for the treatment of gallstone-induced acute pancreatitis, citing the relevant Recommendations.

## Management of bile duct stones in gallstoneassociated acute pancreatitis
Clinical questions (CQ) 1. Is an emergency endoscopy approach beneficial in the treatment of gallstone-induced acute pancreatitis?

## An emergency endoscopy approach is beneficial in patients with acute pancreatitis in whom bile duct obstruction is suspected or there are complications from cholangitis (recommendation a)
Emergency endoscopic approaches to the management of bile duct stones in gallstone-associated acute pancreatitis include endoscopic sphincterotomy (ES), endoscopic papillary balloon dilation (EPBD), endoscopic nasobiliary drainage (ENBD), and stenting. Those procedures are performed to remove gallstones and to drain the bile duct, which mostly results in relieving the obstruction of the pancreatic duct. The endoscopic approach seems to be most beneficial in those patients with acute pancreatitis suspected of having concomitant gallstones complicated with the occurrence or exacerbation of jaundice, and in patients complicated by cholangitis. The decision whether or not to perform one-stage choledocholithotomy after ES or endoscopic biliary drainage must be based on the pathophysiological condition of the patient and the skill of the physician. It is important to refer any patient who requires an endoscopic approach to an advanced medical unit if the patient meets the criteria for transfer (see page ).
Emergency or early endoscopic procedures for acute pancreatitis have been assessed in four randomized controlled trials (RCTs; Level 1b), 2-5 and a metaanalysis of these RCTs has been performed (Level 1a). [bib_ref] Meta-analysis of randomized controlled trials of endoscopic retrograde cholangiography and endoscopic sphincterotomy..., Sharma [/bib_ref] The metaanalysis involved a total of 834 patients, comprising 460 patients treated by endoscopic retrograde cholangiopancreatography (ERCP) followed by ES (ERCP/ES group) and 374 patients treated conservatively (conservative treatment group). The analysis led to the conclusion that the ERCP/ES group had lower incidences of morbidity and mortality [fig_ref] Table 1: Reported morbidity and mortality rates in early ERCP/ES and conservative treatment groups [/fig_ref] , but because pancreatitis patients with treated by ERCP or ES alone have never been analyzed, it remains unclear whether ERCP or ES is more useful.
The results of two studies (Level 1b) 2,3 that published data stratified by severity indicate that ERCP/ES is not very useful in patients with mild pancreatitis, and a report expressing a negative opinion in regard to early endoscopic treatment (Level 1b) 5 excluded patients with jaundice from the analysis, and the percentage of subjects with gallstone pancreatitis was only 19%. It is concluded from these reports that urgent ERCP/ES is useful only in severe gallstone pancreatitis.
However, there are differences in severity assessment, particularly of severe cases, between Japan and Western countries, and no convincing evidence supporting the application of emergency ERCP/ES in patients with severe cases has been established in Japan. It is currently thought that the indications for emergency ERCP/ES should be restricted to patients suspected of having prolonged biliary duct obstruction, as manifested by the occurrence or exacerbation of jaundice, and to patients complicated by cholangitis. Various other techniques besides ERCP/ES are used for biliary drainage and are generally accepted in Japan. A report, entitled "Evaluation of urgent treatment for impacted bile duct stones" (published in 1992 in Japanese), claims that endoscopic nasobiliary drainage (ENBD) is a useful and safe urgent treatment method for impacted bile duct stones, although no high-quality evidence supported by RCTs or metaanalysis has yet emerged to support that report.
In terms of the safety of ERCP/ES in the acute stage of pancreatitis, no difference has been found between the incidence of complications after early intervention (within 48 h of onset) and the incidence after delayed intervention (Level 3b), [bib_ref] Early or delayed endoscopic papillotomy (EPT) in gallstone pancreatitis, Rosseland [/bib_ref] and it has been reported that ERCP/ES within 24 to 72 h after onset is safe (Level 2b). [bib_ref] Early endoscopic cholangiopancreatography and sphincterotomy in acute biliary pancreatitis: report of 50..., Uomo [/bib_ref] Similar results were reported in a retrospective study of a large number of patients (Level 4). [bib_ref] Outcome of surgical and endoscopic management of biliary pancreatitis, Aiyer [/bib_ref] The four RCTs referred to above 2-5 have suggested bleeding as a complication of ERCP/ES, but the bleeding occurred in only a few patients with mild pancreatitis and was never a direct cause of death. Based on the reports from overseas, we cannot conclude that ERCP/ES is highly risky in the acute stage of pancreatitis. According to the results of a third nationwide survey in Japan (in 2000) of accidental complications from gastrointestinal endoscopy (Level 4), the incidence of accidental complications of ERCP performed for examination purposes and of ES done to treat the papilla of Vater was 0.1% and 0.7%, respectively, and the mortality rate was 0.006% and 0.048%, respectively. The issue of whether or not ERCP/ES is indicated should be carefully evaluated and adequate care should be taken to prevent accidental complications. Effective performance obviously requires an advanced medical institution with experienced specialists and a special unit whose staff is capable of carrying out emergency ERCP/ES examinations and dealing with bleeding and other complications.

## Surgical approach

## Cq2. is one-stage cholecystectomy followed by common bile duct (cbd) clearance safer and more effective than endoscopic procedures?

## Open choledochotomy or sphincterotomy (operative removal of cbd stones is recommended) (recommendation d)
In Japan, choledocholithotripsy with emergency endoscopic procedures (ES, EPBD) is performed by endoscopists, as well as by many surgeons, and it has become the treatment of first choice for CBD clearance. One-stage cholecystectomy and CBD clearance has not been demonstrated to be safer and more effective than endoscopic procedures, and it is not recommended in either the JPN Guidelines or the International Association of Pancreatology (IAP) guidelines. 10

## Cq3. when should laparoscopic cholecystectomy be undertaken in patients with gallstone pancreatitis?

## Laparoscopic cholecystectomy should be considered after recovery from an attack of gallstone pancreatitis and should be performed during the same hospital stay (choledochotomy and cbd clearance are performed as required) (recommendation b)
Cholelithiasis is one of the major causes of acute pancreatitis, and gallstone-induced acute pancreatitis is an absolute indication for cholecystectomy (and choledochotomy, when necessary). However, there has been no consensus regarding the timing of this surgical intervention. One RCT claims that the earlier surgery is performed after onset, the more beneficial it is, while another RCT has proposed delayed surgery once the inflammatory process has subsided. The latter RCT (Level 1b) [bib_ref] Gallstone pancreatitis: biliary tract pathology in relation to time of operation, Stone [/bib_ref] compared earlier surgery (within 72 h of hospital admission) and delayed surgery, and the results suggested that the earlier surgery was more beneficial.
Because the results showed no significant difference in the incidence of complications (8.3% vs 10.3%) or the mortality rate (2.8% vs 6.9%), this RCT concluded that surgery on the bile duct system with the aim of removing the cause of the pancreatitis or preventing its progression could be performed safely even in the acute state. According to another RCT (Level 1b), [bib_ref] Gallstone pancreatitis: a prospective randomized trial of the timing of surgery, Kelly [/bib_ref] which is often quoted as grounds to justify delayed surgery, patients subjected to early surgery (within 48 h of hospitalization) had a significantly higher complication rate (30.1% vs 5.1%) and mortality rate (15.1% vs 2.4%) than those subjected to delayed surgery. This conflicting evidence may be explained by potential differences in the severity of the disease in the patients included in the clinical trials. Discussion of the timing of surgery alone, without adequate consideration of the impact of severity, has caused confusion in clinical settings. However, the introduction of emergency ERCP/ES 2,3 has completely changed the options available for the management of gallstone pancreatitis and has dramatically reduced the need for performing surgery in the acute stage.
There are two options in regard to delayed surgery: (i) surgery during the same hospital stay as that for the initial treatment, and (ii) surgery during rehospitalization after a sufficient recovery period. Because the rate of recurrence of pancreatitis during the recovery period after discharge is 32% to 61% (Level 3b), [bib_ref] The timing of biliary surgery in acute pancreatitis, Ranson [/bib_ref] [bib_ref] Biliary pancreatitis: clinical presentation and surgical management, Frei [/bib_ref] [bib_ref] Acute biliary pancreatitis. The roles of laparoscopic cholecystectomy and endoscopic retrograde cholangio-pancreatography, Deiorio [/bib_ref] patients with mild uncomplicated gallstone pancreatitis should undergo biliary tract exploration and cholecystectomy after the symptoms have been alleviated. Whenever possible, even patients with severe disease should undergo surgery during the same hospital stay as that for the initial treatment.
Laparoscopic cholecystectomy (LC) has been increasingly used to treat gallstone pancreatitis over the past 10 years. According to prospective cohort studies reported to date (Levels 1b-2c), [bib_ref] Laparoscopic cholecystectomy with endoscopic retrograde cholangiopancreatography for acute gallstone pancreatitis, Rhodes [/bib_ref] [bib_ref] Laparoscopic cholecystectomy for biliary pancreatitis, Tate [/bib_ref] [bib_ref] Laparoscopic management of acute biliary pancreatitis, Ballestra-Lopez [/bib_ref] [bib_ref] Minimally invasive treatment of acute biliary pancreatitis, Ricci [/bib_ref] [bib_ref] Acute gallstone pancreatitis: timing of laparoscopic cholecystectomy in mild and severe disease, Uhl [/bib_ref] [bib_ref] Preoperative versus postoperative endoscopic retrograde cholangiopancreatography in mild to moderate gallstone pancreatitis:..., Chang [/bib_ref] LC was associated with a completion rate of 94.5% (range, 79% to 100%), a complication (morbidity) rate of 5.5% (range, 0% to 10%), and a mortality rate of 0.4% (range, 0% to 2.5%; [fig_ref] Table 3: Prospective cohort studies of laparoscopic cholecystectomy employed for gallstone-associated acute pancreatitis [/fig_ref] , implying that LC resulted in performance equal to or better than that of laparotomy. Based on these results, the use of LC in mild gallstone pancreatitis is feasible and its clinical usefulness has been demonstrated.
The Procedure (1) has become increasingly popular in Japan. However, opinions differ concerning the application of ERCP in all patients with gallstone-associated pancreatitis. Some surgeons argue that ERCP should be performed only when choledocholithiasis is suspected on the basis of blood studies and other diagnostic imaging, or when it is diagnosed during IOC (Level 1b-2b). [bib_ref] Preoperative versus postoperative endoscopic retrograde cholangiopancreatography in mild to moderate gallstone pancreatitis:..., Chang [/bib_ref] [bib_ref] Selective preoperative endoscopic retrograde cholangiopancreatography in laparoscopic biliary surgery, Rijna [/bib_ref] The risk inherent in ERCP should be noted, particularly in patients with acute pancreatitis (Level 2b). [bib_ref] Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study, Loperfido [/bib_ref] It may be possible to substitute IOC for preoperative ERCP as a standard method to confirm those patients who are less likely to have choledocholithiasis, if the surgeons in charge of this procedure have sufficient experience and technique to perform IOC successfully. The choice of which of the above four procedures to opt for when choledocholithiasis is discovered by IOC depends on the skill and technique of the specialist physicians currently at each institution. Collection of more data on the safety, invasiveness, and completion rates associated with each of these procedures is an important task for the future.
[table] Table 1: Reported morbidity and mortality rates in early ERCP/ES and conservative treatment groups [/table]
[table] Table 3: Prospective cohort studies of laparoscopic cholecystectomy employed for gallstone-associated acute pancreatitis [/table]