Scandinavian Journal of Surgery 94: 124–129, 2005

ALGORITHM FOR THE DIAGNOSIS AND TREATMENT OF ACUTE BILIARY PANCREATITIS N. Alexakis, J. P. Neoptolemos Division of Surgery and Oncology, University of Liverpool, Liverpool, UK

ABSTRACT

Gallstones are the commonest cause of acute pancreatitis in developed countries. There is now a considerable evidence base consolidated by a series of systematic reviews, metaanalyses and guidelines that has established a clear algorithm for diagnosis and management. In the majority of patients the combination of ultrasonography and serum alanine transaminase > 60 iu/l < 48hours of symptoms will identify gallstones as the cause. The simplest method of severity assessment is a high level of serum C-reactive protein (> 150 mg/l up to 72 hours after symptoms). In mild disease, all fit patients must undergo laparoscopic cholecystectomy with intraoperative cholangiography or if not fit for surgery then endoscopic sphincterotomy during the same admission to prevent further attacks. All patients with severe disease should undergo endoscopic sphincterotomy in less than 72 hours. Patients with > 30 % necrosis should undergo fine needle aspiration for bacteriology. Necrosectomy is indicated for infected necrosis or sterile necrosis if there are persisting clinically significant symptoms. There is increasing evidence for the use of minimally invasive pancreatic necrosectomy. Enteral nutrition should be instituted whenever possible but antibiotics should be reserved for patients with proven sepsis. The presence of fungal infection requires active anti-fungal therapy. Patients with severe disease should undergo cholecystectomy at a later stage. Patients who have undergone necrosectomy require long-term follow-up because of delayed complications. Key words: Acute biliary pancreatitis; gallstones; diagnosis; management; endoscopic sphincterotomy

INTRODUCTION Acute pancreatitis is a disease with an overall mortality of approximately 4–6 % (which increases to 17– 39 % in severe disease) and substantive morbidity (1–4). Gallstones are the commonest cause of acute pancreatitis in developed countries representing around 60 % of all cases (1, 2). Identification of these

Correspondence: John P. Neoptolemos, M.D. Division of Surgery and Oncology Royal Liverpool University Hospital 5th Floor UCD The Duncan Building Daulby Street, Liverpool K69 3GA, UK Email: [email protected]

patients is important, since there are specific therapeutic implications and clear management strategies are now supported by a substantive evidence base (Figs 1 and 2). DIAGNOSIS OF ACUTE PANCREATITIS The diagnosis is based on a typical clinical presentation plus a serum amylase at least three times the upper normal limit. Serum amylase peaks at around 24 hours after the onset of the attack and then exponentially declines over the next 5–7 days. Serum lipase and elastase are also diagnostic but are not superior to the amylase test (5). An emergency contrast enhanced computed tomography scan must be performed if there is any diagnostic uncertainty.

Algorithm for the diagnosis and treatment of acute biliary pancreatitis

Fig. 1. Algorithm for the management of mild gallstone acute pancreatitis.

Fig. 2. Algorithm for the management of severe gallstone acute pancreatitis.

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INITIAL MANAGEMENT: RESUSCITATION AND TREATMENT OF ANY ORGAN DYSFUNCTION Patients with acute pancreatitis are usually hypovolaemic and need optimal fluid resuscitation and close monitoring in an appropriate setting (6). It is important to recognise and treat any associated organ dysfunction (7). IDENTIFICATION OF PATIENTS WITH BILIARY PANCREATITIS The recommended initial examination is ultrasonography to identify the presence of stones in the gallbladder and/ or in the main bile duct (MBD). The sensitivity of the US in the detection of gallstones is > 95 % in uncomplicated cases; however in the setting of acute pancreatitis, sensitivity for gallstone detection is only 67–78 % due to the ileus and bowel distension (8). Furthermore, sensitivity in the detection of MBD stones is between 25–90 %. Liver biochemistry is helpful for the diagnosis of biliary pancreatitis. A meta-analysis found that a 3-fold increase of serum alanine transaminase (> 60 iu/l < 48hours of symptoms) will identify gallstones as the cause in patients with pancreatitis with a positive predictive value of 95 % (9) and this has been confirmed by a recent study (10). It should be kept in mind that around 10–15 % of patients with biliary pancreatitis present with normal serum liver enzyme and bilirubin levels (11). Magnetic resonance cholangiography (MRCP) has a high sensitivity (84–95 %), specificity (96–100 %), positive predictive value (91–100 %) and negative predictive value (92–98 %) for the detection of choledocholithiasis (12–15) but its role in biliary pancreatitis has not been evaluated. In particular is the performance of MCRP in severely ill patients in whom the diagnosis of biliary pancreatitis relies on ultrasonography and biochemical tests. The accuracy of endoluminal ultrasonography in diagnosing choledocholithiasis is high and similar to that of MRCP (16). PREDICTION OF DISEASE SEVERITY Most patients will have mild disease but 10–20 % will develop severe disease (17). It is important to determine as early as possible whether the attack is likely to be mild or severe for purposes of management strategy and optimum use of resources. Clinical judgement alone can be difficult in determining this, especially during the first 24–48 hours when disease severity may rapidly change. The Atlanta classification defines that severe disease is associated with organ failure and/or local complications (necrosis, abscess, pseudocyst) and is characterised by > 3 Ranson criteria, or > 8 APACHE II score points (18). The Ranson criteria have no validity > 48 hours of disease onset, while the Apache II system can be used at any time, but suffers from complexity. The Balthazar CT score is based on the extent of pancreatic

necrosis and the number of acute fluid collections (19). The serum level of the acute phase C-reactive protein at a cut-off level of > 150mg/l, at 48–72 hours following symptom onset has independent prognostic value for severe disease and is as accurate as the multiple scoring systems (20). In a large study, the sensitivity, specificity, positive predictive value and negative predictive value 48 hours after admission of the APACHE II score were 56 %, 64 %, 30 %, and 85 %, of the Ranson score were 89 %, 64 %, 38 % and 96 % and of the C-reactive protein cut off were 86 %, 61 %, 37 %, 37 % and 94 %, respectively (21). Urinary trypsinogen activation peptide accurately predicts severity at 24 hours after symptom onset (21) (58 %, 73 %, 39 % and 86 %, respectively) whilst the serum amyloid A level (another acute phase protein) had a better prediction than C-reactive protein at 24 and 48 hours following admission and symptom onset and maintained discrimination between mild and severe disease beyond the initial phase (22). MANAGEMENT OF PATIENTS WITH PREDICTED SEVERE ACUTE PANCREATITIS Patients with a severe attack and certain high risk patients (elderly, with gross obesity, requiring ongoing volume resuscitation) will need to be managed on an intensive therapy or high dependency unit (6). Early enteral nutrition by a naso-jejunal tube is safe and well tolerated in severe acute pancreatitis (23) but care must be taken to provide sufficient calories. Parenteral nutrition is more expensive, carries the risks of sepsis and metabolic complications (24). Recent meta-analyses agree that enteral nutrition did not reduce mortality and although it was associated with a lower incidence of complications (25, 26), this needs to be interpreted in the light of missing data and heterogeneity (26). Contrast enhanced computed tomography is the best way to assess the extent of pancreatic necrosis with an overall accuracy of 87 %, a sensitivity of 100 % in cases of extended necrosis and of 50 % in minor necrosis and specificity of almost 100 % (19). Contrast enhanced computed tomography must be performed > 72 hrs from onset of symptoms to allow delineation of the necrosis (19). Magnetic resonance imaging is also a reliable staging method with similar sensitivity and specificity to that of contrast enhanced computed tomography (27). ENDOSCOPIC SPHINCTEROTOMY IN PATIENTS WITH SEVERE GALLSTONE PANCREATITIS The first important study of the role of endoscopic retrograde cholangiography (ERCP) in altering the course of acute biliary pancreatitis was performed in Leicester UK, in which 121 patients were prospectively stratified for disease severity prior to randomisation (28). The mortality rate was one (2 %) in the 59 patients randomized to urgent ERCP +/– endoscopic sphincterotomy compared to five (8 %) in the 62 patients randomized to conservative treatment

Algorithm for the diagnosis and treatment of acute biliary pancreatitis

and the complication rates were 10 (17 %) and 17 (61 %), respectively. The differences were significant in patients with a predicted severe attack with mortality and complications rates of one (4 %) and six (24 %) respectively in the 25 patients predicted severe and treated by endoscopic sphincterotomy compared to five (18 %) and 17 (61 %, p < 0.01) respectively in the 28 patients predicted severe in the conservative group (28). Critics of the study state that the benefits were due to the relief of concomitant cholangitis (6 in the urgent endoscopic sphincterotomy group and 5 in the conservative group) but if these patients were excluded from the analysis, there is still benefit in the endoscopic sphincterotomy group, which is significant in the severe cases (complications 15 % vs 60 %, p = 0.003) (28). In addition, the hospital stay was shorter in the predicted severe urgent endoscopic sphincterotomy group (28). Fan et al from Hong Kong prospectively randomized 195 patients with acute pancreatitis to either endoscopic sphincterotomy within 24 hours of presentation or conventional therapy (29). Overall there was a reduction in biliary sepsis in the urgent endoscopic sphincterotomy group compared to the conservatively management group (0 % vs 12 %) with apparently no significant difference in mortality or complications (29). One of the study problems is that the method of severity assessment (blood glucose and serum urea at admission) had low sensitivity (29). Furthermore, only 127 (65 %) of the patients had gallstones (29). Analysis of patients with gallstones reveals similar results as those from the UK trial: in the 30 patients with severe pancreatitis treated endoscopically there was only one (3 %) death and four (13 %) with morbidity compared with five (18 %, p=0.09) deaths and 15 (54 %, p = 0.003) with complications in the 28 patients with severe pancreatitis treated conservatively (29). Moreover ERCP/endoscopic sphincterotomy was performed in 18 patients with a severe attack at a median of 60 hours (29). Thus 64 % of the conservative group with severe pancreatitis also had ERCP/endoscopic sphincterotomy and mostly within 72 hours (29). A multi-centre trial from Germany randomised 238 patients with suspected biliary pancreatitis to ERCP +/– endoscopic sphincterotomy within 72 hours or conservative treatment and did not show any benefit (30). There were, however, many problems with this study. Patients with obstructive jaundice were excluded and underwent emergency endoscopic sphincterotomy (30). The severity was only determined retrospectively and was undefined in some patients (30). Because endoscopic sphincterotomy was performed within 72 hours, severity scoring would have been completed after endoscopic sphincterotomy in many cases and any apparent positive influence of endoscopic sphincterotomy on the course of severe disease might have been lost by moving patients to the mild disease category before completion of the severity scoring (30). There were 17 (13.5 %) patients from the 126 patients in the endoscopic sphincterotomy group who developed cholangitis, compared to 13 (11.6 %) cases in the 112 patients that had conservative treatment, an obser-

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vation that indicates an inadequate endoscopic sphincterotomy technique (30). Moreover, there were 10 (38 %) related deaths in the 26 patients with severe disease that had an endoscopic sphincterotomy compared to four (20 %) deaths in 20 patients with severe pancreatitis treated conservatively (30). The high mortality of 38 % in the severe patients treated by endoscopic sphincterotomy contrasts sharply with mortalities of 4 % and 3 % in comparable patients in the UK and Hong Kong studies respectively( 28, 29). The study also had poor recruitment of approximately two patients per hospital per year (30). A further study from Poland has been published only as an abstract and detailed analysis cannot be performed (31). A meta-analysis (32) concluded that ERCP plus endoscopic sphincterotomy reduces morbidity and mortality in acute biliary pancreatitis but it was based on the pooled data from all previous four studies in which the Polish study (31) had the largest number of patients (n = 280). The 2002 NIH consensus on ERCP states that in patients with severe biliary pancreatitis, early intervention with ERCP reduces morbidity and mortality compared with delayed ERCP (33). The 2002 International Association of Pancreatology guidelines did not provide any recommendations on this subject (34). The conclusion of a Cochrane review in 2004 was that the odds of having complications are reduced in predicted severe disease by early endoscopic sphincterotomy (34). Moreover these results are controlled for confounding due to associated acute cholangitis and are robust for clinical and statistical heterogeneity (34). The 2004 consensus guidelines of the Critical Care Societies recommends that ERCP should be performed within 72 hours in the setting of obstructive jaundice and acute pancreatitis due to suspected or confirmed gallstones or in severe acute pancreatitis (without obstructive jaundice) (6). It must be emphasised that endoscopic sphincterotomy should be performed in severe disease even if no MBD stones are visualised in cases highly suggestive of disease of biliary origin such as presence of gallstones, dilated bile ducts, high bilirubin or an elevated alanine transaminase. CHOLECYSTECTOMY IN PATIENTS WITH MILD GALLSTONE PANCREATITIS TO PREVENT FURTHER ATTACKS A laparoscopic cholecystectomy should be performed in all patients with mild disease prior to hospital discharge as they run a 30–40 % risk of recurrent attacks even within weeks from the first episode (34, 36, 37). Routine cholangiography during laparoscopic cholecystectomy followed by selective postoperative endoscopic sphincterotomy has been found to be more efficient than routine pre-operative endoscopic retrograde cholangiopancreatography (38). Laparoscopic common bile duct exploration and postoperative ERCP are both safe and reliable in clearing common bile duct stones. If the patient is unfit for surgery, successful endoscopic sphincterot-

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omy is an acceptable alternative to prevent recurrent attacks (39). Surgically fit patients who had undergone endoscopic sphincterotomy stone extraction and have concomitant cholelithiasis should undergo cholecystectomy. A trial from Amsterdam recruited 120 patients who had undergone ES with stone extraction and randomised them to laparoscopic cholecystectomy within 6 weeks or a wait and see policy (40). After a median follow-up of 30 months, 27 (47 %) of 59 had biliary symptoms compared to one (2 %) of 49 who had cholecystectomy. Twenty two of these 27 patients underwent cholecystectomy (40).

The 2004 consensus statement of Critical Care Societies recommended against the routine use of prophylactic antibiotics due to the lack of conclusive evidence (6). There is the problem of the microbial shift from Gram negative to Gram positive organisms and the development of fungal infection associated with a high mortality (49). Moreover, there is concern about the emergence of resistant organisms leading to prolonged treatment (50). Antibiotics should be used once sepsis is established using accepted international criteria (51) in accordance with Critical Care Societies guidelines (52). The presence of fungal infection requires active anti-fungal therapy (49).

SURGERY IN PATIENTS WITH SEVERE GALLSTONE ACUTE PANCREATITIS

FOLLOW-UP

Because the features of the systemic inflammatory response syndrome are identical to those of sepsis, clinical parameters will not identify pancreatic infection before it is too late. Thus from day 5–7 of a severe attack all patients must undergo a contrast enhanced computed tomography (34). If there is > 30 % necrosis there should be weekly computed tomography-guided fine needle aspiration for bacteriology and fungi (FNAB) which has a sensitivity of 96 % for detecting pancreatic infection (41). The indications for surgery in severe acute pancreatitis are now well defined: positive FNAB stain or culture or extra-intestinal gas on a contrast enhanced computed tomography scan are indications for necrosectomy (42). Other indications for surgery include sterile necrosis with persisting systemic or local symptoms despite 3–4 weeks of maximal conservative treatment (31). Necrosectomy must be delayed for at least 2–3 weeks to allow demarcation of the necrosis (34). In a recent study, necrosectomy was performed after a median of 31 days from disease onset (4). Conservative management of patients with sterile necrosis has a mortality rate of 1.8 % while mortality in patients with infected necrosis who undergo surgery is 24 %–39 % (4, 42, 43). There are three main techniques that can be used for necrosectomy: open necrosectomy with closed lesser sac lavage (44), repeated laparotomies with zipper to close the peritoneum after each intervention or left open as laparostomy (45) and minimally invasive necrosectomy (46). Surviving patients with severe disease should undergo cholecystectomy at a later stage (>6 weeks) as there is increased morbidity and longer hospital stay if they have an early operation (34, 37, 47). PROPHYLACTIC ANTIBIOTICS AND USE OF SEVERITY MODIFIERS The 2002 IAP guidelines state that the use of prophylactic antibiotics reduces infection rates in necrotising pancreatitis but may not improve survival (34). This was prior to the largest double blind randomized trial by Isenmann et al in 2004 that found no benefit for the use of prophylactic antibiotics (48).

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Received: April 6th, 2005