- Email: [email protected]
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
PANCREAS UPDATE
0889-8553/99 $8.00
+ .OO
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS When and in Whom? Klaus Mergener, MD, and John Baillie, MB, ChB, FRCP(G)
Gallstones and alcohol remain the main causes of acute pancreatitis worldwide. In industrialized countries, gallstones account for 34% to 54% of the 4.8 to 24.2 cases of acute pancreatitis per 100,000 people ann~ally.’~ The management of acute pancreatitis remains challenging; although most patients with mild pancreatitis have self-limited disease, requiring only simple supportive measures, severe pancreatitis remains a deadly disease, with an overall mortality of up to 10%. Close monitoring of patients, preferably in an intensive care unit, and the management of local and systemic complications remain the mainstays of treatment. Endoscopists are often asked to perform endoscopic retrograde cholangiography (ERCP) in patients with acute pancreatitis if gallstones are suspected. Whether or not patients benefit from this intervention and, if so, when it should be performed are questions that have now been addressed in several randomized, controlled clinical trials. The results of these studies are reviewed, and a suggested algorithm for the management of patients with suspected acute biliary pancreatitis is provided. PATHOGENESIS An association between gallstones and pancreatitis was suggested in 1856, by Bernard.6 In 1901, OpieZ9performed an autopsy on a patient
From the Medizinische Klinik und Poliklinik, Johannes-Gutenberg-Universitaet (KM), Mainz, Germany; and Division of Gastroenterology, Duke University Medical Center (JB), Durham, North Carolina
GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 28 NUMBER 3 SEFTEMBER 1999
601
602
MERGENER & BAILLIE
who had died of severe pancreatitis. Finding a gallstone impacted at the ampulla of Vater, he argued that obstruction of the common channel between the bile duct and the main pancreatic duct led to bile reflux into the latter, triggering pancreatitis. This common channel theory of pancreatitis is supported by experimental studies in the as well as by clinical observations. Gallstones can be recovered from the feces of approximately 90% of patients with acute pancreatitis compared with only 10% of patients with cholelithiasis without pancreatitis.*In patients with acute pancreatitis who underwent urgent surgical intervention, bile duct stones were found in 63% to 78%, compared with only 3% to 33% of patients with stones who underwent delayed surgery.20 Opie’s theory, however, has been challenged for the following reasons: (1) A common channel is found in only 70% to 80% of patients with gallstone pancreatitis, and (2) because pancreatic duct pressure usually exceeds that of the bile duct, bile reflux into the pancreas is unlikely. The duodenal reflux hypothesis states that duodenal contents (containing bacterial toxins, lysolecithin, and enterokinases) refluxing through a sphincter of Oddi that has been rendered transiently incompetent by the passage of a gallstone may be the initiating event in acute pancreatitis. A third hypothesis proposes that obstruction of the pancreatic duct alone (without reflux of bile or duodenal juice) is the main pathogenic event. It seems plausible that elements of all three theories play a role in the pathogenesis of acute pancreatitis. Although the inappropriate activation and release of pancreatic enzymes (especially the proteolytic enzyme, trypsin) has long been considered to be the final common pathway for events precipitating acute pancreatitis? more recent work on mediators of the inflammatory response, especially cytokines, shows this to be too simplistic. It is clear that interleukins (e.g., IL-6, IL-8), platelet-activating factor (PAF), and tumor necrosis factor-a (TNF-a) play a major role in the systemic (extrapancreatic) complications of acute pancreatitis.21Studies suggest that the PAF inhibitor, lexipafant, may reduce the morbidity and mortality of acute pancreatitis if administered within 48 hours of its onset (see the article by I m ~ i e ) . ~ ~ DIAGNOSIS OF ACUTE BlLlARY PANCREATITIS
Identifying the underlying cause of acute pancreatitis is important for predicting the risk of recurrence and to guide the decision to perform diagnostic or therapeutic ERCP. Although gallstones and alcohol account for 70% to 80% of cases of acute pancreatitis, other causes, such as hyperlipidemia, hypercalcemia, drug sensitivity, trauma, infection, and familial pancreatitis, should be considered and excluded by a careful history, physical examination, and laboratory studies (Table 1). Risk factors for cholesterol gallstones should be noted, including female sex, age, obesity, rapid weight loss, pregnancy, and certain drugs (estrogens, clofibrate, octreotide, ceftriaxone). Gallstone pancreatitis not infrequently follows cholecystectomy, especially in the era of laparoscopic surgery,
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
603
Table 1. CONDITIONS ASSOCIATED WITH ACUTE PANCREATITIS
Cholelithiasis, choledocholithiasis, or biliary microlithiasis Ethanol misuse Drugs Azathioprine, 6-mercaptopurine, asparaginase Pentamidine, didanosine Hydrochlorothiazide, furosemide Tetracyclines, sulfonamides Valproic acid Estrogens Sulfasalazine Iatrogenic (e.g., ERCP) Trauma Hypercalcemia Hyperlipidemia Pancreas divisum* Familial pancreatitis Ischemia Penetrating gastric or duodenal ulcer Pancreatic tumors Pregnancy Infections Mycoplasma Mumps Coxsackie B HIV (?) Venoms (scorpion/spider bites) Sphincter of Oddi dysfunction Idiouathic ‘A normal variant in 7% to 8% of white populations. ERCP = Endoscopic retrograde cholangiopancreatography; HIV = human immunodeficiency virus. Modified from Mergener K, Baillie J: Fortnightly review: Acute pancreatitis. BMJ 31644-48, 1998; with permission.
when small stones are easily milked from the gallbladder neck or cystic duct into the common bile duct during the procedure. Pancreatitis occurring within days of laparoscopic cholecystectomy should be assumed to be of gallstone origin. Serum amylase and lipase elevations can confirm the diagnosis of acute pancreatitis, but they do not help to distinguish between the different causes. Although early studies suggested that a lipase-to-amylase ratio greater than 2 identifies alcoholic pan~reatitis,’~ more recent studies concluded that the positive predictive value of this ratio is Likewise, the magnitude of serum amylase and lipase elevation does not distinguish between causes of pancreatitis, and it does not correlate with the severity of the attack or predict the clinical course. The most reliable biochemical predictor of gallstones as the cause of acute pancreatitis is elevation of the serum alanine aminotransferase (ALT): An ALT elevation of threefold or higher has a positive predictive value of 95% for diagnosing acute biliary pancreatiti^.^^ Elevations of serum bilirubin and alkaline phosphatase are not specific for this diagnosis. Transabdominal ultrasound and computed
604
MERGENER & BAILLIE
tomography (CT) of the abdomen are often performed to confirm the diagnosis of acute pancreatitis. These tests (especially ultrasound) are fairly accurate in detecting the presence of cholelithiasis but have limited sensitivity for diagnosing choledocholithiasis. Transabdominal ultrasound during an attack of acute pancreatitis is often hindered by the presence of gas in the small bowel. In the absence of radiologic abnormalities, clinical suspicion associated with biochemical abnormalities may be the only clue to the diagnosis of acute pancreatitis (see the article on endoscopic ultrasound elsewhere in this issue).
INDICATIONS FOR ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY Thirty percent of cases of acute pancreatitis were once considered
idiopathic after a careful search for a cause was unrevealing.34The theory that many cases of so-called idiopathic pancreatitis are caused by gallstones too small to be visualized by conventional imaging (microlithiasis) was proposed more than 60 years ago.8Lee et alZ2found no obvious cause for acute pancreatitis in 31 of 86 consecutive patients (36%) after conventional investigation. In these 31 patients, evaluation for microlithiasis (calcium bilirubinate or cholesterol monohydrate crystals) by microscopic examination of centrifuged bile (obtained at ERCP or by duodenal aspiration after cholecystokinin [CCK] stimulation) was positive in 74% (23 of 31 cases). Patients who subsequently underwent treatment by endoscopic sphincterotomy or cholecystectomy experienced fewer recurrences of acute pancreatitis during follow-up compared to untreated patients (10% versus 73%, X.01). In a similar study by Ros et a1,32 67% of patients with unexplained pancreatitis had microlithiasis, and uncontrolled treatment with cholecystectomy or chemical dissolution (ursodeoxycholic acid) prevented recurrence in most cases. The sensitivity, specificity, and positive and negative predictive values for the microscopic detection of biliary microlithiasis have been reported to be 83%, 1009'0, 88%, and 93%.'O Idiopathic pancreatitis should not be diagnosed until biliary microlithiasis has been excluded, therefore elective ERCP with collection of bile should be performed in every patient with unexplained pancreatitis. If biliary crystals are found, cholecystectomy or, in selected patients, biliary sphincterotomy, can prevent recurrence of pancreatitis in most patients. ERCP may also be beneficial in patients with unexplained pancreatitis to detect pancreas divisum, ampullary masses, choledochoceles, structural abnormalities of the pancreatic duct (stones, strictures, pseudocysts) and motility disorders of the biliary or pancreatic sphincter, determined by manometry. Pancreatitis associated with a hypertensive pancreatic sphincter remains a poorly understood and probably underdiagnosed phenomenon. Studies suggest that many patients with sphincter of Oddi dysfunction also have high pressures in the pancreatic duct suggesting that pressures in both sphincters should be measured in patients with idiopathic pancreatitis. Because of the significant
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
605
risk of causing pancreatitis by performing pancreatic manometry and sphincterotomy, these procedures should be undertaken with caution, preferably by specialists at referral centers. Occasionally, ERCP may detect a pancreatic duct stricture complicating abdominal trauma not reported or recalled by the patient. Unexplained pancreatic duct strictures in adults should be considered suspicious for malignancy and should be investigated with a dedicated pancreatic protocol using intravenous contrast-enhanced spinal CT scan or endoscopic ultrasound (see other articles in this issue). Despite the increasing accuracy of CT-guided and endoscopic ultrasound-guided fine needle aspirates and needle biopsies, small pancreatic neoplasms may defy histologic diagnosis. Sometimes it is necessary to send a patient with recurrent pancreatitis and an unexplained pancreatic duct stricture for blind surgical resection of part or all of the pancreas (e.g., Whipple procedure) because delayed diagnosis of pancreatic adenocarcinoma usually results in death. PREDICTION OF SEVERITY AND OUTCOME IN ACUTE PANCREATITIS
Patients with severe attacks of acute pancreatitis have significant mortality and are therefore most appropriately managed in an intensive care unit.26Numerous scoring systems have been developed to allow early stratification of patients into mild and severe categories. Ranson31 developed an 11-factor system initially in a group of patients with alcoholic pancreatitis that was subsequently modified for use in patients with biliary pancreatitis and is commonly used in the United States (Table 2). Imrie’s group from Glasgow, Scotland, proposed a somewhat ~ simplified eight-factor system that is widely used in E u r ~ p e .The
Table 2. RANSON’S CRITERIA OF SEVERITY OF ACUTE PANCREATITIS On Admission Age >55 y White blood cell count >16,000/mm3 Glucose >ZOO mg/dL Lactate dehydrogenase >350 IU/L Aspartate aminotransferase >250 U/L During Initial 48 Hours of Admission Hematocrit decrease of >10 Blood urea nitrogen increase of >5 mg/dL Calcium <8 mg/dL Partial pressure of oxygen <60 mm Hg Base deficit >4 mEq/L Fluid sequestration >6 L From Ranson JHC Etiologic and prognostic factors in human acute pancreatitis: A review. Am J Gastroentero17763M38,1982; with permission.
606
MERGENER & BAILLIE
APACHE I1 system (an acute illness prognostic score widely used in intensive care units) is more cumbersome but can be applied at the time of admission (the Ranson and Imrie criteria require 48 hours’ observation to complete the assessment). Additional ways to predict severity, such as the use of serum markers (e.g., C-reactive protein, trypsinogen activating peptides, leukocyte elastase) and the return from peritoneal lavages? have been reported to be effective but are not widely used in clinical practice. An abdominal CT scan enhanced by the use of intravenous contrast medium shows the presence and extent of pancreatic necrosis, which has definite prognostic implications. The development of extrapancreatic organ failure (e.g., pulmonary, renal, hepatic, cardiac), however, is probably the most accurate predictor of severe and poor outcome.9 CONSERVATIVE MANAGEMENT OF ACUTE PANCREATITIS
A detailed discussion of the conservative management of acute pancreatitis is beyond the scope of this article and can be found elsewhere (see other articles in this issue).26Initially, patients with acute pancreatitis (of any origin) should be given nothing by mouth, intravenous hydration, and frequent parenteral analgesia, usually with narcotic agents. If they have a prolonged ileus (>1 week), persistent nausea or vomiting, or pain on eating or drinking despite apparent improvement in bowel function, they require assisted nutrition, either by enteral (nasojejunal) feeding or by the intravenous (parenteral) route (see the article on nutrition by Scolapio). If tolerated by the patient, enteral feeding is preferred because it avoids the risks of central venous catheterization (including infection) and maintains the integrity of the gut mucosal absorptive mechanisms. Enteral feeding may also reduce the risk of bacterial translocation across the small bowel wall, which encourages infection in pancreatitis. Prophylactic antibiotics may reduce sepsis in patients with pancreatic necrosis, and it has been suggested that all patients predicted to develop severe pancreatitis should receive them (see article by Ratschko et a1).I6Broad-spectrum antibiotics with activity against gram-negative enteric bacteria and demonstrated ability to penetrate pancreatic parenchyma should be chosen. The importance of close monitoring, especially during the first 24 to 48 hours after onset of symptoms, to detect deterioration and the development of local and systemic complications (e.g., shock, renal failure, respiratory insufficiency) cannot be overemphasized. TIMING OF SURGERY AND ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY IN ACUTE BlLlARY PANCREATITIS
In 1980, a case series by Acosta et a12 describing operative decompression of the biliary tree in a group of patients with gallstone pancre-
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
607
atitis revived the interest of surgeons in this procedure. The authors found a mortality of only 2.9% (1 of 46) in their patients compared to 16% (14 of 86) in historical controls. A subsequent prospective trial, however, reported a sobering 48% mortality after early surgery compared with 11% after delayed surgeryzo Today, wise surgeons avoid operative intervention early in the course of acute pancreatitis. Patients who have recovered from gallstone pancreatitis and have an intact gallbladder containing stones should undergo elective cholecystectomy, usually performed by the laparoscopic route. Because most patients pass the offending stone well before they go to surgery, routine preoperative ERCP cannot be justified because the yield of biliary stones is Patients with biliary obstruction (with or without sepsis) as indicated by rising or persistently elevated serum bilirubin level and dilated intrahepatic bile ducts on noninvasive imaging studies should undergo preoperative ERCP and sphincterotomy if stones are found, with the aim of decompressing the bile duct. Patients who do not have evidence of ongoing biliary obstruction should have an intraoperative cholangiogram performed at the time of cholecystectomy. If bile duct stones are seen on the intraoperative cholangiogram, the surgeon has a number of management options: The surgeon may perform open or laparoscopic bile duct exploration to recover the stones, or the patient can be referred for postoperative ERCP (usually done the following day). Intraoperative ERCP is technically possible but logistically difficult and is not commonly employed. The algorithm for biliary stone management has to be tailored to reflect the skill and experience of both the surgeon and the endoscopist. For example, if the local success rate for bile duct cannulation at ERCP is 50% or less, a preoperative ERCP may be justifiable when there is suspicion that biliary stones may be present but no cholangitis or jaundice. A failed preoperative ERCP influences the surgeon's approach to the cholecystectomy. In the authors' opinion, neither endoscopists with a selective cannulation rate of less than 80% nor those who can perform only diagnostic studies should be doing ERCP.I7 Sphincterotomy and biliary drainage using stents or nasobiliary drains are mandatory skills for those performing ERCP. URGENT INTERVENTION IN ACUTE BILIARY PANCREATITIS
After beginning as a purely diagnostic procedure in 1968, ERCP entered the therapeutic arena with initial reports of biliary sphincterotomy in 1974.". l9 Endoscopists were initially reluctant to apply this technique in patients with acute pancreatitis for fear of exacerbating the acute episode or causing complications, such as hemorrhage and perforation. Early experience suggested that these concerns were largely unsubstantiated. In addition, some patients dramatically improved after endoscopic intervention to decompress the obstructed ampulla of Vater. Thus far, four randomized, controlled trials looking at the use of ERCP
608
MERGENER & BAILLIE
in patients with acute biliary pancreatitis have been completed. These have helped clarify the role of ERCP in the management of this group of patients. Because enrollment criteria, study results, and data interpretation vary considerably among these studies, it is useful to review them individually. The first prospective, randomized trial of urgent ERCP for acute pancreatitis was published by a group from Leicester, England, in 1988.27 A total of 121 patients with gallstone pancreatitis were randomized to receive either conventional conservative treatment or urgent ERCP within 72 hours of onset of the attack; endoscopic sphincterotomy and stone extraction were performed only in those patients whose ERCP showed common bile duct stones. The study included patients with both predicted mild and severe pancreatitis; stratification was based on modified Glasgow (Imrie) criteria. Common bile duct stones were found in 63% of the predicted severe pancreatitis patients but in only 26% of those with predicted mild disease. All the common bile duct stones could be removed endoscopically without complications. The authors reported that (1) ERCP can be performed safely in acute pancreatitis by an experienced endoscopist; (2) there was a statistically significant reduction in major complications of severe pancreatitis secondary to common bile duct stones after ERCP, endoscopic sphincterotomy, and stone extraction (12% versus 61%); (3) a trend toward reduction in mortality was also observed in those with predicted attacks; and (4) urgent endoscopic sphincterotomy almost halved the hospital stay for patients with predicted severe attacks (median 9.5 days versus 17 days). Although a statistical difference in mortality was not demonstrated, this study provided a rational basis for the application of ERCP, endoscopic sphincterotomy, and stone extraction in selected cases of acute biliary pancreatitis. The second study was a prospective, randomized study from Hong Kong12 that included 195 patients with acute pancreatitis of all causes, of whom 127 (65%) had common bile duct stones at ERCP. Sixty-four were randomized to ERCP within 24 hours, and 63 were treated conservatively. In the ERCP group, 37 of 64 patients (58%) underwent endoscopic sphincterotomy and stone extraction. In the conservative treatment group, 22 of 63 patients (35%)subsequently were deemed to need ERCP because of clinical deterioration; 20 of 22 (910/,)of these late ERCP patients had either common bile duct or gallbladder stones. As in the Leicester study, the Hong Kong trial patients with predicted severe pancreatitis who were randomized to early ERCP had reduced morbidity (13% versus 54%) and mortality (3% versus 18%). There was no difference in overall outcome between the ERCP and conservative treatment groups of patients with predicted mild pancreatitis. The reduction in episodes of biliary sepsis in the ERCP group remained significant when patients with predicted severe and mild pancreatitis were evaluated together, leading the authors to conclude that ERCP within 24 hours is indicated in all patients with severe attacks of gallstone pancreatitis as well as those patients with predicted mild pancreatitis who have biliary
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATVIS
609
sepsis. Caution is needed when extrapolating the results of the Hong Kong trial to patients in Western societies. Bile duct stones cause almost 100% of cases of acute pancreatitis in Hong Kong, which is not the case in Europe and America. The prognostic score employed in the Hong Kong study for stratifying the pancreatitis as severe (serum urea concentration >45 mg/dL and plasma glucose >198 mg/dL on admission) was unusual and may have overestimated the number of patients at risk for evere disease. ERCP was used both for diagnosis and for treatment in $is study, without other imaging studies (e.g., ultrasound, CT), which would commonly be performed in Western countries. Nonetheless, when the data from Hong Kong are taken together with those from the Leicester study, they emphasize the potential benefit of early ERCP in a select population of patients with predicted severe pancreatitis. The third trial was a multicenter, prospective study from GermanyI3 that included 238 patients with acute biliary pancreatitis without evidence of biliary obstruction who were randomized to receive ERCP within 72 hours or conventional therapy. ERCP was successful in 96% of 126 patients, of whom 58 (46%) had common bile duct stones. Given that the patients most likely to have stones (those with cholangitis or jaundice) were excluded, this was an unexpectedly high yield. Twenty of the 112 patients in the conservative treatment group subsequently underwent ERCP; 13 of them (12%)had common bile duct stones. There was no significant difference in morbidity or mortality between the two groups. Patients randomized to early ERCP, however, had a higher incidence of respiratory failure (defined as failure to maintain an arterial oxygen tension of at least 60 mm Hg) and more severe complications. Stratification of the patients according to predicted severity of pancreatitis did not affect the results. Concerns have been expressed regarding the design, performance, and statistical interpretation of this study.33For example, 22 centers were involved, contributing a mean of 2.4 patients per center per year. Many of the centers entered fewer patients than this; only three centers contributed 20 or more patients. The overall low enrollment raises questions about ERCP volume and therefore expertise in performing urgent ERCP in sick patients in many of the participating centers. A further concern is the apparent excess of respiratory failure in patients assigned to early ERCP; this was not observed in the two prior single-center studies. Reviewers have speculated that overuse of statistical significance and the way certain complications were defined may have biased the results against ERCP. The study was discontinued early because of concerns about the excess of morbidity and possibly mortality in the ERCP treatment group. As a result, enrollment in the study fell considerably short of the numbers predicted by a power In light of the calculation to be required for statistical significan~e.~~ problems described, the authors’ conclusion that ERCP is contraindicated or dangerous in patients with acute biliary pancreatitis cannot be accepted without qualifications. The fourth randomized trial by Nowak et a128in Poland is different in its design from the three previous studies. Three years after the data
610
MERGENER & BAILLIE
were presented at Digestive Diseases Week in the United States, the study has still not been published as a paper in a peer-reviewed journal, which severely limits ability to analyze the data critically. All 280 patients with acute biliary pancreatitis in this study underwent urgent endoscopy within 24 hours of the onset of symptoms; 25% were found to have stones impacted at the duodenal papilla, and all of these were treated by immediate endoscopic sphincterotomy. The remaining 205 patients were randomized to conventional treatment or endoscopic sphincterotomy regardless of the cholangiographic findings. The authors showed a significant advantage for patients treated endoscopically, both in terms of morbidity (17% versus 369'0, P<.OOl) and mortality (2% versus 13%, R.001). These outcomes were most impressive when the endoscopic intervention was early. All patients seemed to benefit, however, regardless of predicted severity. The authors concluded that urgent ERCP and endoscopic sphincterotomy are indicated in all patients with acute biliary pancreatitis. CONCLUSIONS
How the existing data regarding endoscopic management of acute biliary pancreatitis be interpreted? Patients with predicted severe gallstone pancreatitis who have evidence of persistent or progressive biliary obstruction (cholangitis, jaundice) benefit from early ERCP and endoscopic sphincterotomy for stone extraction and biliary decompression. Do all patients with predicted severe gallstone pancreatitis, regardless of whether or not they have evidence of biliary obstruction, merit urgent ERCP, as Nowak et alZ8suggest? The Folsch study from GermanyI3 suggests that this approach would put patients who would not be expected to benefit from this intervention at increased risk of complications and death. There are as yet unpublished data (R. Kozarek, personal communication) suggesting that many patients with predicted severe pancreatitis have pancreatic duct disruption that may benefit from endoscopic stenting. This may be an alternative use of ERCP that would make a difference in the outcome of these ill patients. A publication based on these data is eagerly awaited. What tends to be forgotten in the discussion of ERCP in relation to gallstone pancreatitis is that these procedures are some of the most arduous undertaken by endoscopists. The patients are often in the intensive care unit, where fluoroscopy is usually suboptimal and sometimes nonexistent. The patients may have coagulopathy, limiting endoscopic sphincterotomy; in these circumstances, placing a biliary stent or nasobiliary drain without endoscopic sphincterotomy for temporary decompression works well. The routine use of prelaparoscopic cholecystectomy ERCP in patients with presumed gallstone pancreatitis cannot be justified. Intraoperative cholangiography should be part of every biliary surgeon's skill set, and this technique should be liberally applied to identify patients with persistent common bile duct stones for early postoperative ERCP. Percutaneous cholangiog-
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
611
I Acute PancreatitisI Gallstone? Imaging +ve ALD3x nl
Predicted Mild
Improving No cholangitis or progressive jaundice?
Improving No cholangitis or progressive jaundice
No early ERCP Proceed with Lap Cholecystx
No data to support early ERCP
Cholangitis or progressive jaundice
I
If CBD stones present, next day ERCPl sphincterotomy
Early ERCP for CBD decompression indicated Interval Lap Cholecystx without I.O.C.
Figure 1. Endoscopic management of gallstone pancreatitis.
raphy is an option when ERCP fails for technical reasons, although the need for interventional radiology should be limited if endoscopists have proper training in diagnostic and therapeutic ERCP. Laparoscopic common bile duct exploration is also a management option for common bile duct stones. This procedure adds time and technical difficulty to laparoscopic cholecystectomy. Where surgeons have access to competent ERCP endoscopists, next-day ERCP has become the preferred management when common bile duct stones are seen during intraoperative cholangiography.
References 1. Acosta JM, Ledesma CL: Gallstone migration as a cause of acute pancreatitis. N Engl J Med 290:484-487,1974 2. Acosta JM, Pelligrini CA, Skinner DB Etiology and pathogenesis of acute biliary pancreatitis. Surgery 88118-125,1980
612
MERGENER & BAILLIE
3. Baillie J: Treatment of acute biliary pancreatitis [edit]. N Engl J Med 336:286-287, 1997 4. Banks PA: Predictors of severity in acute pancreatitis. Pancreas 6(supp 1):S7-S12, 1991 5. Berk JE: The management of acute pancreatitis: A critical assessment as Dr. Bockus would have wished. Am J Gastroenterol 90:696-703, 1995 6. Bernard C: Le cors de physiologic experimental. Paris, JB Beuilliere, 1856 7. Blarney SL, Imrie CW, ONeill J, et al: Prognostic factors in acute pancreatitis. Gut 25:1340-1346, 1984
8. Bockus HL, Sahy H, Willard JH, et al: Comparison of biliary drainage and cholecystography in gallstone diagnosis with special reference to bile microscopy. J A M 96311317, 1931 9. Bradley E L A clinically based classification system for acute pancreatitis. Arch Surg 128:586-590, 1993 10. Buscail L, Escourrou J, Delvaux M, et al: Microscopic examination of bile directly
collected during endoscopic cannulation of the papilla: Utility in patients with suspected microlithiasis. Dig Dis Sci 3711&120, 1992 11. Classen M, Demling L Endoskopische Spinkterotomie der Papilla Vateri und Steinextraktion aus dem Ductus Choledochus. Dtsch Med Wochenschr 99:496-497, 1974 12. Fan S-T, Lai ECS, Mok FPT, et al: Early treatment of acute biliary pancreatitis by endoscopic papillotomy. N Engl J Med 328:228-232, 1993 13. Folsch U, Nitsche R, Ludtke R, et a1 Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. N Engl J Med 336:237-242, 1997 14. Go V, Everhart J: Pancreatitis. In Everhart J (ed): Digestive Diseases in the United States: Epidemiology and Impact. Publication no. 94-1447. Washington, DC, US Government Printing Office, 1994, pp 691-712 15. Gumaste W, Dave PB, Weissman D, et a1 Lipase/amylase ratio: A new index that distinguishes acute episodes of alcoholic from non-alcoholic pancreatitis. Gastroenterology 101:1361-1366, 1991 16. Johnson CD: Antibiotic prophylaxis in severe acute pancreatitis. Br J Surg 83:883-884, 1996 17. Jowell PS, Baillie J, Branch MS, et al: Quantitative assessment of procedural competence: A prospective study of training in ERCP. Ann Intern Med 125:9883-9889, 1996
18. Karimgani I, Porter KA, Langenvin RE, et al: Prognostic factors in sterile pancreatic necrosis. Gastroenterology 1041636-1640, 1993 19. Kawai K, Akasaka Y, Murakami K, et al: Endoscopic sphincterotomy of the ampulla of Vater. Gastrointest Endosc 20:148-151, 1974 20. Kelly TR, Wagner D S Gallstone pancreatitis: A prospective randomized trial of the timing of surgery. Surgery 104:60(r605, 1988 21. Kusske AM, Rongione AJ, Reber HA: Cytokines and acute pancreatitis [edit]. Gastroenterology 110639442, 1996 22. Lee SP, Nicholls JF, Park Hz: Biliary sludge as a cause of acute pancreatitis. N Engl J Med 326589-593, 1992 23. Lerch MM, Saluja AK, Runzi M, et al: Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opposum. Gastroenterology 104853-861, 1993 24. McKay CJ, Curran F, Sharples C, et al: Prospective placebo-controlled randomized trial of lexipafant in predicted severe acute pancreatitis. Br J Surg M1239-1243, 1997 25. Mergener K Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis [letter]. N Engl J Med 336:1836, 1997 26. Mergener K, Baillie J: Fortnightly review: Acute pancreatitis. BMJ 3164448, 1998 27. Neoptolemos JP, Carr-Locke DL, London NJ, et al: Controlled trial of urgent endoscopic retrograde cholangiopancreatographyand endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 2:979-983, 1988 28. Nowak A, Nowakowska-Dulawa E, Marek T, et a1 Final results of the prospective randomized controlled study on endoscopic sphincterotomy versus conventional management in acute biliary pancreatitis [abstr]. Gastroenterology 108:8380, 1995 29. Opie EL The etiology of acute hemorrhagic pancreatitis. Johns HopHosp Bull 121:182-188, 1901 30. Pezzilli R, Billi P, Miglioli M, et al: Serum amylase and lipase concentrations and
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
31. 32. 33.
34. 35. 36.
613
lipase/amylase ratio in the assessment of etiology and severity of acute pancreatitis. Dig Dis Sci 38:1265-1269, 1993 Ranson JHC: Etiologic and prognostic factors in human acute pancreatitis: A review. Am J Gastroenterol77633-638, 1982 Ros E, Navarro S, Bru C, et al: Occult microlithiasis in “idiopathic” acute pancreatitis: Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology 101:1701-1709, 1991 Soetikno RM, Carr-Locke DL: Endoscopic management of acute gallstone pancreatitis. Gastrointest Endosc Clin North Am 8:l-12, 1998 Steinberg WM: Acute pancreatitis-never leave a stone untumed. N Engl J Med 326:635-637, 1992 Tamasky PR, Hawes RH: Endoscopic diagnosis and therapy of unexplained (idiopathic) acute pancreatitis. Gastrointest Endosc Clin North Am 8:1>37, 1998 Tenner S, Dubner H, Steinberg W Predicting gallstone pancreatitis with laboratory parameter: A meta analysis. Am J Gastroenterol 89:1863-1866, 1994
Address reprint requests to John Baillie, MB, ChB, FRCP(G) Division of Gastroenterology Box 3189 Duke University Medical Center Durham, NC 27710
0889-8553/99 $8.00
+ .OO
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS When and in Whom? Klaus Mergener, MD, and John Baillie, MB, ChB, FRCP(G)
Gallstones and alcohol remain the main causes of acute pancreatitis worldwide. In industrialized countries, gallstones account for 34% to 54% of the 4.8 to 24.2 cases of acute pancreatitis per 100,000 people ann~ally.’~ The management of acute pancreatitis remains challenging; although most patients with mild pancreatitis have self-limited disease, requiring only simple supportive measures, severe pancreatitis remains a deadly disease, with an overall mortality of up to 10%. Close monitoring of patients, preferably in an intensive care unit, and the management of local and systemic complications remain the mainstays of treatment. Endoscopists are often asked to perform endoscopic retrograde cholangiography (ERCP) in patients with acute pancreatitis if gallstones are suspected. Whether or not patients benefit from this intervention and, if so, when it should be performed are questions that have now been addressed in several randomized, controlled clinical trials. The results of these studies are reviewed, and a suggested algorithm for the management of patients with suspected acute biliary pancreatitis is provided. PATHOGENESIS An association between gallstones and pancreatitis was suggested in 1856, by Bernard.6 In 1901, OpieZ9performed an autopsy on a patient
From the Medizinische Klinik und Poliklinik, Johannes-Gutenberg-Universitaet (KM), Mainz, Germany; and Division of Gastroenterology, Duke University Medical Center (JB), Durham, North Carolina
GASTROENTEROLOGY CLINICS OF NORTH AMERICA VOLUME 28 NUMBER 3 SEFTEMBER 1999
601
602
MERGENER & BAILLIE
who had died of severe pancreatitis. Finding a gallstone impacted at the ampulla of Vater, he argued that obstruction of the common channel between the bile duct and the main pancreatic duct led to bile reflux into the latter, triggering pancreatitis. This common channel theory of pancreatitis is supported by experimental studies in the as well as by clinical observations. Gallstones can be recovered from the feces of approximately 90% of patients with acute pancreatitis compared with only 10% of patients with cholelithiasis without pancreatitis.*In patients with acute pancreatitis who underwent urgent surgical intervention, bile duct stones were found in 63% to 78%, compared with only 3% to 33% of patients with stones who underwent delayed surgery.20 Opie’s theory, however, has been challenged for the following reasons: (1) A common channel is found in only 70% to 80% of patients with gallstone pancreatitis, and (2) because pancreatic duct pressure usually exceeds that of the bile duct, bile reflux into the pancreas is unlikely. The duodenal reflux hypothesis states that duodenal contents (containing bacterial toxins, lysolecithin, and enterokinases) refluxing through a sphincter of Oddi that has been rendered transiently incompetent by the passage of a gallstone may be the initiating event in acute pancreatitis. A third hypothesis proposes that obstruction of the pancreatic duct alone (without reflux of bile or duodenal juice) is the main pathogenic event. It seems plausible that elements of all three theories play a role in the pathogenesis of acute pancreatitis. Although the inappropriate activation and release of pancreatic enzymes (especially the proteolytic enzyme, trypsin) has long been considered to be the final common pathway for events precipitating acute pancreatitis? more recent work on mediators of the inflammatory response, especially cytokines, shows this to be too simplistic. It is clear that interleukins (e.g., IL-6, IL-8), platelet-activating factor (PAF), and tumor necrosis factor-a (TNF-a) play a major role in the systemic (extrapancreatic) complications of acute pancreatitis.21Studies suggest that the PAF inhibitor, lexipafant, may reduce the morbidity and mortality of acute pancreatitis if administered within 48 hours of its onset (see the article by I m ~ i e ) . ~ ~ DIAGNOSIS OF ACUTE BlLlARY PANCREATITIS
Identifying the underlying cause of acute pancreatitis is important for predicting the risk of recurrence and to guide the decision to perform diagnostic or therapeutic ERCP. Although gallstones and alcohol account for 70% to 80% of cases of acute pancreatitis, other causes, such as hyperlipidemia, hypercalcemia, drug sensitivity, trauma, infection, and familial pancreatitis, should be considered and excluded by a careful history, physical examination, and laboratory studies (Table 1). Risk factors for cholesterol gallstones should be noted, including female sex, age, obesity, rapid weight loss, pregnancy, and certain drugs (estrogens, clofibrate, octreotide, ceftriaxone). Gallstone pancreatitis not infrequently follows cholecystectomy, especially in the era of laparoscopic surgery,
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
603
Table 1. CONDITIONS ASSOCIATED WITH ACUTE PANCREATITIS
Cholelithiasis, choledocholithiasis, or biliary microlithiasis Ethanol misuse Drugs Azathioprine, 6-mercaptopurine, asparaginase Pentamidine, didanosine Hydrochlorothiazide, furosemide Tetracyclines, sulfonamides Valproic acid Estrogens Sulfasalazine Iatrogenic (e.g., ERCP) Trauma Hypercalcemia Hyperlipidemia Pancreas divisum* Familial pancreatitis Ischemia Penetrating gastric or duodenal ulcer Pancreatic tumors Pregnancy Infections Mycoplasma Mumps Coxsackie B HIV (?) Venoms (scorpion/spider bites) Sphincter of Oddi dysfunction Idiouathic ‘A normal variant in 7% to 8% of white populations. ERCP = Endoscopic retrograde cholangiopancreatography; HIV = human immunodeficiency virus. Modified from Mergener K, Baillie J: Fortnightly review: Acute pancreatitis. BMJ 31644-48, 1998; with permission.
when small stones are easily milked from the gallbladder neck or cystic duct into the common bile duct during the procedure. Pancreatitis occurring within days of laparoscopic cholecystectomy should be assumed to be of gallstone origin. Serum amylase and lipase elevations can confirm the diagnosis of acute pancreatitis, but they do not help to distinguish between the different causes. Although early studies suggested that a lipase-to-amylase ratio greater than 2 identifies alcoholic pan~reatitis,’~ more recent studies concluded that the positive predictive value of this ratio is Likewise, the magnitude of serum amylase and lipase elevation does not distinguish between causes of pancreatitis, and it does not correlate with the severity of the attack or predict the clinical course. The most reliable biochemical predictor of gallstones as the cause of acute pancreatitis is elevation of the serum alanine aminotransferase (ALT): An ALT elevation of threefold or higher has a positive predictive value of 95% for diagnosing acute biliary pancreatiti^.^^ Elevations of serum bilirubin and alkaline phosphatase are not specific for this diagnosis. Transabdominal ultrasound and computed
604
MERGENER & BAILLIE
tomography (CT) of the abdomen are often performed to confirm the diagnosis of acute pancreatitis. These tests (especially ultrasound) are fairly accurate in detecting the presence of cholelithiasis but have limited sensitivity for diagnosing choledocholithiasis. Transabdominal ultrasound during an attack of acute pancreatitis is often hindered by the presence of gas in the small bowel. In the absence of radiologic abnormalities, clinical suspicion associated with biochemical abnormalities may be the only clue to the diagnosis of acute pancreatitis (see the article on endoscopic ultrasound elsewhere in this issue).
INDICATIONS FOR ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY Thirty percent of cases of acute pancreatitis were once considered
idiopathic after a careful search for a cause was unrevealing.34The theory that many cases of so-called idiopathic pancreatitis are caused by gallstones too small to be visualized by conventional imaging (microlithiasis) was proposed more than 60 years ago.8Lee et alZ2found no obvious cause for acute pancreatitis in 31 of 86 consecutive patients (36%) after conventional investigation. In these 31 patients, evaluation for microlithiasis (calcium bilirubinate or cholesterol monohydrate crystals) by microscopic examination of centrifuged bile (obtained at ERCP or by duodenal aspiration after cholecystokinin [CCK] stimulation) was positive in 74% (23 of 31 cases). Patients who subsequently underwent treatment by endoscopic sphincterotomy or cholecystectomy experienced fewer recurrences of acute pancreatitis during follow-up compared to untreated patients (10% versus 73%, X.01). In a similar study by Ros et a1,32 67% of patients with unexplained pancreatitis had microlithiasis, and uncontrolled treatment with cholecystectomy or chemical dissolution (ursodeoxycholic acid) prevented recurrence in most cases. The sensitivity, specificity, and positive and negative predictive values for the microscopic detection of biliary microlithiasis have been reported to be 83%, 1009'0, 88%, and 93%.'O Idiopathic pancreatitis should not be diagnosed until biliary microlithiasis has been excluded, therefore elective ERCP with collection of bile should be performed in every patient with unexplained pancreatitis. If biliary crystals are found, cholecystectomy or, in selected patients, biliary sphincterotomy, can prevent recurrence of pancreatitis in most patients. ERCP may also be beneficial in patients with unexplained pancreatitis to detect pancreas divisum, ampullary masses, choledochoceles, structural abnormalities of the pancreatic duct (stones, strictures, pseudocysts) and motility disorders of the biliary or pancreatic sphincter, determined by manometry. Pancreatitis associated with a hypertensive pancreatic sphincter remains a poorly understood and probably underdiagnosed phenomenon. Studies suggest that many patients with sphincter of Oddi dysfunction also have high pressures in the pancreatic duct suggesting that pressures in both sphincters should be measured in patients with idiopathic pancreatitis. Because of the significant
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
605
risk of causing pancreatitis by performing pancreatic manometry and sphincterotomy, these procedures should be undertaken with caution, preferably by specialists at referral centers. Occasionally, ERCP may detect a pancreatic duct stricture complicating abdominal trauma not reported or recalled by the patient. Unexplained pancreatic duct strictures in adults should be considered suspicious for malignancy and should be investigated with a dedicated pancreatic protocol using intravenous contrast-enhanced spinal CT scan or endoscopic ultrasound (see other articles in this issue). Despite the increasing accuracy of CT-guided and endoscopic ultrasound-guided fine needle aspirates and needle biopsies, small pancreatic neoplasms may defy histologic diagnosis. Sometimes it is necessary to send a patient with recurrent pancreatitis and an unexplained pancreatic duct stricture for blind surgical resection of part or all of the pancreas (e.g., Whipple procedure) because delayed diagnosis of pancreatic adenocarcinoma usually results in death. PREDICTION OF SEVERITY AND OUTCOME IN ACUTE PANCREATITIS
Patients with severe attacks of acute pancreatitis have significant mortality and are therefore most appropriately managed in an intensive care unit.26Numerous scoring systems have been developed to allow early stratification of patients into mild and severe categories. Ranson31 developed an 11-factor system initially in a group of patients with alcoholic pancreatitis that was subsequently modified for use in patients with biliary pancreatitis and is commonly used in the United States (Table 2). Imrie’s group from Glasgow, Scotland, proposed a somewhat ~ simplified eight-factor system that is widely used in E u r ~ p e .The
Table 2. RANSON’S CRITERIA OF SEVERITY OF ACUTE PANCREATITIS On Admission Age >55 y White blood cell count >16,000/mm3 Glucose >ZOO mg/dL Lactate dehydrogenase >350 IU/L Aspartate aminotransferase >250 U/L During Initial 48 Hours of Admission Hematocrit decrease of >10 Blood urea nitrogen increase of >5 mg/dL Calcium <8 mg/dL Partial pressure of oxygen <60 mm Hg Base deficit >4 mEq/L Fluid sequestration >6 L From Ranson JHC Etiologic and prognostic factors in human acute pancreatitis: A review. Am J Gastroentero17763M38,1982; with permission.
606
MERGENER & BAILLIE
APACHE I1 system (an acute illness prognostic score widely used in intensive care units) is more cumbersome but can be applied at the time of admission (the Ranson and Imrie criteria require 48 hours’ observation to complete the assessment). Additional ways to predict severity, such as the use of serum markers (e.g., C-reactive protein, trypsinogen activating peptides, leukocyte elastase) and the return from peritoneal lavages? have been reported to be effective but are not widely used in clinical practice. An abdominal CT scan enhanced by the use of intravenous contrast medium shows the presence and extent of pancreatic necrosis, which has definite prognostic implications. The development of extrapancreatic organ failure (e.g., pulmonary, renal, hepatic, cardiac), however, is probably the most accurate predictor of severe and poor outcome.9 CONSERVATIVE MANAGEMENT OF ACUTE PANCREATITIS
A detailed discussion of the conservative management of acute pancreatitis is beyond the scope of this article and can be found elsewhere (see other articles in this issue).26Initially, patients with acute pancreatitis (of any origin) should be given nothing by mouth, intravenous hydration, and frequent parenteral analgesia, usually with narcotic agents. If they have a prolonged ileus (>1 week), persistent nausea or vomiting, or pain on eating or drinking despite apparent improvement in bowel function, they require assisted nutrition, either by enteral (nasojejunal) feeding or by the intravenous (parenteral) route (see the article on nutrition by Scolapio). If tolerated by the patient, enteral feeding is preferred because it avoids the risks of central venous catheterization (including infection) and maintains the integrity of the gut mucosal absorptive mechanisms. Enteral feeding may also reduce the risk of bacterial translocation across the small bowel wall, which encourages infection in pancreatitis. Prophylactic antibiotics may reduce sepsis in patients with pancreatic necrosis, and it has been suggested that all patients predicted to develop severe pancreatitis should receive them (see article by Ratschko et a1).I6Broad-spectrum antibiotics with activity against gram-negative enteric bacteria and demonstrated ability to penetrate pancreatic parenchyma should be chosen. The importance of close monitoring, especially during the first 24 to 48 hours after onset of symptoms, to detect deterioration and the development of local and systemic complications (e.g., shock, renal failure, respiratory insufficiency) cannot be overemphasized. TIMING OF SURGERY AND ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY IN ACUTE BlLlARY PANCREATITIS
In 1980, a case series by Acosta et a12 describing operative decompression of the biliary tree in a group of patients with gallstone pancre-
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
607
atitis revived the interest of surgeons in this procedure. The authors found a mortality of only 2.9% (1 of 46) in their patients compared to 16% (14 of 86) in historical controls. A subsequent prospective trial, however, reported a sobering 48% mortality after early surgery compared with 11% after delayed surgeryzo Today, wise surgeons avoid operative intervention early in the course of acute pancreatitis. Patients who have recovered from gallstone pancreatitis and have an intact gallbladder containing stones should undergo elective cholecystectomy, usually performed by the laparoscopic route. Because most patients pass the offending stone well before they go to surgery, routine preoperative ERCP cannot be justified because the yield of biliary stones is Patients with biliary obstruction (with or without sepsis) as indicated by rising or persistently elevated serum bilirubin level and dilated intrahepatic bile ducts on noninvasive imaging studies should undergo preoperative ERCP and sphincterotomy if stones are found, with the aim of decompressing the bile duct. Patients who do not have evidence of ongoing biliary obstruction should have an intraoperative cholangiogram performed at the time of cholecystectomy. If bile duct stones are seen on the intraoperative cholangiogram, the surgeon has a number of management options: The surgeon may perform open or laparoscopic bile duct exploration to recover the stones, or the patient can be referred for postoperative ERCP (usually done the following day). Intraoperative ERCP is technically possible but logistically difficult and is not commonly employed. The algorithm for biliary stone management has to be tailored to reflect the skill and experience of both the surgeon and the endoscopist. For example, if the local success rate for bile duct cannulation at ERCP is 50% or less, a preoperative ERCP may be justifiable when there is suspicion that biliary stones may be present but no cholangitis or jaundice. A failed preoperative ERCP influences the surgeon's approach to the cholecystectomy. In the authors' opinion, neither endoscopists with a selective cannulation rate of less than 80% nor those who can perform only diagnostic studies should be doing ERCP.I7 Sphincterotomy and biliary drainage using stents or nasobiliary drains are mandatory skills for those performing ERCP. URGENT INTERVENTION IN ACUTE BILIARY PANCREATITIS
After beginning as a purely diagnostic procedure in 1968, ERCP entered the therapeutic arena with initial reports of biliary sphincterotomy in 1974.". l9 Endoscopists were initially reluctant to apply this technique in patients with acute pancreatitis for fear of exacerbating the acute episode or causing complications, such as hemorrhage and perforation. Early experience suggested that these concerns were largely unsubstantiated. In addition, some patients dramatically improved after endoscopic intervention to decompress the obstructed ampulla of Vater. Thus far, four randomized, controlled trials looking at the use of ERCP
608
MERGENER & BAILLIE
in patients with acute biliary pancreatitis have been completed. These have helped clarify the role of ERCP in the management of this group of patients. Because enrollment criteria, study results, and data interpretation vary considerably among these studies, it is useful to review them individually. The first prospective, randomized trial of urgent ERCP for acute pancreatitis was published by a group from Leicester, England, in 1988.27 A total of 121 patients with gallstone pancreatitis were randomized to receive either conventional conservative treatment or urgent ERCP within 72 hours of onset of the attack; endoscopic sphincterotomy and stone extraction were performed only in those patients whose ERCP showed common bile duct stones. The study included patients with both predicted mild and severe pancreatitis; stratification was based on modified Glasgow (Imrie) criteria. Common bile duct stones were found in 63% of the predicted severe pancreatitis patients but in only 26% of those with predicted mild disease. All the common bile duct stones could be removed endoscopically without complications. The authors reported that (1) ERCP can be performed safely in acute pancreatitis by an experienced endoscopist; (2) there was a statistically significant reduction in major complications of severe pancreatitis secondary to common bile duct stones after ERCP, endoscopic sphincterotomy, and stone extraction (12% versus 61%); (3) a trend toward reduction in mortality was also observed in those with predicted attacks; and (4) urgent endoscopic sphincterotomy almost halved the hospital stay for patients with predicted severe attacks (median 9.5 days versus 17 days). Although a statistical difference in mortality was not demonstrated, this study provided a rational basis for the application of ERCP, endoscopic sphincterotomy, and stone extraction in selected cases of acute biliary pancreatitis. The second study was a prospective, randomized study from Hong Kong12 that included 195 patients with acute pancreatitis of all causes, of whom 127 (65%) had common bile duct stones at ERCP. Sixty-four were randomized to ERCP within 24 hours, and 63 were treated conservatively. In the ERCP group, 37 of 64 patients (58%) underwent endoscopic sphincterotomy and stone extraction. In the conservative treatment group, 22 of 63 patients (35%)subsequently were deemed to need ERCP because of clinical deterioration; 20 of 22 (910/,)of these late ERCP patients had either common bile duct or gallbladder stones. As in the Leicester study, the Hong Kong trial patients with predicted severe pancreatitis who were randomized to early ERCP had reduced morbidity (13% versus 54%) and mortality (3% versus 18%). There was no difference in overall outcome between the ERCP and conservative treatment groups of patients with predicted mild pancreatitis. The reduction in episodes of biliary sepsis in the ERCP group remained significant when patients with predicted severe and mild pancreatitis were evaluated together, leading the authors to conclude that ERCP within 24 hours is indicated in all patients with severe attacks of gallstone pancreatitis as well as those patients with predicted mild pancreatitis who have biliary
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATVIS
609
sepsis. Caution is needed when extrapolating the results of the Hong Kong trial to patients in Western societies. Bile duct stones cause almost 100% of cases of acute pancreatitis in Hong Kong, which is not the case in Europe and America. The prognostic score employed in the Hong Kong study for stratifying the pancreatitis as severe (serum urea concentration >45 mg/dL and plasma glucose >198 mg/dL on admission) was unusual and may have overestimated the number of patients at risk for evere disease. ERCP was used both for diagnosis and for treatment in $is study, without other imaging studies (e.g., ultrasound, CT), which would commonly be performed in Western countries. Nonetheless, when the data from Hong Kong are taken together with those from the Leicester study, they emphasize the potential benefit of early ERCP in a select population of patients with predicted severe pancreatitis. The third trial was a multicenter, prospective study from GermanyI3 that included 238 patients with acute biliary pancreatitis without evidence of biliary obstruction who were randomized to receive ERCP within 72 hours or conventional therapy. ERCP was successful in 96% of 126 patients, of whom 58 (46%) had common bile duct stones. Given that the patients most likely to have stones (those with cholangitis or jaundice) were excluded, this was an unexpectedly high yield. Twenty of the 112 patients in the conservative treatment group subsequently underwent ERCP; 13 of them (12%)had common bile duct stones. There was no significant difference in morbidity or mortality between the two groups. Patients randomized to early ERCP, however, had a higher incidence of respiratory failure (defined as failure to maintain an arterial oxygen tension of at least 60 mm Hg) and more severe complications. Stratification of the patients according to predicted severity of pancreatitis did not affect the results. Concerns have been expressed regarding the design, performance, and statistical interpretation of this study.33For example, 22 centers were involved, contributing a mean of 2.4 patients per center per year. Many of the centers entered fewer patients than this; only three centers contributed 20 or more patients. The overall low enrollment raises questions about ERCP volume and therefore expertise in performing urgent ERCP in sick patients in many of the participating centers. A further concern is the apparent excess of respiratory failure in patients assigned to early ERCP; this was not observed in the two prior single-center studies. Reviewers have speculated that overuse of statistical significance and the way certain complications were defined may have biased the results against ERCP. The study was discontinued early because of concerns about the excess of morbidity and possibly mortality in the ERCP treatment group. As a result, enrollment in the study fell considerably short of the numbers predicted by a power In light of the calculation to be required for statistical significan~e.~~ problems described, the authors’ conclusion that ERCP is contraindicated or dangerous in patients with acute biliary pancreatitis cannot be accepted without qualifications. The fourth randomized trial by Nowak et a128in Poland is different in its design from the three previous studies. Three years after the data
610
MERGENER & BAILLIE
were presented at Digestive Diseases Week in the United States, the study has still not been published as a paper in a peer-reviewed journal, which severely limits ability to analyze the data critically. All 280 patients with acute biliary pancreatitis in this study underwent urgent endoscopy within 24 hours of the onset of symptoms; 25% were found to have stones impacted at the duodenal papilla, and all of these were treated by immediate endoscopic sphincterotomy. The remaining 205 patients were randomized to conventional treatment or endoscopic sphincterotomy regardless of the cholangiographic findings. The authors showed a significant advantage for patients treated endoscopically, both in terms of morbidity (17% versus 369'0, P<.OOl) and mortality (2% versus 13%, R.001). These outcomes were most impressive when the endoscopic intervention was early. All patients seemed to benefit, however, regardless of predicted severity. The authors concluded that urgent ERCP and endoscopic sphincterotomy are indicated in all patients with acute biliary pancreatitis. CONCLUSIONS
How the existing data regarding endoscopic management of acute biliary pancreatitis be interpreted? Patients with predicted severe gallstone pancreatitis who have evidence of persistent or progressive biliary obstruction (cholangitis, jaundice) benefit from early ERCP and endoscopic sphincterotomy for stone extraction and biliary decompression. Do all patients with predicted severe gallstone pancreatitis, regardless of whether or not they have evidence of biliary obstruction, merit urgent ERCP, as Nowak et alZ8suggest? The Folsch study from GermanyI3 suggests that this approach would put patients who would not be expected to benefit from this intervention at increased risk of complications and death. There are as yet unpublished data (R. Kozarek, personal communication) suggesting that many patients with predicted severe pancreatitis have pancreatic duct disruption that may benefit from endoscopic stenting. This may be an alternative use of ERCP that would make a difference in the outcome of these ill patients. A publication based on these data is eagerly awaited. What tends to be forgotten in the discussion of ERCP in relation to gallstone pancreatitis is that these procedures are some of the most arduous undertaken by endoscopists. The patients are often in the intensive care unit, where fluoroscopy is usually suboptimal and sometimes nonexistent. The patients may have coagulopathy, limiting endoscopic sphincterotomy; in these circumstances, placing a biliary stent or nasobiliary drain without endoscopic sphincterotomy for temporary decompression works well. The routine use of prelaparoscopic cholecystectomy ERCP in patients with presumed gallstone pancreatitis cannot be justified. Intraoperative cholangiography should be part of every biliary surgeon's skill set, and this technique should be liberally applied to identify patients with persistent common bile duct stones for early postoperative ERCP. Percutaneous cholangiog-
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
611
I Acute PancreatitisI Gallstone? Imaging +ve ALD3x nl
Predicted Mild
Improving No cholangitis or progressive jaundice?
Improving No cholangitis or progressive jaundice
No early ERCP Proceed with Lap Cholecystx
No data to support early ERCP
Cholangitis or progressive jaundice
I
If CBD stones present, next day ERCPl sphincterotomy
Early ERCP for CBD decompression indicated Interval Lap Cholecystx without I.O.C.
Figure 1. Endoscopic management of gallstone pancreatitis.
raphy is an option when ERCP fails for technical reasons, although the need for interventional radiology should be limited if endoscopists have proper training in diagnostic and therapeutic ERCP. Laparoscopic common bile duct exploration is also a management option for common bile duct stones. This procedure adds time and technical difficulty to laparoscopic cholecystectomy. Where surgeons have access to competent ERCP endoscopists, next-day ERCP has become the preferred management when common bile duct stones are seen during intraoperative cholangiography.
References 1. Acosta JM, Ledesma CL: Gallstone migration as a cause of acute pancreatitis. N Engl J Med 290:484-487,1974 2. Acosta JM, Pelligrini CA, Skinner DB Etiology and pathogenesis of acute biliary pancreatitis. Surgery 88118-125,1980
612
MERGENER & BAILLIE
3. Baillie J: Treatment of acute biliary pancreatitis [edit]. N Engl J Med 336:286-287, 1997 4. Banks PA: Predictors of severity in acute pancreatitis. Pancreas 6(supp 1):S7-S12, 1991 5. Berk JE: The management of acute pancreatitis: A critical assessment as Dr. Bockus would have wished. Am J Gastroenterol 90:696-703, 1995 6. Bernard C: Le cors de physiologic experimental. Paris, JB Beuilliere, 1856 7. Blarney SL, Imrie CW, ONeill J, et al: Prognostic factors in acute pancreatitis. Gut 25:1340-1346, 1984
8. Bockus HL, Sahy H, Willard JH, et al: Comparison of biliary drainage and cholecystography in gallstone diagnosis with special reference to bile microscopy. J A M 96311317, 1931 9. Bradley E L A clinically based classification system for acute pancreatitis. Arch Surg 128:586-590, 1993 10. Buscail L, Escourrou J, Delvaux M, et al: Microscopic examination of bile directly
collected during endoscopic cannulation of the papilla: Utility in patients with suspected microlithiasis. Dig Dis Sci 3711&120, 1992 11. Classen M, Demling L Endoskopische Spinkterotomie der Papilla Vateri und Steinextraktion aus dem Ductus Choledochus. Dtsch Med Wochenschr 99:496-497, 1974 12. Fan S-T, Lai ECS, Mok FPT, et al: Early treatment of acute biliary pancreatitis by endoscopic papillotomy. N Engl J Med 328:228-232, 1993 13. Folsch U, Nitsche R, Ludtke R, et a1 Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. N Engl J Med 336:237-242, 1997 14. Go V, Everhart J: Pancreatitis. In Everhart J (ed): Digestive Diseases in the United States: Epidemiology and Impact. Publication no. 94-1447. Washington, DC, US Government Printing Office, 1994, pp 691-712 15. Gumaste W, Dave PB, Weissman D, et a1 Lipase/amylase ratio: A new index that distinguishes acute episodes of alcoholic from non-alcoholic pancreatitis. Gastroenterology 101:1361-1366, 1991 16. Johnson CD: Antibiotic prophylaxis in severe acute pancreatitis. Br J Surg 83:883-884, 1996 17. Jowell PS, Baillie J, Branch MS, et al: Quantitative assessment of procedural competence: A prospective study of training in ERCP. Ann Intern Med 125:9883-9889, 1996
18. Karimgani I, Porter KA, Langenvin RE, et al: Prognostic factors in sterile pancreatic necrosis. Gastroenterology 1041636-1640, 1993 19. Kawai K, Akasaka Y, Murakami K, et al: Endoscopic sphincterotomy of the ampulla of Vater. Gastrointest Endosc 20:148-151, 1974 20. Kelly TR, Wagner D S Gallstone pancreatitis: A prospective randomized trial of the timing of surgery. Surgery 104:60(r605, 1988 21. Kusske AM, Rongione AJ, Reber HA: Cytokines and acute pancreatitis [edit]. Gastroenterology 110639442, 1996 22. Lee SP, Nicholls JF, Park Hz: Biliary sludge as a cause of acute pancreatitis. N Engl J Med 326589-593, 1992 23. Lerch MM, Saluja AK, Runzi M, et al: Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opposum. Gastroenterology 104853-861, 1993 24. McKay CJ, Curran F, Sharples C, et al: Prospective placebo-controlled randomized trial of lexipafant in predicted severe acute pancreatitis. Br J Surg M1239-1243, 1997 25. Mergener K Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis [letter]. N Engl J Med 336:1836, 1997 26. Mergener K, Baillie J: Fortnightly review: Acute pancreatitis. BMJ 3164448, 1998 27. Neoptolemos JP, Carr-Locke DL, London NJ, et al: Controlled trial of urgent endoscopic retrograde cholangiopancreatographyand endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 2:979-983, 1988 28. Nowak A, Nowakowska-Dulawa E, Marek T, et a1 Final results of the prospective randomized controlled study on endoscopic sphincterotomy versus conventional management in acute biliary pancreatitis [abstr]. Gastroenterology 108:8380, 1995 29. Opie EL The etiology of acute hemorrhagic pancreatitis. Johns HopHosp Bull 121:182-188, 1901 30. Pezzilli R, Billi P, Miglioli M, et al: Serum amylase and lipase concentrations and
ENDOSCOPIC TREATMENT FOR ACUTE BILIARY PANCREATITIS
31. 32. 33.
34. 35. 36.
613
lipase/amylase ratio in the assessment of etiology and severity of acute pancreatitis. Dig Dis Sci 38:1265-1269, 1993 Ranson JHC: Etiologic and prognostic factors in human acute pancreatitis: A review. Am J Gastroenterol77633-638, 1982 Ros E, Navarro S, Bru C, et al: Occult microlithiasis in “idiopathic” acute pancreatitis: Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology 101:1701-1709, 1991 Soetikno RM, Carr-Locke DL: Endoscopic management of acute gallstone pancreatitis. Gastrointest Endosc Clin North Am 8:l-12, 1998 Steinberg WM: Acute pancreatitis-never leave a stone untumed. N Engl J Med 326:635-637, 1992 Tamasky PR, Hawes RH: Endoscopic diagnosis and therapy of unexplained (idiopathic) acute pancreatitis. Gastrointest Endosc Clin North Am 8:1>37, 1998 Tenner S, Dubner H, Steinberg W Predicting gallstone pancreatitis with laboratory parameter: A meta analysis. Am J Gastroenterol 89:1863-1866, 1994
Address reprint requests to John Baillie, MB, ChB, FRCP(G) Division of Gastroenterology Box 3189 Duke University Medical Center Durham, NC 27710