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Correspondence to: Field F Willingham, MD, MPH, Director of Endoscopy, Emory University School of Medicine, 1365 Clifton Road, NE, Building B STE 1200, Atlanta, GA 30322, United States. email@example.com
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The aim of this article is to review the literature regarding post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. We searched for and evaluated all articles describing the diagnosis, epidemiology, pathophysiology, morbidity, mortality and prevention of post-ERCP pancreatitis (PEP) in adult patients using the PubMed database. Search terms included endoscopic retrograde cholangiopancreatography, pancreatitis, ampulla of vater, endoscopic sphincterotomy, balloon dilatation, cholangiography, adverse events, standards and utilization. We limited our review of articles to those published between January 1, 1994 and August 15, 2009 regarding human adults and written in the English language. Publications from the reference sections were reviewed and included if they were salient and fell into the time period of interest. Between the dates queried, seventeen large (> 500 patients) prospective and four large retrospective trials were conducted. PEP occurred in 1%-15% in the prospective trials and in 1%-4% in the retrospective trials. PEP was also reduced with pancreatic duct stent placement and outcomes were improved with endoscopic sphincterotomy compared to balloon sphincter dilation in the setting of choledocholithiasis. Approximately 34 pharmacologic agents have been evaluated for the prevention of PEP over the last fifteen years in 63 trials. Although 22 of 63 trials published during our period of review suggested a reduction in PEP, no pharmacologic therapy has been widely accepted in clinical use in decreasing the development of PEP. In conclusion, PEP is a well-recognized complication of ERCP. Medical treatment for prevention has been disappointing. Proper patient selection and pancreatic duct stenting have been shown to reduce the complication rate in randomized clinical trials.
The first endoscopic pancreatogram was obtained in 1968, and in 1974, biliary sphincterotomy was first described[1-2]. This was followed by the first report of papillotomy for the management of choledocholithiasis and in subsequent years, numerous endoscopic techniques evolved to address pancreaticobiliary disease. As computerized axial tomography and magnetic resonance imaging have improved, endoscopic retrograde cholangiopancreatography (ERCP) has evolved from primarily a diagnostic procedure into primarily a therapeutic procedure.
As the indications for ERCP have increased, a greater focus on recognizing and preventing complications has emerged. Asymptomatic hyperamylasemia, cardiopulmonary depression, hypoxia, aspiration, intestinal perforation, bleeding, cholangitis, adverse medication reactions, sepsis, acute pancreatitis and death all are recognized complications of ERCP. Post-ERCP pancreatitis (PEP) remains the leading cause of morbidity and mortality post procedure and has been at the center of studies designed to improve procedural outcomes[4-9].
Over the last 15 years, in large prospective trials the overall and pancreatitis complication rates following ERCP have ranged from 2.4% to 15.9%[10-13] and 1.0% to 15.1%[14-16] respectively. Some studies have suggested that lower rates of PEP can be achieved; however the incidence of pancreatitis remains high particularly in at-risk patient populations. Pancreatitis continues to be the major cause of post-procedure morbidity and mortality[17-22] (Table (Table11).
PEP has been defined as the presence of new pancreatic-type abdominal pain associated with at least a threefold increase in serum amylase concentration occurring 24 h after an ERCP, with pain severe enough to require admission to the hospital or to extend an admitted patient’s length of stay. This definition was developed in 1991 based upon approximately 15 000 procedures evaluated during a consensus workshop. The severity of PEP was defined according to length of stay (mild pancreatitis 2-3 d, moderate pancreatitis 4-10 d and severe pancreatitis more than 10 d or intensive care admission or local complications secondary to pancreatitis). This consensus definition has not been uniformly adopted and many studies published after 1991 have used different criteria to define PEP and classify severity.
Several studies have challenged the serum amylase threshold of three times the upper limit of normal, arguing that this definition is not always consistent with the clinical and morphological features of pancreatitis[24-30]. Variations in the published studies regarding the criteria for serum amylase elevationhave included twice[28-31], four times[10,32-33] and five times[25-26,33-35] the upper limit of the normal.
In regard to the severity of PEP, there is also heterogeneity in criteria used in published studies. Some authors have used the Atlanta criteria published in 1993 to define severity[36-38]. The Atlanta criteria incorporate systemic complications of PEP by integrating the Acute Physiologic and Chronic Health Evaluation (APACHE) II classification and the Ranson’s criteria to define the severity[38-40]. An APACHE II score greater than 8 or a Ranson’s score with 3 or more of 11 criteria would be defined as severe PEP. Some studies have used the APACHE II classification alone to grade the severity of PEP. Other studies have used combinations of criteria to define the presence and severity of PEP or have established unique definitions[31,36,42-45]. The heterogeneity of criteria in the literature on PEP hinders direct comparison of the published clinical trials.
The pathophysiology of PEP is not well understood. Mechanical, hydrostatic, chemical, enzymatic, allergic, thermal, cytokine and microbiological factors have all been proposed as causes[37,46-49]. Many studies suggest that PEP results from mechanical trauma with injury of the papilla or pancreatic sphincter causing swelling of the pancreatic duct and obstruction to the flow of pancreatic enzymes. This hypothesis remains controversial and no consensus related to the pathogenesis of PEP has been established.
The cascade of events leading to acute pancreatitis has been characterized in three phases. The first phase is characterized by premature activation of trypsin within the pancreatic acinar cells. The second phase is characterized by intrapancreatic inflammation. The third phase is characterized by extrapancreatic inflammation. Inflammation in the second and third phases has been described in a four step process with (1) activation of inflammatory cells; (2) chemoattraction of activated inflammatory cells; (3) activation of adhesion molecules resulting in binding of inflammatory cells to the endothelium; and (4) migration of activated inflammatory cells into areas of inflammation. Recent studies have evaluated proinflammatory markers (TNF, IL-1, IL-6, IL-8, PAF and IL-10) in the setting of PEP[51-54]. While three randomized control trials suggested a protective effect using low and high dose (4 μg/kg and 20 μg/kg) interleukin 10 given intravenously 15-30 min prior to ERCP, subsequent studies using similar IL-10 protocols did not support these findings[55-56]. Though not demonstrated to date, modulation of proinflammatory pathways could represent an appealing goal for studies evaluating PEP and the systemic inflammatory response.
Although the triggers of the inflammatory cascade are not yet well understood, procedural and patient- related factors have been clearly associated with the incidence of PEP. ERCP is the most technically difficult endoscopic procedure performed in both inpatient and outpatient settings by trainees and experienced endoscopists. While trauma to the duodenum or papilla during endoscopy without cannulation rarely causes pancreatitis, cannulation of the papilla, especially in moderate to difficult cases, has been associated with high rates of PEP. Procedures involving multiple (> 1-4) or failed attempts at cannulation, multiple pancreatic injections (≥ 2-5), pancreatic acinarization and prolonged cannulation time (> 10 min) have been associated with PEP. Operator experience, ampullary balloon dilation, pre-cut access sphincterotomy, endoscopic sphincterotomy (ES), sphincter of Oddi manometry, distal common bile duct diameters of ≤ 1 cm, presence of a pancreatic stricture, papillectomy and procedures not involving stone removal have also been associated with higher risks for developing PEP[10,12,20,29,35,46,57-60] (Table (Table22).
While there is no established mandate for procedure volume for competence in ERCP, a prospective study published in 1996 to evaluate the number of supervised ERCPs a physician must perform to achieve procedural competence was reported to be at least 180 procedures. In the United States, the American Society for Gastrointestinal Endoscopy and the American College of Gastroenterology have published quality indicators for ERCP. It is expected that competent endoscopists will be able to perform sphincterotomy, clear the common bile duct of stones, provide relief of biliary obstruction and successfully place stents for bile leaks in ≥ 85% of cases.
There have been few studies published in regard to operator experience in ERCP and this issue remains controversial. A recent study in Austria demonstrated a case volume exceeding 50 ERCPs per year had higher success and lower overall complication rates. It is generally agreed that the case mix at high volume and academic referral centers may include a greater proportion of difficult and high-risk cases which may confound the relationship between experience and complication rates.
While operator experience is felt to be critical for high quality outcomes, many large prospective and retrospective trials have not shown consistent data correlating inexperience with PEP. Higher rates of bleeding have been reported after endoscopic sphincterotomy with a mean case volume of < 1 per wk and trainee involvement was associated with severe or fatal complications in a recent retrospective analysis. A large prospective trial however, found that case volume had no effect on the incidence of PEP. A prospective survey of ERCP in the United Kingdom in 2007 based on self reported surveys demonstrated that 15% of all credentialed endoscopists performed less than 50 ERCPs per year as compared to 61% of those in training with 11% of deaths with endoscopists performing less than 50 ERCPs per year. Although the rates of PEP were low at 1.5%, the success rates for bile duct stone extraction and biliary stent placement were 62% and 73% respectively. The authors summarized that in the UK there is a need for fewer operators and greater experience in those performing therapeutic endoscopy. In the same year, a study in France showed no risk associated with operator inexperience.
Cannulation techniques to access the pancreatic and biliary ducts include the use of sphincterotomes or straight or curved catheters with guide-wires or contrast injection. When an initial attempt at cannulation fails, access may be achieved after placement of a pancreatic guide-wire or stent to help guide the endoscopist towards the common bile duct and away from the pancreatic duct. Precut access papillotomy is frequently employed in referral centers when conventional approaches fail. Rare or experimental techniques such as the use of endoscopic scissors or endoscopic dissection with a cotton swab have been reported but are rarely employed in clinical practice.
Compared to standard catheters, the use of sphincterotomes may reduce failed attempts to obtain biliary access, decrease time required to cannulate the common bile duct and decrease the rate of PEP[68-69]. Selective sphinctertome cannulation with a guide wire may be associated with a reduced rate of PEP compared to cannulation with contrast injection[68-72] (Table (Table3).3). In 2008, a large prospective controlled trial randomized 430 patients into sphincterotome plus guide-wire versus conventional cannulation arms. The series demonstrated a significantly higher rate of cannulation with guide-wires but failed to show a significant difference in the rate of PEP between the two approaches. The authors reported an 8.8%-14.9% increased risk of PEP after greater than 4 attempts at the papilla, highlighting the importance of cannulation with fewer attempts. These findings are consistent with previous studies[10,73].
Multiple pancreatic duct injections (≥ 2-5)[10,20,29,59] and pancreatic acinarization[12,20,35] have been recognized as risk factors for PEP. Differences in the osmolality and ionicity of contrast media have been studied with varying results in terms of impact on PEP[30,33,60,74-76]. A recent meta-analysis of thirteen randomized controlled trials indicated there was no significant difference between high and low- osmolality contrast media. Earlier studies suggested that there was a decreased risk of PEP with the use of non–ionic contrast agents, however this has not been consistently demonstrated. One large retrospective analysis of 14 331 ERCPs suggested that less opacification of the pancreatic duct, head versus tail, resulted in significantly lower rates of PEP. Although there is heterogeneity, clinical trial data suggest that hydrostatic pressure may play a role in the development of pancreatitis.
The theory that PEP is caused by pancreatic duct obstruction is supported by the majority of randomized controlled trials that demonstrate a decreased incidence of pancreatitis in high risk patients with the placement of a pancreatic duct stent[18,77-84]. In the three largest studies published to date evaluating the rate of pancreatitis with pancreatic duct stent placement, there were significant differences with decreased rates of PEP of 10.4%, 14.8% and 52.3%[17,78-79]. While pancreatic duct stenting has been shown to decrease the risk of PEP, it has not been able to prevent it. Despite stent placement, pancreatitis occurs in 2.0%-14% of cases[78-79,81,83-84] and some studies fail to demonstrate a statistically significant protective effect[60,83-84] (Table (Table44).
In the setting of choledocholithiasis, endoscopic papillary balloon dilatation (EPBD), ES and mechanical lithotripsy are the techniques used to extract obstructing stones. There have been multiple studies that have established the increased rate of PEP with EPBD ranging from 4.9%-20.0% versus 0.42%-10.0% with ES[85-88]. Prospective trials support this observation; however it is difficult to generalize the findings given the many factors that contribute to procedural complications[89-93] (Table (Table5).5). Balloon dilation may also be required in some clinical settings. If a patient has had a prior sphincterotomy and has limited remaining tissue for incision, balloon dilation may be necessary to enlarge the bile duct insertion and enable stone extraction.
Given the high risk of PEP in certain populations, identifying a clear indication is critical in reducing the complication rate. It has been well recognized that ERCP is riskiest in patients who need it the least[21,94]. Large prospective trials have demonstrated that female gender, age less than 60-70 years, suspected SOD and recurrent or prior PEP were associated with a higher risk of PEP[10,12,20,29,35,57,95] (Table (Table2).2). Though widely accepted, there has been some heterogeneity across studies. For example, one smaller trial suggested an age of less than 50 as a significant risk factor. A recent large retrospective study of 16 855 patients demonstrated the highest rates of PEP were associated with patients with SOD but there was no significant increase in younger patients or in women. Alternatively, a meta-analysis evaluating five patient- related risk factors demonstrated a relative risk of SOD of 4.09 (95% CI 1.93 to 3.12; P < 0.001) and female gender of 2.23 (95% CI 1.75 to 2.84; P < 0.001). One study demonstrated a 10 fold increase in the development of PEP in patients with SOD.
Some factors may be protective as well. Studies have suggested that the absence of chronic pancreatitis, the presence of obesity, older age (> 80) and a history of alcohol consumption or cigarette smoking may be associated with a decreased risk of PEP. Proper patient selection and identification of patients at higher risk is the most effective means of reducing the incidence of PEP.
There has been great interest in the affect of pharmacologic agents on PEP. Preventing cellular injury and pancreatic tissue auto-digestion may involve blocking the premature activation of proteolytic enzymes within the acinar cells[19,101-109]. Though conceptually straightforward, the goal of blocking this activation has been difficult to achieve. Multiple trials have been performed with a goal of reducing the incidence or severity of PEP. Approximately 34 (Table (Table6)6) pharmacologic agents and procedures (e.g. topical application of pharmacologic agents injected or sprayed on to the papilla) have been evaluated for potential prevention of PEP in controlled trials. Most clinical trials have been disappointing and a minority of studies has demonstrated benefit (Table (Table77)[14,15,31,34,42-45,55,56,59,96,110-161].
Allopurinol has been shown in two of five prospective trials to decrease the incidence of PEP[110,112]. In these trials showing benefits, allopurinol was given in 300 mg or 600 mg doses at 15 h and 3 h prior to ERCP. When reviewing other studies of allopurinol, these effects were not significant in patients dosed on a different 4 h and 1 h regimen and with varying dose concentrations of allopurinol[111,113,114]. This may suggest that not only the dose but timing of allopurinol administration is important in the reduction of PEP. Diclofenac, a non steroidal anti-inflammatory drug, was evaluated in three trials. With diclofenac 100 mg PR dosed immediately after ERCP, the incidence of PEP was decreased[44,131] but a trial evaluating diclofenac 50 mg PO at 30-90 min prior to ERCP and up to 4-6 h post ERCP showed no decrease in PEP. In regard to glyceryl trinitrate, hydrocortisone and interleukin-10, all agents were shown in one randomized control trial to show benefit. However in studies with larger numbers of patients[31,56,128] these findings were found to be statistically insignificant.
Gabexate[145,146,148], octreotide[135,136], somatostatin[156,159] and ulinastatin have all been reported to show a reduction in PEP. However there have been studies evaluating each of these agents with similar designs that report no significant reduction in the incidence of PEP. These differences could be explained by the selection of patients, number of patients, clinical presentation and timing of administration or dosage of the agent under investigation.
While the use of allopurinol, cephtazidime, diclofenac, gabexate, glyceryl trinitrate, hydrocortisone, indomethacin, interleukin-10, nafamostat mesylate, octreotide, somatostatin and ulinastatin have shown promise in clinical trials, there is currently no accepted pharmacologic intervention to prevent pancreatitis and in some cases (gabexate, nafamostat and somatostatin) the pharmacologic agent is not approved for use in some countries. Nevertheless, pharmacologic prevention remains an active area of research.
Once mild or moderate PEP has occurred it usually quickly resolves with conservative therapy. Although there are no specific guidelines for the treatment of PEP, a recent study demonstrated that a protocol-based management strategy was associated with less severe pancreatitis, shorter lengths of hospital stay, need for fewer imaging studies and less use of antibiotics. Practice guidelines for acute pancreatitis treatment are available and may be applicable to PEP as well.
In patients with persistent or severe PEP, two important markers of severity are multisystem organ failure and pancreatic necrosis, both of which require aggressive management. Early identification of organ failure, pancreatic necrosis, perforation (especially in the setting of endoscopic sphincterotomy), biliary damage/ leak and pancreatic fluid collections are important clinical branch points, potentially requiring more intensive intervention. Checking serum transaminases, amylase and lipase is not routinely recommended post- ERCP. If assessed, elevations are commonly observed post procedure. These elevations are likely secondary to intermittent biliary, pancreatic or papillary obstruction. 46% of patients in a recent study were reported to have elevated liver test elevations after ERCP and only 5.4% of them had PEP. Asymptomatic elevations are not an indication for a change in management and repeat ERCP is performed only with a clear indication.
Although there is controversy related to enteral feeding during treatment of acute pancreatitis, patients who are unlikely to resume oral nutrition within five days require nutritional support which can be provided via TPN or enteral routes. There appears to be some advantages to enteral feeding and a recent study found that initiating oral nutrition after mild acute pancreatitis with a low fat soft diet appeared to be safe but did not result in a shorter length of hospitalization.
Acute pancreatitis is the most common complication after ERCP. The pathophysiology is not well understood but theories regarding mechanical, hydrostatic, chemical, enzymatic, allergic, thermal, cytokine and microbiological factors have been proposed. While trauma during endoscopy without cannulation rarely causes pancreatitis, procedural factors involving cannulation, access and pancreaticobiliary drainage have been associated with PEP. Although operator experience is important in high quality outcomes, many large prospective and retrospective trials have not shown consistent data associating inexperience with increased incidence, perhaps due to the importance of case-mix in outcome. Patient-related risk factors are well recognized with Sphincter of Oddi dysfunction and a history of PEP conferring additional risk in the post-procedure setting. However, obesity, older age, alcohol consumption and cigarette smoking may be protective. Approximately 34 pharmacologic agents have been evaluated and 63 clinical trials have been performed in an effort to identify an agent to prevent PEP. Over the last 15 years, no pharmacologic agent has been accepted in reducing PEP due to a lack of reproducibility, heterogeneity in outcomes and/or limitations in study design. Proper patient selection and identification of risk factors pre-procedure is the most effective means of reducing the incidence of PEP.
Peer reviewers: Tony CK Tham, MD, Consultant Gastroenterologist, Ulster Hospital, Dundonald, Belfast BT16 1RH, Northern Ireland, United Kingdom; Everson Luiz de Almeida Artifon, MD, PhD, FASGE, University of Sao Paulo School of Medicine, Rua Guimaraes Passos, Vila Mariana, Sao Paulo 04107030, Brazil
S- Editor Zhang HN L- Editor Roemmele A E- Editor Liu N