Endoscopic retrograde cholangiopancreatography associated pancreatitis: A 15-year review

Abstract

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.

Key Words: Cholangiopancreatography endoscopic retrograde; Adverse effects; Pancreatitis; Prevention and control/therapy; Risk assessment; Risk factors; Ampulla of vater; Sphincter of oddi; Humans

INTRODUCTION

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[3] 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 1).

Table 1 Clinical trials evaluating the incidence of overall complications and post-ERCP pancreatitis.

Author	Country	Year published	n	No. ERCP	Overall complications (%)	Post-ERCP pancreatitis (%)
Large prospective trials
Wang[20]	China	2009	2691	3178	7.92	4.31
Kapral[62]	Austrian	2008	NRa	3132	12.60	5.10
Dundee[23]	Australia	2007	563	700	5.71	3.71
Williams[24]	United Kingdom	2007	4561	5234	5.00	1.60
Bhatia[25]	India	2006	1497	1497	NRa	3.80
Cheng 2006 and Sherman 2003b[111,154]	United States	2006	1115	NRa	NRa	15.10
Andriulli[59]	Italy	2004	1127	1050	NRNRa	4.80
Christensen[13]	Denmark	2004	NRa	1177	15.90	3.80
Barthet	France	2002	658	1159	NRa	3.50
Vandervoort[10]	United States	2002	1223	1223	11.20	7.20
Freeman[58]	United States	2001	NRa	1963	NRa	6.70
Masci[35]	Italy	2001	2103	2044	4.95	1.80
DePalma[27]	Italy	1999	535	NRa	NRa	5.30
Deans[11]	United Kingdom	1997	958	1000	2.40	1.00
Johnson[28]	United States	1997	1979	NRa	NRa	10.40
Freeman[29]	United States and Canada	1996	2347	NRa	9.80	5.40
Loperfido[12]	Italy	1995	2769	NRa	4.00	1.30
Large retrospective trials
Cotton[29]	United States	2009	11497	NRa	4.00	2.60
Lukens[30]	United States	2009	2606	3924	3.12	0.97
Andriulli[31]	Italy	2007	16855	NRa	6.85	3.47
Cheon[60]	United States	2007	9872	14331	NRa	4.00

^aNot reported;

^bSame patient cohort; ERCP: Endoscopic retrograde cholangiopancreatography.

DIAGNOSIS OF PEP

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)[23]. 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[41]. 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.

PATHOPHYSIOLOGY OF PEP

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[50]. The second phase is characterized by intrapancreatic inflammation. The third phase is characterized by extrapancreatic inflammation[50]. 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[50]. 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[14], 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.

PROCEDURAL RELATED FACTORS ASSOCIATED WITH PEP

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[7]. 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 2).

Table 2 Patient and procedural risk factors associated with post-ERCP pancreatitis.

Patient related factors

Female sex

Young age

History of or suspected sphincter of oddi dysfunction

History of pancreatitis, recurrent pancreatitis or post-ERCP pancreatitis

Procedure related factors

Difficult or multiple cannulation attempts

Multiple pancreatic contrast injections

Pancreatic acinarization

Precut sphincterotomy

Endoscopic papillary balloon dilation

Sphincter of oddi manometry

Distal common bile duct diameter ≤ 1 cm

Presence of a pancreatic stricture

Procedures not involving stone removal

OPERATOR EXPERIENCE

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[61]. 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[62].

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[63]. 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[19] and trainee involvement was associated with severe or fatal complications in a recent retrospective analysis[64]. A large prospective trial however, found that case volume had no effect on the incidence of PEP[29]. 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[65]. In the same year, a study in France showed no risk associated with operator inexperience[66].

CANNULATION TECHNIQUES

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[67].

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 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[73]. 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].

Table 3 Frequency of post-ERCP pancreatitis - conventional contrast based cannulation versus guide-wire cannulation in randomized trials.

				Rate of pancreatitis
Author	Year published	Country	n	CC (%)	GWC (%)	P value
Lee[72]	2009	Korea	300	11.30	2.00	0.001
Bailey[73]	2008	Australia	430	7.90	6.20	0.48
Artifon[70]	2007	Brazil and United States	300	16.60	8.60	0.037
Lella[69]	2004	Italy	392	4.10	0.00	< 0.01
Cortas[68]	1999	Canada	47	10.30	5.60	NRa

n: Patients included in final analysis; GWC: Guide-wire cannulation (papillotome with guide-wire assistance); CC: Conventional cannulation (papillotome with contrast injection);

^aNot reported.

PANCREATIC DUCT INJECTION

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[76]. Earlier studies suggested that there was a decreased risk of PEP with the use of non–ionic contrast agents[74], however this has not been consistently demonstrated[75]. 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[60]. Although there is heterogeneity, clinical trial data suggest that hydrostatic pressure may play a role in the development of pancreatitis.

PANCREATIC DUCT STENTING

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 4).

Table 4 Randomized controlled trials evaluating the effect of pancreatic duct stenting on prevention of post-ERCP pancreatitis.

Author	Country	Year published	n	Rate of post-ERCP pancreatitis		P value
				Without stent (%)	With stent (%)
Tsuchiya[84]	Japan	2007	64	12.50	3.10	NRa
Sofuni[78]	Japan	2007	201	13.60	3.20	0.02
Harewood[77]	United States	2005	19	33.00	0.00	0.02
Fazel[85]	United States	2003	74	28.00	5.00	< 0.05
Tarnasky[18]	United States	1998	80	26.00	7.00	0.03
Smithline[87]	United States	1993	93	18.00	14.00	0.299

n: Patients included in final analysis;

^aNot reported.

BILIARY STONE EXTRACTION

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 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.

Table 5 Frequency of post-ERCP pancreatitis - endoscopic sphincterotomy vs endoscopic papillary balloon dilation in randomized studies.

Author	Year published	Country	n	Rate of pancreatitis		P value
				ES (%)	EPBD (%)
DiSario[98]b	2004	United States	237	0.83	15.38	< 0.05
Fujita[87]	2003	Japan	282	2.80	10.90	< 0.05
Vlavianos[92]	2003	United Kingdom	202	1.01	4.86	NRa
Arnold[89]	2001	Germany	60	10.00	20.00	NRa
Bergman[99]	1997	The Netherlands	202	6.93	6.93	NRa

n: Patients included in final analysis; ES : Endoscopic sphincterotomy; EPBD: Endoscopic papillary balloon dilation;

^bMulti-centered;

^aNot reported.

PATIENT-RELATED RISK FACTORS ASSOCIATED WITH PEP

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 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[95]. 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[64]. 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)[96]. One study demonstrated a 10 fold increase in the development of PEP in patients with SOD[97].

Some factors may be protective as well. Studies have suggested that the absence of chronic pancreatitis[58], the presence of obesity[98], older age (> 80)[99] and a history of alcohol consumption or cigarette smoking may be associated with a decreased risk of PEP[100]. Proper patient selection and identification of patients at higher risk is the most effective means of reducing the incidence of PEP.

PHARMACOLOGIC AGENTS EVALUATED IN PREVENTION/REDUCITON 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 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 7)[14,15,31,34,42-45,55,56,59,96,110-161].

Table 6 Pharmacologic agents evaluated for potential reduction/prevention of post-ERCP pancreatitis.

Pharmacologic agent	RCT showed benefit
Allopurinol	Yes
Cephtazidime	Yes
Diclofenac	Yes
Gabexate	Yes
Glyceryl trinitrate	Yes
Hydrocortisone	Yes
Indomethacin	Yes
Interleukin-10 (IL-10)	Yes
Nafamostat mesylate	Yes
Octreotide	Yes
Somatostatin	Yes
Ulinastatin	Yes
Anticholinergic drugs	No
Aprotinin	No
Botulinum toxin	No
Calcitonin	No
Epinephrine	No
Fresh frozen plazma	No
Glucagon	No
H-2 Blocker	No
Heparin	No
Lidocaine	No
Methylprednisolone	No
N-aceytyl cysteine (NAC)	No
Natural beta-carotene	No
Nifedipine	No
Nitroglycerin	No
Parenteral nutrition	No
Pentoxifylline	No
Prednisone	No
Recombinant PAF acetylhydrolase (rPAF-AH)	No
Selenium	No
Semapimod	No

Table 7 Randomized controlled trails of pharmacologic agents evaluated for reduction or prevention of post-ERCP pancreatitis.

				Rate of post-ERCP pancreatitis (%)
Agent	Author	Factor studied	n	Overall	Control	Intervention	P value
Allopurinol
	Martinez–Torres[110]	Allopurinol 300 mg PO at 15 h; 300 mg PO at 3 h before ERCP	170	NRa	9.40	2.30	0.049
	Romagnuolo[111]b	Allopurinol 300 mg PO at 1 h before ERCP	586	NRa	4.10	5.50	0.440
	Katsinelos[112]	Allopurinol 600 mg PO at 15 h; 600 mg PO at 3 h before ERCP	243	10.20	17.80	3.20	< 0.001
	Mosler[113]	Allopurinol 600 mg PO at 4 h; 300 mg PO at 1 h before ERCP	346	12.55	12.14	12.96	0.520
	Budzynska[114]	Allopurinol 200 mg PO at 15 h; 200 mg PO at 3 h before ERCP	300	10.70	7.90	12.10	0.320
Beta-carotene
	Lavy[115]	Natural beta-carotene 2 g at 12 h before ERCP	321	9.60	9.60	10.00	NRa
Botulinum toxin
	Gorelick[116]	Botulinum toxin injection after biliary sphincterotomy	26	NRa	43.00	25.00	0.340
Cephtazidime
	Raty[117]	Cephtazidime 2g IV 30 min before ERCP	321	NRa	9.38	2.58	0.009
Hydrocortisone
	Kwanngern[118]	Hydrocortisone 100 mg IV at 1 h before ERCP	120	6.67	11.86	1.64	0.031
	Manolakopoulos[119]b	Hydrocortisone 100 mg IV at 30 min before ERCP	340	10.00	13.00	7.10	0.380
	De Palma[31]	Hydrocortisone 100 mg IV immediately before ERCP	529	5.30	4.90	5.70	NS
Prednisone
	Sherman[120]b	Prednisone 40 mg PO at 15 h and at 3 h before ERCP	1115	15.07	13.60	16.60	0.190
	Budzynska[114]	Prednisone 40 mg at 15 h; 40 mg at 3 h before ERCP		10.70	7.90	12.00	0.330
Methylprednisolone
	Dumot[43]	Methylprednisolone 125 mg IV immediately before ERCP	286	NRa	8.70	12.40	0.340
Heparin
	Barkay[42]	Unfractionated heparin 5000 IU SC 20-30 min before ERCP	106	NRa	7.40	7.80	NS
	Rabenstein[121]	Low molecular weight heparin Certoparin 3000 IU SC the day before ERCP	448	8.50	8.81	8.14	0.870
Interlukin-10
	Sherman[56]b	IL-10 8 μg/kg IV 15-30 min before ERCP	305	17.38	14.30	15.40	0.830
		IL-10 20 μg/kg IV 15-30 min before ERCP				22.00	0.140
	Deviere[14]	IL-10 4 μg/kg IV 30 min before ERCP	144	29.90	24.40	10.41	0.046
		IL-10 20 μg/kg IV 30 min before ERCP				6.81	0.017
	Dumot[55]	IL-10 8 μg/kg IV 15 min before ERCP	200	10.00	9.10	10.90	0.650
N-acetyl cystine
	Milewski[122]	NAC 600 mg IV BID × 2 d after ERCP	106	9.43	11.76	7.27	NS
	Katsinelos[123]	NAC 70 mg/kg 2 h before and 35 mg/kg 4 h intervals for 24 h after procedure	249	10.80	9.60	12.10	> 0.500
Nifedipine
	Prat[124]	Nifedipine 20 mg PO 3-6 h before ERCP	155	15.50	17.70	13.20	NS
	Sand[125]	Nifedipine 20 mg PO q 8 h the day of ERCP	166	3.61	4.00	4.00	NRa
Nitroglycerin
	Hao[126]	Glyceryl trinitrate 5 mg IV and 100 mg vitamin C 5 min before ERCP maneuvers	74	16.20	25.00	7.90	0.012
	Beauchant[127]b	Nitroglycerin bolus of 0.1 mg, then 35 g/kg/min IV for 6 h after ERCP	208	12.00	15.00	10.00	0.260
	Kaffes[128]	Transdermal glyceryl trinitrate patch (15 mg) precordial area 30-40 min before ERCP	318	NRa	7.40	7.70	NS
	Moreto[129]	Transdermal glyceryl trinitrate patch (15 mg) precordial area 30-40 min before ERCP	144	9.00	15.00	4.00	0.030
	Sudhindran[130]	Glyceryl trinitrate 2 mg SL 5 min before ERCP	186	13.00	18.00	8.00	< 0.050
Diclofenac
	Khoshbaten[131]	Diclofenac 100 mg PR immediately after ERCP	100	15.00	26.00	4.00	< 0.010
	Cheon[132]	Diclofenac 50 mg at 30-90 min before and at 4-6 h after ERCP	207	16.40	16.70	16.20	NS
	Murray[44]	Diclofenac 100 mg PR immediately after ERCP	220	11.00	15.45	6.36	0.049
Indomethacin
	Sotoudehmanesh[133]	Indomethacin 100 mg PR after ERCP	442	4.98	6.78	3.16	OR 0.4 (0.2 - 1.1)
Octreotide
	Kisli[134]	Octreotide 0.1 mg gtt 60 min before ERCP and continued during and after ERCP	120	NRa	11.49	15.15	NS
	Li[135]b	Octreotide 0.3 mg gtt 1 h before -6 h after ERCP; then 0.1 mg SC; 12 h later 0.1 mg SC	832	3.85	5.26	2.42	0.046
	Thomopoulos[136]	Octreotide 500 μg TID starting 24 h before ERCP	201	10.89	8.90	2.00	0.03
	Testoni[137]b	Octreotide 200 μg TID × 24 h before ERCP	114	NRa	14.30	12.00	NS
	Hardt[138]	Octreotide 200 μg SC the night before ERCP	94	NRa	NRa	NRa	NS
	Duvnjak[139]	Octreotide 0.5 mg SC 60 min before ERCP	209	NRa	9.52	3.85	NS
	Arvanitidis[140]	Octreotide 0.1 mg SC 30 min before; 8 h and 16 h after ERCP	73	10.95	11.11	10.81	NS
	Tulassay[45]b	Octreotide 0.1 mg SC 45 min after ERCP	1199	7.84	6.00	5.90	NS
	Arcidiacono[141]	Octreotide 0.1 mg SC 120 and 30 min before; 4 h after ERCP	151	6.62	NRa	NRa	NS
	Baldazzi[142]	Octreotide 0.1 mg SC 45 min before; 6 h after ERCP	100	NRa	NRa	NRa	NRa
	Testoni[143]	Octreotide 0.2 mg SC before ERCP	60	NRa	NRa	NRa	NS
	Testoni[34]	Octreotide 200 μg TID × 3 d before ERCP	60	NRa	NRa	NRa	NS
Gabexate
	Ueki[144]	Gabexate 600 mg IV 60-90 min before and 22 h after ERCP	68	2.90	NRa	2.90	NS
	Manes[145]b	Gabexate mesylate 500 mg within 1 h before ERCP	608	5.60	9.40	3.90	< 0.01
		Gabexate mesylate 500 mg within 1h after ERCP				3.40	< 0.01
	Xiong[146]	Gabexate 300 mg IV 30 min before gtt until 4 h after ERCP	200	6.70	10.50	3.10	0.04
	Fujishiro[151]b	Gabexate 900 mg/1500 mL gtt for 13 h beginning 1 h before ERCP	139	NRa	NRa	4.30	NS
	Andriulli[59]b	Gabexate 500 mg 30 min before gtt until 6 h after ERCP	1127	5.60	4.80	5.80	NS
	Masci[96]b	Gabexate 500 mg IV 30 min before gtt until 6.5 h after ERCP and 1 g IV for 13 h after ERCP	434	1.80	2.20	1.40	NS
	Andriulli[147]b	Gabexate 500 mg IV 30 min before and 2 h after ERCP	579	8.60	6.50	8.10	NS
	Cavallini[148]b	Gabexate 1 g IV 30-90 min before gtt until 12 h after ERCP	418	5.00	8.00	2.00	0.03
Nafamostat mesylate
	Choi[149]	Nafamostat mesylate 20 mg gtt 1 h before and for 24 h after ERCP	704	5.40	7.40	3.30	0.018
Ulinastatin
	Yoo[150]	Ulinastatin 100 000 U gtt after ERCP for 5.5 h	227	6.20	5.60	6.70	0.715
	Ueki[144]	Ulinastatin 150 000 units 60-90 min before & for 22 h after ERCP	68	2.90	2.90	2.90	NS
	Fujishiro[151]b	Ulinastatin 150 000 units 1 h before, during; 11 h after ERCP				6.50	NS
		Ulinastatin 50 000 units				8.50	NS
	Tsujino[152]b	Ulinastatin 150 000 U gtt 10 min before ERCP	406	5.17	7.40	2.90	0.041
Pentoxifylline
	Kapetanos[153]	Pentoxifylline 400 mg PO TID before ERCP	320	4.38	3.00	5.60	0.28
Recombinant PAF acetylhydrolase
	Sherman[154]b	Recombinant PAF acetylhydrolase (rPAF-AH) 1 mg/kg gtt < 1 h before ERCP	600	17.60	19.60	17.50	0.59
		Recombinant PAF acetylhydrolase (rPAF-AH) 5 mg/kg gtt < 1 h before ERCP				15.90	0.34
Semapimod
	van Westerloo[155]	Semapimod IV 50 mg/100 mL glucose gtt 1 h before ERCP	242	11.98	14.88	9.09	0.117
Somatostatin
	Lee[156]b	Somatostatin 3 mg in 500 mL NS gtt 12 h starting 30min before ERCP	391	6.65	9.60	3.60	0.02
	Andriulli[59]b	Somatostatin 750 μg IV 30 min before and continued for 6 h after ERCP				6.30	NS
	Arvanitidis[157]	Somatastatin 4 μg/kg gtt 12 h on identification of the papilla and before introduction of the catheter	372	NRa	9.80	1.70	< 0.05
		Somatostatin 3 mg gtt 12 h on identification of the papilla and before introduction of the catheter				1.70	< 0.05
	Poon[158]	Somatostatin 250 mg IV bolus immediately after ERCP	270	NRa	13.30	4.40	0.01
	Andriulli[147]b	Somatastatin 750 μg IV 30 min before and 2 h after ERCP				11.50	NS
	Poon[159]	Somatostatin 3 mg in 500 mL NS gtt for 12 h starting 30 min before ERCP	220	5.91	10.00	3.00	0.03
	Bordas[160]	Natural somatostatin 4 mg/kg IV on identification of the papilla and before introduction of the catheter	160	NRa	10.00	2.50	< 0.05
Topical spray on papilla
	Matsushita[15]	Epinephrine (10 mL of 0.02%) sprayed on papilla before cannulation	370	1.10	2.16	0.00	0.123
	Schwartz[161]	Lidocaine (10 mL of 1%) sprayed on the major papilla before cannulation	294	4.08	3.04	4.32	0.73

PEP: Post-ERCP pancreatitis; ERCP: Endoscopic retrograde cholangiopancreatography; IL-10: Ingerlukin-10; NAC: N-acetyl cystine; NS: Not significant;

^aNot reported/unable to acquire primary data from publication;

^bMulti-centered.

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[132]. In regard to glyceryl trinitrate[129], hydrocortisone[118] and interleukin-10[14], 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[152] 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.

MANAGEMENT OF PEP

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[102]. Practice guidelines for acute pancreatitis treatment are available and may be applicable to PEP as well[50].

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[23]. 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[103]. 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[104].

CONCLUSION

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.