2014 Prophylaxis Post Ercp Pancreatitis PDF

Guideline 799
Prophylaxis of post-ERCP pancreatitis:

European Society of Gastrointestinal Endoscopy (ESGE)
Guideline Updated June 2014
Authors Jean-Marc Dumonceau1, Angelo Andriulli2, B. Joseph Elmunzer3, Alberto Mariani4, Tobias Meister5, Jacques Deviere6,
Tomasz Marek7, Todd H. Baron8, Cesare Hassan9, Pier A. Testoni4, Christine Kapral10
Institutions Institutions are listed at the end of article.
Bibliography This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE).
DOI http://dx.doi.org/ It addresses the prophylaxis of post-endoscopic retrograde cholangiopancreatography (post-ERCP)
10.1055/s-0034-1377875
pancreatitis.
Published online: 22.8.2014
Endoscopy 2014; 46: 799815
Georg Thieme Verlag KG Main recommendations attempted using a guidewire rather than the
Stuttgart New York 1 ESGE recommends routine rectal administra- contrast-assisted method and a prophylactic
ISSN 0013-726X tion of 100 mg of diclofenac or indomethacin pancreatic stent should be placed.
immediately before or after ERCP in all patients 4 ESGE suggests that needle-knife fistulotomy
Corresponding author
Jean-Marc Dumonceau,
without contraindication. In addition to this, in should be the preferred precut technique in pa-
MD PhD the case of high risk for post-ERCP pancreatitis tients with a bile duct dilated down to the papil-
Gedyt Endoscopy Center (PEP), the placement of a 5-Fr prophylactic pan- la. Conventional precut and transpancreatic
Beruti 2347 (C1117AAA) creatic stent should be strongly considered. Sub- sphincterotomy present similar success and
Buenos Aires lingually administered glyceryl trinitrate or 250 complication rates; if conventional precut is se-
Argentina g somatostatin given in bolus injection might lected and pancreatic cannulation is easily ob-
Fax: +52886100
be considered as an option in high risk cases if tained, ESGE suggests attempting to place a
[email protected]
nonsteroidal anti-inflammatory drugs (NSAIDs) small-diameter (3-Fr or 5-Fr) pancreatic stent
are contraindicated and if prophylactic pancre- to guide the cut and leaving the pancreatic stent
atic stenting is not possible or successful. in place at the end of ERCP for a minimum of
2 ESGE recommends keeping the number of 12 24 hours.
cannulation attempts as low as possible. 4 ESGE does not recommend endoscopic papil-
3 ESGE suggests restricting the use of a pancre- lary balloon dilation as an alternative to sphinc-
atic guidewire as a backup technique for biliary terotomy in routine ERCP, but it may be advan-
cannulation to cases with repeated inadvertent tageous in selected patients; if this technique is
cannulation of the pancreatic duct; if this meth- used, the duration of dilation should be longer
od is used, deep biliary cannulation should be than 1 minute.
Abbreviations 1. Introduction
! !
CT computed tomography The Guideline on prophylaxis of post-ERCP pan-
DGW double guidewire creatitis (PEP) issued by the European Society of
EPBD endoscopic papillary balloon dilation Gastrointestinal Endoscopy (ESGE) in 2010 aimed
ESGE European Society of Gastrointestinal to provide a qualified basis for gastrointestinal
Endoscopy endoscopists to take measures to minimize the
ERCP endoscopic retrograde cholangio- incidence and severity of PEP [1]. Shortly before
pancreatography the publication of the ESGE Guideline, nonsteroi-
NSAID nonsteroidal anti-inflammatory drug dal anti-inflammatory drugs (NSAIDs) were re-
PEP post-ERCP pancreatitis portedly rarely used in clinical practice for pre-
PGW pancreatic guidewire vention of PEP (16 % of respondents to a survey
RCT randomized controlled trial performed in June 2009), and this was attributed
SOD sphincter of Oddi dysfunction by survey participants to the lack of sufficient
SOM sphincter of Oddi manometry data [2]. Similarly, in an Austrian nationwide
ULN upper limit of normal ERCP survey, PEP prophylaxis was administered
Dumonceau Jean-Marc et al. Updated ESGE Guideline for PEP prophylaxis Endoscopy 2014; 46: 799815
800 Guideline
in only 4.0 % of patients in 2010 and in 7.0 % of patients in 2011 tion is not ideal as it is mainly based on the length of hospitaliza-
[3]. A more recent survey from the UK found that the proportion tion.
of endoscopists using NSAIDs had increased to 34.6 % in 2012 [4]. New information since 2009:
Obviously, prophylactic measures against PEP are still greatly un- The Atlanta classification of acute pancreatitis was updated in
derused in daily clinical practice. At the same time, PEP is still the 2012 [7]. Although this classification provides clear definitions
most frequent and severe complication encountered following to classify acute pancreatitis, its limitations include the fact that
ERCP. it was not primarily developed to define PEP. Also, the benefit of
New evidence that has become available since the publication of a contrast-enhanced computed tomography (CT) scan has not
the ESGE Guideline in 2010 is discussed in the present update been demonstrated in the setting of PEP (contrast-enhanced CT
and new recommendations are issued. scan is required if abdominal pain suggests strongly that acute
pancreatitis is present, but the serum amylase and/or lipase ac-
tivity is less than three times the upper limit of normal [ULN]).
2. Methods According to this classification, the diagnosis of PEP requires
! two of the three following criteria: (i) abdominal pain consistent
ESGE commissioned this update of the Guideline on prevention with acute pancreatitis (acute onset of a persistent, severe, epi-
of PEP. Methods similar to those used in the previous Guideline gastric pain often radiating to the back); (ii) serum lipase or amy-
were applied [1]. A literature search of PubMed/MEDLINE, a lase activity at least three times greater than the ULN; and (iii)
search using the Cochrane Library, Embase, and the internet was characteristic findings of acute pancreatitis on contrast-en-
performed to identify publications since 2009 on this topic. The hanced CT and, less commonly, magnetic resonance imaging or
search focused on fully published prospective studies, particular- transabdominal ultrasonography. This classification defines
ly randomized controlled trials (RCTs) and meta-analyses. Retro- three degrees of severity based on the presence or absence of or-
spective analyses and pilot studies were also included if they ad- gan failure (plus its duration) and of local or systemic complica-
dressed topics not covered in the prospective studies. tions.
Thereafter, the commissioned authors met once and subsequent- A prospective study has shown the two definitions presented
ly developed the updated Guideline. The Guideline committee above to be poorly correlated [8].
chairs (C.K., J.M.D.) worked with the subgroup leaders (C.K., T.M., The Pancreatitis Across Nations Clinical Research and Education
A.A., T.M., P.T., T.B., J.M.D.) who developed draft proposals that Alliance (PANCREA) has defined four degrees of severity for pan-
were distributed and reviewed electronically. In May 2014, a creatitis, based on the presence or absence of complications, both
draft prepared by C.K. and J.M.D. was sent to all group members. local (necrosis of the pancreas and/or peripancreatic tissue) and
After agreement on a final version, the manuscript was sent to all systemic (cardiovascular, renal, or respiratory organ failure) [9].
individual ESGE members and individual ESGE member societies,
and was reviewed by two experts selected by the ESGE Govern-
ing Board. After incorporation of comments, the manuscript was 4. Incidence, risk factors, and severity of PEP
then sent to the journal Endoscopy for publication. The final !
wording of the Guideline document was agreed by all commis- 4.1. Incidence
sioned authors. Statement 2010:
Pancreatitis is the most frequent complication after ERCP with an
incidence of 3.5 % in unselected patients; it is of mild or moderate
3. Definitions severity in approximately 90 % of cases.
! Statement 2014:
Statement 2010: No changes.
None. Background:
Statement 2014: Data on incidence rate and severity of PEP were mainly based on
Two definitions of PEP may currently be used, neither of these a systematic review of 21 prospective studies involving more
being ideal in the setting of PEP: the consensus definition and than 16 000 patients [10]. Post-ERCP pancreatitis was found to
grading of severity of PEP according to Cotton et al. and the be the most frequent complication following ERCP, with an inci-
more recent revised Atlanta international consensus definition dence of 3.47 % (95 % confidence interval [95 %CI] 3.19 % 3.75 %).
and classification of acute pancreatitis. Based upon data from studies that have included unselected pa-
Background: tients, PEP is mild, moderate, and severe in 45 %, 44 %, and 11 %
The consensus definition and grading of severity of PEP devel- of cases, respectively. Death occurs in 3 % of cases of PEP (95 %CI
oped by Cotton et al. has been used for > 20 years [5]. It has al- 1.65 % 4.51 %) [10].
lowed standardized reporting of the incidence and severity of New information since 2009:
PEP. Post-ERCP pancreatitis was originally defined as clinical Few new data have become available and these have yielded sim-
pancreatitis with amylase at least three times the upper limit of ilar results. In an ERCP benchmarking program, PEP was reported
normal at more than 24 hours after the procedure, requiring hos- to occur in 4.2 % of 13 513 unselected procedures [3]. In a retro-
pital admission or a prolongation of planned admission. Various spective study of 886 procedures, 39 patients (4.4 %) were diag-
modifications were introduced by Freeman et al. who proposed nosed with pancreatitis, of mild moderate, and severe type in
using lipase as a possible alternative to amylase and defining clin- 69 %, 23 %, and 8 %, respectively [11].
ical pancreatitis as new or worsened abdominal pain, hence
taking into account patients who undergo ERCP in the setting of
acute pancreatitis or of a flare of chronic pancreatitis [6]. The
grading system for the severity of PEP by the consensus defini-
Guideline 801
Adjusted odds ratios (95 % confi- Pooled incidence of PEP in patients Table 1 Independent risk factors
dence intervals in parentheses with vs. those without risk factor for post-endoscopic retrograde
except where indicated other- cholangiopancreatography (post-
1
ERCP) pancreatitis (PEP).
wise)
Patient-related risk factors
Definite risk factors
Suspected sphincter of Oddi 1.91 (1.37 2.65) 8.6 % vs. 2.5 %
dysfunction (SOD)
Female gender 3.5 (1.1 10.6) 4.0 % vs. 2.1 %*
Previous pancreatitis 2.46 (1.93 3.12) 6.7 % vs. 3.8 %
Likely risk factors
Previous PEP 8.7 (3.2 23.86) 30 % vs. 3.5 %
Younger age Range of odds ratios: 1.09 2.87 6.2 % vs. 2.6 %
Nondilated extrahepatic bile ducts 3.8 % vs. 2.3 %
Absence of chronic pancreatitis 1.87 (1.00 3.48) 4.0 % vs. 3.1 %
Normal serum bilirubin 1.89 (1.22 2.93) 4.15 % vs. 1.43 %
Procedure-related risk factors
Definite risk factors
Cannulation attempts duration 1.76 (1.13 2.74) 3.8 % vs. 10.8 %
> 10 minutes 2
Pancreatic guidewire passages > 1 2.77 (1.79 4.30) 2.9 % vs. 9.5 %
Pancreatic injection 2.2 (1.60 3.01) 3.3 % vs. 1.7 %
Likely risk factors
Precut sphincterotomy 3 2.3 (1.4 3.7) 5.3 % vs. 3.1 %
Pancreatic sphincterotomy 3.07 (1.64 5.75) 2.6 % vs. 2.3 %
Biliary balloon sphincter dilation 4.51 (1.51 13.46) 9.3 % vs. 2.6 %
Failure to clear bile duct stones 3.35 (1.33 9.10) 1.7 % vs. 1.6 %
Intraductal ultrasound (IDUS) 4 2.41 (1.33 4.39) 8.37 % vs. 2.76 %
1
For definite or likely risk factors, adjusted odds ratios are reproduced either from Masci et al. [20] or from included studies that identified
the characteristic as an independent risk factor. Pooled incidences were calculated using figures available in all of the included studies
that provided sufficient data for calculation [6, 16, 17, 19, 21, 22, 25 27, 115, 116, 177]. (See text for details about included studies)
2
Cannulation attempts of duration > 5 minutes may already increase the incidence of PEP as shown by Halttunen et al. (11.7 % vs. 2.7 %
for cannulation attempts 5 minutes vs. < 5 minutes, respectively) [115].
3
Evidence is growing that precut sphincterotomy is not a definite risk factor for PEP by itself, the increased risk of PEP being related to
cannulation efforts that preceded precut [28].
4
Based on one retrospective study [29].
4.2. Risk stratification New information since 2009:

4.2.1 Hospital and endoscopist volume for ERCP A prospective Swedish study of 12 718 procedures showed no
Statement 2010: significant difference among PEP rates in centers with low (< 100
There is no evidence that hospital ERCP volume has an influence ERCPs/year), medium, and high ( > 500 ERCPs/year) volumes [18].
on the incidence of PEP; data about a potential relationship be- In a prospective multicenter study that included 3635 ERCPs in
tween PEP incidence and endoscopist case volume are conflict- 11 high volume ( > 200 ERCPs/year) and 10 low volume centers
ing. Low annual case volumes, of endoscopists and centers, are (median of 275 and 45 ERCPs/year, respectively), there was no
associated with higher ERCP failure rates (Evidence level 2 + ). significant difference in the incidence of PEP (3.9 % vs. 3.1 %)
Statement 2014: [19]. However, these results were confounded because a higher
No changes. proportion of patients at high risk of PEP was treated in high vol-
Background: ume centers. In this study, the PEP rates did not differ significant-
Factors that may affect the outcome of ERCP that are specifically ly between expert and nonexpert operators (3.8 % vs. 5.5 %,
related to hospital procedure volume include availability of respectively; P = 0.34).
equipment and adequacy of anesthesia, endoscopic and radiolo-
gic support, and nursing assistance. The number of ERCPs per- 4.2.2. Patient- and procedure-related risk factors for PEP
formed in many centers is not as high as commonly believed: in Statement 2010:
three large (regional or national) studies, the median annual Independent patient-related and procedure-related risk factors
number of ERCPs was between 49 and 235 [12 14]. In one large for PEP are listed in
" Table 1. Risk factors synergistically increase
study, the median annual number of ERCPs per endoscopist was the risk of PEP (Evidence level 1 + ).
111 and 40 % of endoscopists performed fewer than 50 sphinc- Statement 2014:
terotomies/year [15]. Risk factors for PEP, in particular those related to the procedure
Multivariate analyses from two prospective audits performed in (cannulation attempts > 10 minutes and pancreatic guidewire
England and Italy (66 and 9 centers, respectively) found no signif- passages > 1) have been updated in " Table 1. Risk factors syner-
icant association between annual hospital volume of ERCPs and gistically increase the risk of PEP.
incidence of PEP [16, 17]. Background:
Independent risk factors for PEP were presented in a table based
on data from a meta-analysis [20] plus those from five prospec-
802 Guideline
tive, multicenter studies that analyzed potential risk factors for at a cutoff of 4 times the ULN had a negative and positive predic-
PEP using multivariate analysis [6, 16, 17, 21, 22]. The list was not tive value for PEP of 99 % and 15 %, respectively.
exhaustive because not all potential risk factors had been ana- New information since 2009:
lyzed. For example, ampullectomy is generally considered to be Two studies confirmed previous findings. A prospective study
a definitive risk factor for PEP on the basis of several small pro- from Brazil that included 300 patients showed that serum hyper-
spective studies [23, 24]. amylasemia < 1.5 times the ULN at 4 hours and < 2 times the ULN
As risk factors for PEP were shown to be independent by multi- at 12 hours had a negative predictive value of 94 % for the devel-
variate analysis, they might have a cumulative effect. Freeman et opment of PEP [8]. Serum hyperamylasemia following ERCP had a
al. calculated the adjusted odds ratio (OR) for various combina- poor positive predictive value for PEP. A retrospective study in-
tions of risk factors by using data prospectively collected from vestigated, in addition to the 4-hour post-ERCP serum amylase
about 2000 ERCPs: the highest risk of PEP (42 %) was found for fe- level, the impact of having a pancreatogram in predicting PEP
male patients with a normal serum bilirubin level, suspected among 886 ERCPs [11]; the negative predictive value of serum
sphincter of Oddi dysfunction (SOD), and difficult biliary cannu- amylase < 2.5 times ULN for moderate or severe PEP was 99.2 %
lation [21]. and 100 %, in patients who, respectively, did and did not have a
New information since 2009: pancreatogram.
Suspected or known dysfunction of the sphincter of Oddi, female
gender, younger age, and previous history of pancreatitis are
well-known independent risk factors for PEP. A recent prospec- 5. Pharmacologic agents available for PEP prophylaxis
tive study confirmed these findings [25]. In a large ERCP series !
that included 11 497 procedures, SOD was confirmed as an inde- 5.1. Introduction
pendent risk factor [26]. Recently, in a Swedish case control Post-ERCP pancreatitis appears unavoidable even in the hands of
study of 12 718 ERCP procedures, independent risk factors were expert endoscopists. Consequently, attempts to reduce the rate of
young age, female gender, prolonged procedure time, and elec- this complication by pharmacological intervention should be
tive ERCP; whereas rendezvous procedures reduced the risk of pursued. While a few medications have proven effective for pre-
PEP [18]. Another prospective multicenter study confirmed inde- venting PEP, we acknowledge that multiple factors in addition to
pendent procedure- and patient-related risk factors for PEP (> 10 efficacy influence the decision to issue a clinical recommenda-
attempts to cannulate the papilla of Vater, OR 14.9; previous PEP, tion. In particular, the magnitude of benefit, as expressed by the
OR 8.7; precut, OR 3.1; pancreatic duct cannulation, OR 2.1) [19]. number needed to treat (NNT), the robustness and consistency of
Some of these predictors were confirmed in two other studies supporting RCTs, the safety profile of the medication, its ease of
[25, 27]. However, needle-knife sphincterotomy was found not administration, availability, and cost were considered in issuing
to be an independent risk factor for PEP [3, 25, 28]. these recommendations.
The role of intraductal ultrasound as a risk factor for PEP remains
unclear but this factor was identified by multivariate analysis (OR 5.2. Drugs with proven efficacy
2.41, P = 0.004) in a retrospective analysis of 2364 ERCP proce- 5.2.1. Nonsteroidal anti-inflammatory drugs (NSAIDs)
dures [29]. Statement 2010:
No new data have become available regarding the synergistic ef- NSAIDs reduce the incidence of PEP; effective PEP prophylaxis
fect of risk factors for PEP. has only been demonstrated using 100 mg of diclofenac or indo-
methacin administered rectally (Evidence level 1 ++). Routine rec-
4.3. Prediction of PEP tal administration of 100 mg of diclofenac or indomethacin im-
Statement 2010: mediately before or after ERCP is recommended (Recommenda-
Serum amylase values less than 1.5 times the ULN, obtained at 2 tion grade A).
4 hours post-ERCP, almost exclude PEP; values more than 3 or 5 Statement 2014:
times the ULN at 4 6 hours post-ERCP have increasing positive NSAIDs reduce the incidence of PEP in patients at high as well as
predictive values for PEP (Evidence level 2 + ). It is recommended low risk for PEP; effective PEP prophylaxis has only been demon-
that serum amylase be determined in patients to be discharged strated using diclofenac or indomethacin administered rectally
on the day of ERCP; patients with amylase values less than 1.5 (Evidence level 1 ++ ). ESGE recommends routine rectal adminis-
times the ULN can be discharged without concern about risk of tration of 100 mg of diclofenac or indomethacin immediately be-
PEP (Recommendation grade B). fore or after ERCP in all patients without contraindication (Re-
Statement 2014: commendation grade A).
Serum amylase or lipase values less than 1.5 and 4 times the ULN, Background:
respectively, obtained at 2 4 hours post-ERCP have a very high Three different meta-analyses pooled data from four RCTs that
negative predictive value for PEP (Evidence level 2 +). ESGE sug- compared rectally administered diclofenac or indomethacin at a
gests testing serum amylase or lipase 2 6 hours after ERCP in pa- dose of 100 mg vs. placebo [31 33]. Two RCTs evaluated the ef-
tients presenting with pain and who are to be discharged on the fect of rectal administration of 100 mg diclofenac immediately
day of ERCP; patients with amylase or lipase values less than 1.5 after the procedure, while the other two evaluated rectal admin-
and 4 times the ULN, respectively, can be discharged without istration of 100 mg indomethacin immediately before the proce-
concern about risk of PEP (Recommendation grade B). dure. Both schedules showed similar results. Patients who were
Background: considered to be at high risk for PEP were included in two stud-
The recommendations were based on five studies that reported ies. Overall, PEP occurred in 4.4 % patients in the treatment
similar predictive values based on serum amylase levels obtained groups vs. 12.5 % patients in the placebo groups with an estima-
2 to 6 hours following ERCP. In one study of PEP [30], lipase values ted pooled relative risk (RR) of 0.36 (95 %CI 0.22 0.60), and an
NNT to prevent one episode of PEP of 15. The administration of
Guideline 803
Table 2 Meta-analyses published in 2009 or later that assessed the effect of NSAIDs on post-endoscopic retrograde cholangiopancreatography (post-ERCP)
pancreatitis (PEP). 1
First author, Studies, n PEP incidence OR NNT Comments

year (Patients, n) (95 %CI)
NSAIDs Placebo
Dai, 6 8.9 % 16.8 % 0.46 n.a. Inclusion of placebo-controlled RCTs only
2009 [31] (1300) (0.32 0.65) (diclofenac or indomethacin administered oral-
ly or rectally). Different ERCP techniques and
criteria for pancreatitis, low number of high risk
patients
Ding, 10 8.0 % 13.9 % 0.57 17 Different NSAIDs (diclofenac, indomethacin,
2012 [39] (2269) (0.38 0.86) 1 valdecoxib) and different administration routes
(oral, rectal, intraduodenal, intramuscular and
intravenous) and ERCP techniques; moderate
and severe PEP also reduced.
Moderate/severe PEP: RR 0.46 (0.28 0.38);
NNT, 34
Yaghoobi, 4 5.1 % 10.3 % 0.49 20 Only rectal NSAIDs;
2013 [40] (1470) (0.34 0.71) significant decrease of PEP incidence in both
high risk and low risk patients, moderate and
severe PEP also reduced.
Moderate/severe PEP: RR 0.45 (0.24 0.83)
Sun, 7 6.4 % 16.0 % 0.45 n.a. Only rectal NSAIDs;
2013 [41] (1846) (0.34 0.61) 1 both diclofenac and indomethacin effective,
significant in both high risk and average-risk
cohorts, moderate and severe PEP reduced.
Mild PEP: RR 0.54 (0.35 0.83)
Moderate/severe PEP: RR 0.39 (0.22 0.70)
Yuhara, 9 7.8 % 16.0 % 0.55 n.a. Inclusion of RCTs testing rectal, oral, intra-
2014 [42] (1981) (0.43 0.72)* muscular and intravenous NSAIDs (diclofenac,
indomethacin). No significant effect on PEP
with intramuscular administration.
Sethi, 7 6.6 % 15.1 % 0.44 11 Only rectal NSAIDs;
2014 [43] (2133) (0.34 0.57) 1 no difference between diclofenac and indo-
methacin, no difference between timing (pre-
and post-ERCP).
Relative risk in low risk and high risk patients,
respectively: 0.42 (0.26 0.66) and 0.45 (0.31
0.65).
NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio; CI, confidence interval; NNT, number needed to treat; n.a., not available; RCT, randomized controlled trial; RR,
relative risk.
1
Risk reduction.
NSAIDs was associated with a similar decrease in the incidence of that included 228 patients but the results were not significantly
PEP regardless of risk [33]. No adverse events attributable to different from placebo, likely owing to the small sample size [35].
NSAIDs were reported. A lower dosage of diclofenac, either 50 mg or 25 mg in patients
New information since 2009: weighing 50 kg or < 50 kg, respectively, was compared with pla-
Despite previous meta-analytical results, NSAIDs were not com- cebo in a small RCT from Japan: the PEP incidence was 3.9 % vs.
monly used by endoscopists in clinical practice: only 16 % of re- 18.9 % in the diclofenac vs. the control group, respectively (P =
spondents to a survey performed in June 2009, shortly before 0.017) [36]. A small RCT of 80 patients demonstrated a nonsigni-
publication of the ESGE Guideline, used NSAIDs for PEP prophy- ficant trend toward benefit associated with the combination of
laxis and this low figure was attributed to the lack of sufficient intramuscular diclofenac and intensive intravenous fluid admin-
data [2]. A more recent survey (June 2012) found that the propor- istration [37]. On the other hand, it seems that selective cyclo-
tion of endoscopists using NSAIDs has increased to 35 % [4]. oxygenase-2 inhibitor (coxib) administration is ineffective, as
In a multicenter RCT [34], patients at high risk for PEP received shown by an RCT that included 371 patients where intravenous
either a single dose of rectal indomethacin or of placebo immedi- valdecoxib or glyceryl trinitrate (GTN) patch were compared
ately after ERCP. A total of 602 patients were enrolled, including with placebo: the incidence of PEP was similar in all treatment
82 % with a clinical suspicion of SOD and 82 % who received pro- groups (10 %, P = 0.986) [38].
phylactic pancreatic stenting based on the high risk of PEP. Post- Six meta-analyses published between 2009 and 2014 ( " Table 2)
ERCP pancreatitis developed in 9.2 % vs. 16.9 % of patients in the compared NSAIDs vs. placebo administration for prevention of
indomethacin vs. placebo group, respectively (P = 0.005). Of note, PEP, and all of them concordantly showed the benefit of NSAIDs
moderate-to-severe PEP was less frequent in the indomethacin in preventing either mild or moderate/severe PEP. The NNT fig-
vs. placebo group (4.4 % vs. 8.8 %, respectively; P = 0.03). The ben- ures, reported in the majority of these studies, have varied from
efit of 100 mg rectal indomethacin was also confirmed in an RCT 11 to 34 [31, 39 43].
804 Guideline
In a post hoc analysis of an RCT of NSAIDs vs. placebo for PEP pro- matostatin (3 mg given as an infusion over 12 hours) or lower do-
phylaxis, administration of rectal NSAIDs alone was more effec- ses (250 g) given as bolus injection may be most efficacious,
tive and less costly than prophylactic pancreatic stent placement especially for the subgroup of patients at relatively higher risk
alone or combined with rectal NSAIDs [44]. However, the authors for PEP, i. e., those undergoing pancreatic duct injection (OR
cautioned that these findings should not change current clinical 0.35; 95 %CI 0.15 0.82) and biliary sphincterotomy (OR 0.33;
practice because their post hoc observational study did not pro- 95 %CI 0.16 0.70). With regard to octreotide, subgroup analysis
duce the same quality of evidence as their RCT, which supported showed a protective effect when administered at high dose (OR
the use of indomethacin in addition to prophylactic pancreatic 0.42; 95 %CI 0.20 0.90).
stenting in high risk cases [34]. More recently, two RCTs compared the effect of somatostatin vs.
placebo for PEP prophylaxis. In one RCT, the efficacy of somatos-
5.3. Possibly effective drugs tatin alone could not be assessed because the treatment group re-
5.3.1. Somatostatin and octreotide ceived somatostatin plus diclofenac [47]; the other RCT found
Statement 2010: that high dose somatostatin was associated with a reduction of
Based on an ad hoc meta-analysis of results from 10 high quality post-ERCP hyperamylasemia, but not incidence of PEP [48].
RCTs, somatostatin proved to be ineffective in preventing PEP
(Evidence level 1 ++). We do not recommend universal adminis- 5.3.2. Protease inhibitors
tration of prophylactic somatostatin in average-risk patients un- Statement 2010:
dergoing ERCP (Recommendation grade A). Administration of so- Prophylaxis with gabexate or ulinastatin does not reduce the in-
matostatin might be more efficacious using specific dose sche- cidence of PEP (Evidence 1 ++). Neither drug is recommended for
dules, but caution is needed when interpreting the results of sub- prophylaxis of PEP (Recommendation grade A).
group analyses as they often exaggerate differences between Statement 2014:
treatments in RCTs. Some meta-analytical results seem to support the benefit of ga-
Octreotide administration did not affect the overall incidence of bexate and ulinastatin at high doses for averting PEP but their
PEP when data from eight high quality trials were pooled (Evi- clinical use cannot be recommended owing to the discordance
dence level 1 ++). Prophylaxis with octreotide is not recommen- of the data. A novel protease inhibitor, nafamostat, is likely effec-
ded (Recommendation grade A). In future studies the efficacy of tive for preventing PEP in patients at low risk of PEP but not in
prophylactic administration of octreotide should be evaluated high risk patients.
using a dose greater than or equal to 0.5 mg. Background:
Statement 2014: Gabexate for PEP prophylaxis has been evaluated in six high qual-
Some meta-analytical results seem to support the benefit of so- ity RCTs [49 54]; when the results were pooled, no significant
matostatin and octreotide for averting PEP but their clinical use difference was found between the control and treatment groups.
cannot be recommended except in well selected cases, owing to Ulinastatin for PEP prophylaxis has been compared with placebo
discordant data from different routes or dosages and the exces- (two RCTs) and with gabexate (two RCTs), with contradictory re-
sively high NNT values (Recommendation grade A). sults [55 58]. Nafamostat is a novel protease inhibitor that inhi-
Background: bits trypsin, a proteolytic enzyme considered to play an initial
Three meta-analyses assessed the effect of somatostatin/octreo- role in the pathogenesis of pancreatitis; compared with gabexate
tide for PEP prophylaxis before the 2010 ESGE Guideline publica- its half-life is 20 times longer and its potency 10 to 100 times
tion [1]; an updated meta-analysis of high quality RCTs (Jadad greater.
score > 3) was performed for writing the ESGE Guideline. Respec- New information since 2009:
tively, 10 and 8 RCTs were included for assessing somatostatin Four meta-analyses assessed the efficacy of protease inhibitors
and octreotide. Overall, the updated meta-analysis found no sig- for PEP prophylaxis [42, 59 61]. Subgroup analysis of 8 high
nificant reduction of PEP incidence with somatostatin vs. placebo quality (Jadad score > 3) RCTs on gabexate administration
(OR 0.57; 95 %CI 0.32 1.03) or with octreotide vs. placebo (OR showed that the agent was not associated with a decreased risk
0.73; 95 % CI, 0.41 1.30). However, subgroup analyses suggested of PEP (RR 0.64; 95 %CI 0.36 1.13) and there was great heteroge-
that some dosages or administration schedules might be asso- neity among the studies. Subgroup analysis of 6 ulinastatin RCTs
ciated with a protective effect against PEP. showed the agent was not associated with a decreased risk of PEP
New information since 2009: in either high quality studies (RR 0.65; 95 %CI 0.33 1.30) or low
A meta-analysis that compared octreotide vs. placebo (18 RCTs, quality studies (RR 0.75; 95 %CI 0.49 1.16).
3171 patients) found no significant difference in PEP incidence The question of drug dosage was addressed in one meta-analysis:
(OR 0.77; 95 %CI 0.56 1.05) [45]. However, at post hoc subgroup when ulinastatin was administered at sufficient doses ( 150 000
analysis, dosage seemed to have an impact: when the compound units), it averted PEP (OR 0.39; 95 %CI 0.19 0.81; NNT 6); in a
was given at a dose 0.5 mg (6 RCTs; 1470 patients) the OR for de- similar fashion, gabexate was effective at either slow infusion of
veloping PEP dropped to 0.45 (95 %CI 0.28 0.73; NNT = 25), high dose ( 150 000 units) (OR 0.44; 95 %CI 0.25 0.79; NNT 7) or
whereas the agent proved ineffective at a dosage < 0.5 mg. Other rapid infusion of low dose (OR 0.37; 95 %CI 0.20 0.69; NNT 6)
subgroup analyses of octreotide administration that assessed [61].
the route (intravenous vs. subcutaneous) and the schedule (be- The benefit of nafamostat has been assessed in a meta-analysis
fore or after ERCP) were inconclusive. that pooled data from 5 RCTs and 2678 patients [42]. This agent
A second meta-analysis assessed the effect of somatostatin (10 lowered the incidence of PEP (RR 0.47; 95 %CI 0.33 0.67). All
RCTs) and of octreotide (7 RCTs) in a total of 3818 patients [46]. three RCTs available as full text found nafamostat to be effective
Overall, somatostatin reduced the risk of PEP (RR 0.52; 95 %CI in low risk patients but not in high risk patients [62 64]. When
0.30 0.90), while octreotide was not effective (RR 0.86; 95 %CI the results observed for high risk patients in the three RCTs were
0.45 1.63). Subgroup analyses suggested that higher doses of so- pooled, PEP incidence was not statistically different in the treat-
Guideline 805
ment vs. the placebo group (8.9 % [32 /358] vs. 13.1 % [37 /283], 5.3.4. Antibiotics
respectively; P = 0.12). Statement 2010:
Ceftazidime reduced the incidence of PEP in a single study (Evi-
5.3.3. Drugs influencing sphincter of Oddi pressure dence grade 1 ). Further data are needed before recommending
Statement 2010: ceftazidime for the prophylaxis of PEP (Recommendation grade
Nitroglycerin reduces the incidence of PEP; however, when ad- C).
ministered transdermally, it is ineffective (Evidence grade 1 ++). Statement 2014:
Side effects such as transient hypotension and headache may oc- Antibiotics have not been proven effective in PEP prophylaxis;
cur. We do not recommend the routine use of nitroglycerin for further data are needed (Recommendation grade C).
prophylaxis of PEP (Recommendation grade A). Background:
There is no evidence that drugs reducing sphincter of Oddi In an RCT that tested ceftazidime for prophylaxis of PEP, the inci-
pressure (other than nitroglycerin) [namely, botulinum toxin, dence of PEP was lower in the treatment than in the control
epinephrine, lidocaine, and nifedipine] reduce the incidence group (2.6 % vs. 9.4 %, respectively; P = 0.009) [76]. This study was
of PEP [cf. section 5.4 below]. of low methodological quality owing to unclear allocation con-
Statement 2014: cealment.
Glyceryl trinitrate (GTN) may be effective in preventing PEP New information since 2009:
when administered sublingually. Topical epinephrine may be ef- A network meta-analysis ranked antibiotics in fourth position
fective to prevent PEP in purely diagnostic ERCP. ESGE does not among 16 drugs for the efficacy of PEP prophylaxis (OR 0.46;
recommend the routine use of GTN or of epinephrine for PEP pro- 95 %CI 0.15 1.07; NNT 21) [75]. However, the difference ob-
phylaxis. No changes concerning botulinum toxin, lidocaine, and served between antibiotics and placebo was not statistically sig-
nifedipine. nificant, only 254 patients were included in the treatment arms
Background: of four RCTs [76 79] included in the meta-analysis (not 1082 as
The influence of GTN on the incidence of PEP was evaluated in stated in the meta-analysis), and two of these RCTs did not have
two meta-analyses that pooled data from 5 RCTs involving 1662 PEP prophylaxis as their primary study endpoint [76, 78].
patients [65, 66]. Both meta-analyses showed an overall signifi-
cant reduction of PEP with an RR of 0.61 (95 %CI 0.44 0.86) and 5.3.5. Intensive hydration
an NNT of 26. In the majority of the patients, GTN was adminis- Statement 2010:
tered transdermally. In a subgroup analysis, transdermal GTN No statement.
failed to show a significant reduction of PEP (RR 0.66; 95 %CI Statement 2014:
0.43 1.01). In a pilot study, intensive hydration seemed to effectively prevent
Botulinum toxin [67], epinephrine [68], lidocaine [69], and nife- PEP. Large-scale RCTs to establish an evidence-based approach to
dipine [70, 71], were not found to prevent PEP in the correspond- intensive hydration are needed.
ing RCTs. New information since 2009:
New information since 2009: Based on a pilot study in 62 patients, intensive hydration in the
A meta-analysis that pooled data from 8 RCTs (1920 patients) periprocedural period with intravenous lactated Ringers solu-
found that GTN decreases PEP incidence compared with placebo tion appears to reduce PEP incidence [80]. None of the patients
(5.9 % vs. 9.8 %, respectively; P = 0.002) [72]. A more recent meta- who received aggressive hydration developed PEP, compared
analysis extended the observation to 12 RCTs (2649 patients) and with 17 % of patients who received standard hydration (P =
found again that GTN reduces the overall incidence of PEP (RR 0.016). No patients had evidence of volume overload. Two obser-
0.67; 95 %CI 0.52 0.87) but was, however, ineffective in lowering vational studies support this strategy of hydration for attenuating
the incidence of moderate to severe PEP (RR 0.70; 95 %CI 0.42 the severity of PEP [81, 82].
1.15) [73]. The route of GTN administration may influence its ef-
fectiveness. Subgroup analyses revealed that sublingual adminis- 5.4. Drugs proven ineffective
tration of GTN was more effective than transdermal and topical Statement 2010:
administration (RR 0.47; 95 %CI 0.28 0.78). There is no evidence that glucocorticoids, drugs reducing sphinc-
The prophylactic merit of topical epinephrine (0.02 %, 20 mL ter of Oddi pressure (other than nitroglycerin), antioxidants, he-
sprayed on the papilla) was compared with placebo in diagnos- parin, interleukin-10, or some anti-inflammatory drugs (other
tic-only ERCP in two RCTs [68, 74]. Matsushita et al. originally than diclofenac and indomethacin), such as pentoxifylline, sema-
evaluated spraying of epinephrine onto the papilla in 370 pa- pimod, and the recombinant platelet-activating factor acetylhy-
tients undergoing diagnostic ERCP [68]; the incidence of PEP drolase, reduce the incidence of PEP (Evidence levels from 1 to
was 0 % in the epinephrine group vs. 2.2 % in the control group 1 ++). None of these drugs is recommended for PEP prophylaxis
(not significant). In the second study, Xu et al. randomized 941 (Recommendation grade A).
patients to topical epinephrine vs. placebo; the rates of PEP Statement 2014:
were 1.95 % vs. 6.45 %, respectively (P = 0.0086) [74]. When the re- No change except for GTN and epinephrine (cf. section 5.3.3
sults of the two studies were pooled in a meta-analysis, topical above).
epinephrine proved efficacious in reducing PEP (OR 0.25; 95 %CI Background:
0.06 0.65; NNT 15) [75]. However, in the two RCTs of epine- The efficacy of glucocorticoids for PEP prophylaxis was evaluated
phrine, only patients with purely diagnostic ERCP were included, in two meta-analyses that included 6 RCTs [83, 84]; the incidence
no guidewire was initially used, cannulation times were very of PEP was not significantly different in the glucocorticoids vs.
long, and the definition of PEP was not standard. Based on these the control group (11.8 % vs. 10.6 %, respectively). Three RCTs
shortcomings, routine use of topical epinephrine cannot be re- that evaluated interleukin-10 have yielded contradictory results
commended for PEP prophylaxis. [85 87]. Subcutaneous heparin was not found to reduce PEP in-
806 Guideline
cidence in 2 RCTs [88, 89]. Drugs potentially reducing the sphinc- NSAIDs with prophylactic pancreatic stenting did not further re-
ter of Oddi pressure (other than GTN and topical epinephrine), duce the risk of PEP [107].
including botulinum toxin, lidocaine, and nifedipine, have not The ideal stent characteristics for PEP prophylaxis and the opti-
been found to reduce PEP incidence in RCTs [67, 68,90 92]. mal duration of stent placement are not definitively known.
Three antioxidant agents, namely allopurinol, N-acetylcysteine, However, a network meta-analysis showed that the probabilities
and natural beta-carotene were not found to be effective in pre- of 5-Fr and 3-Fr stents being ranked as the most efficacious for
venting PEP in 5 RCTs and one meta-analysis [93 98]. the prevention of PEP were 96.8 % vs. 3.1 %, respectively, with 5-
New information since 2009: Fr single-pigtail, unflanged stents and 5-Fr straight, flanged
Regarding heparin, a meta-analysis that analyzed four clinical stents producing similar results [108]. Furthermore, placement
trials (including 3 RCTs) with a total of 1438 patients showed no of 5-Fr stents requires fewer guidewires and is easier than that
beneficial effect of prophylactic heparin for the prevention of PEP of 3-Fr stents [109, 110]. It is believed that stents need to remain
[99]. Regarding antioxidant supplementation, a meta-analysis of in place for a minimum of 12 24 hours to provide benefit, since
11 RCTs (total, 3010 patients) showed no beneficial effect on the removal at the end of ERCP negates the protection from PEP [111]
incidence and the severity of PEP [100]. Regarding allopurinol, an and early outward migration may also result in PEP [112]. Ad-
RCT found no effect for the prevention of PEP [101]. No new data verse events related to attempted prophylactic pancreatic stent-
are available for glucocorticoids, interleukin-10, pentoxifylline, ing include PEP, stent-induced pancreatic ductal damage, and in-
semapimod, and the recombinant platelet-activating factor acet- ward migration [113]. Removal of proximally migrated small-di-
ylhydrolase. ameter stents can be technically challenging, if not impossible
[114].
6. Pancreatic stent placement for PEP prophylaxis

! 7. ERCP techniques
Statement 2010: !
Prophylactic pancreatic stent placement is recommended to pre- 7.1. General considerations
vent PEP in patients who are at high risk for development of PEP. 7.1.1. Patient position
Short, 5-Fr diameter, plastic pancreatic stents are currently re- Statement 2010:
commended. Passage of the stent from the pancreatic duct There is no evidence that the incidence of PEP is influenced by
should be evaluated within 5 to 10 days of placement and re- patient position during ERCP (Evidence level 2 + + ). Therefore, no
tained stents should be promptly removed endoscopically (Evi- recommendation is made regarding patient position.
dence level 1 + ; Recommendation grade A). Statement 2014:
Prophylactic pancreatic stenting decreases the risk of PEP in high Background:
risk and mixed-case groups; it nearly eliminates the risk of severe Comparisons in RCTs of different patient positions during ERCP
PEP. 5-Fr pancreatic stents are more efficacious than 3-Fr stents showed no significant difference in PEP incidence.
in preventing PEP. ESGE recommends the placement of 5-Fr pan- New information since 2009:
creatic stents in cases at high risk of PEP. Passage of the stent from None.
the pancreatic duct should be evaluated within 5 to 10 days of
placement and retained stents should be promptly removed 7.1.2. Cannulation attempts
endoscopically (Evidence level 1 + ; Recommendation grade A). Statement 2010:
Background: Trauma resulting from repeated attempts at biliary cannulation
Two meta-analyses have demonstrated that, in patients at high has been proven to be a risk factor for the development of PEP
risk of PEP, prophylactic pancreatic stent placement significantly (Evidence level 2 + + ). The number of cannulation attempts
reduces the incidence of PEP [102, 103]. The OR was 0.44 (95 %CI should be minimized (Recommendation grade B).
0.24 0.81), with an absolute risk reduction of 12.0 % (95 %CI 3.0 Statement 2014:
21.0). A multicenter RCT (201 patients) showed a decreased inci- ESGE recommends keeping the number of cannulation attempts
dence of PEP when prophylactic pancreatic stent placement was as low as possible (Recommendation grade B).
performed, regardless of the concomitant occurrence of other Background:
known risk factors for PEP (PEP incidence in the stent vs. no-stent The risk of PEP is higher after multiple attempts at duct cannula-
group, 3.2 % vs. 13.6 %, respectively; P = 0.019) [104]. In these tion [6, 21,115,116]. The rendezvous technique allows cannula-
studies, the risk of severe PEP was nearly eliminated following tion trauma to be minimized, and has been used in most studies
successful placement of a prophylactic pancreatic stent. that evaluated intraoperative endoscopic sphincterotomy.
Pancreatic stent placement was shown to be cost-effective only New information since 2009:
in patients at high risk for PEP [105]. A meta-analysis assessed 5 RCTs that compared preoperative vs.
New information since 2009: intraoperative endoscopic sphincterotomy [117]; PEP was less
A meta-analysis of 14 RCTs with a total of 1541 patients showed a frequent with the latter approach while the incidence of other
significant reduction in the incidence and the severity of PEP ERCP-related complications was similar with both techniques. A
when prophylactic pancreatic stenting was used [106]. In addi- nationwide case control study from Sweden confirmed that the
tion, subgroup analysis showed that pancreatic stenting reduced rendezvous technique was associated with a reduction in the
the risk of PEP in high risk and mixed-case groups. In a network risk of PEP compared with standard cannulation techniques,
meta-analysis, prophylactic pancreatic stenting alone was shown from 3.6 % to 2.2 % (OR 0.5; 95 %CI 0.2 0.9; P = 0.02) [18].
to be less effective than NSAIDs alone, and the combination of
Guideline 807
7.1.3. Contrast medium (Evidence level 1 + + ). The wire-guided technique is recommen-

Statement 2010: ded for deep biliary cannulation (Recommendation grade A).
Injection of contrast medium into the pancreatic duct is an inde- Statement 2014:
pendent predictor of PEP (Evidence level 1 + ). If pancreatic duct No changes.
injection occurs incidentally or is required, the number of injec- Background:
tions and volume of contrast medium injected into the pancreatic The wire-guided biliary cannulation technique entails passage of
duct should be kept as low as possible (Recommendation grade a guidewire inserted through a catheter (most often a hydrophilic
B). Compared with traditional, high-osmolality contrast agents, guidewire inserted into a sphincterotome) for deeply cannulating
low-osmolality contrast agents are costlier but are not associated the bile duct. Two meta-analyses published in 2009 showed that,
with reduction in the rates of PEP (Evidence level 1 ). The rou- in RCTs, the incidence of PEP was significantly lower with the
tine use of these agents for ERCP is not recommended (Recom- wire-guided as compared with the standard contrast-assisted
mendation grade B). cannulation technique [125, 126].
Statement 2014: New information since 2009:
No changes. Five comparative studies and a meta-analysis comparing the
Background: wire-guided vs. the standard contrast-assisted method for selec-
In a large meta-analysis, pancreatic duct injection was found to tive biliary cannulation were published between 2009 and 2013
be an independent predictor of PEP (RR 2.2; 95 %CI 1.60 3.01) [127 132]. Four studies [128 131], two of which were RCTs
[20]. In a retrospective study that included more than 14 000 [128, 131], did not confirm the results of previous meta-analyses
ERCPs, the extent of pancreatic duct injection (head-only vs. that showed a lower risk of PEP with the wire-guided method. In
head and body vs. injection to the tail) was independently asso- most studies, the wire-guided method shortened cannulation
ciated with PEP [118]. The hypothesis that low-osmolality con- and fluoroscopy times. However, in a recent meta-analysis that
trast agents would be less harmful than high-osmolality contrast extended the analysis to 12 RCTs (3450 patients), the wire-guid-
agents because of less important fluid shifts in the pancreas was ed method significantly lowered the incidence of PEP compared
invalidated in a meta-analysis of 13 RCTs that involved 3381 pa- with the contrast-assisted method (RR 0.51; 95 %CI, 0.32 0.82)
tients [119]. [132]. In addition, the wire-guided cannulation technique was
New information since 2009: associated with greater primary cannulation success (RR 1.07;
One article examined the role of low-osmolality contrast agents 95 %CI 1.00 1.15), fewer precut sphincterotomies (RR 0.75; 95 %
but it does not warrant any change in the Guideline [120]. CI 0.60 0.95), and no increase in other ERCP-related complica-
tions.
7.1.4. Carbon dioxide
Statement 2010: 7.1.6. Electrosurgical current
Use of carbon dioxide (CO2) as a replacement for air for luminal Statement 2010:
insufflation during ERCP does not influence the incidence of PEP The incidence of post-sphincterotomy pancreatitis is not influ-
but decreases the incidence and severity of post-procedural ab- enced by the type of electrosurgical current used (whether
dominal pain (Evidence level 1 + ). Carbon dioxide is recommen- pure-cut or blended) (Evidence level 1 + ). Blended current is re-
ded for insufflation, and might be particularly useful for outpati- commended for biliary sphincterotomy, particularly in patients
ent ERCPs, to reduce post-procedural abdominal pain and to at high risk of bleeding (Recommendation grade A).
avoid confusion with PEP (Recommendation grade B). Statement 2014:
No changes. Background:
Background: As pure-cut current produces less edema than blended current
Because of its higher solubility in water compared with nitrogen [133], it was hypothesized that it might reduce the incidence of
and oxygen, the main components of air, carbon dioxide is PEP after biliary sphincterotomy. A meta-analysis of four RCTs
cleared from the bowel following endoscopy much faster than that included 804 patients found no significant difference in the
air (through the bloodstream and respiration). incidence of PEP following the use of pure vs. blended current
New information since 2009: [134]. However, the incidence of bleeding was significantly high-
Three meta-analyses, which included between 5 and 7 RCTs (be- er when pure-cut current was used.
tween 446 and 818 patients), compared carbon dioxide vs. air for New information since 2009:
gut distension during ERCP exclusively [121 123]. All these No new evidence has become available.
meta-analyses found that the use of carbon dioxide reduces
post-ERCP abdominal pain without change in other complication 7.2. Effect of difficult biliary cannulation
rates or in procedure duration. A survey showed that the use of 7.2.1 Definition
carbon dioxide during endoscopy is uncommon; this may be Statement 2010:
related to implementation costs and unawareness by endosco- None.
pists of the advantages of carbon dioxide [124]. Statement 2014:
ESGE recommends that future studies define difficult biliary can-
7.1.5. Cannulation techniques nulation in an intact papilla as any of the following: cannulation
Statement 2010: attempts of duration > 5 minutes, > 5 attempts, or 2 pancreatic
For deep biliary cannulation, the wire-guided technique reduces guidewire passages.
the risk of PEP and increases the success rate of primary cannula-
tion when compared with the standard contrast-assisted method
808 Guideline
Background: New information since 2009:

Many different definitions of difficult biliary cannulation have Seven new studies are summarized in " Table 3 [139 145]. In
been used, which make comparisons between studies impracti- two RCTs that compared the PGW vs. the precut techniques
cal. [142, 143], success rates of biliary cannulation were similar but,
New information since 2009: in one of the RCTs [143], the PGW technique was plagued by a
In an effort to standardize this definition, Halttunen et al. pro- higher incidence of PEP (38 % vs. 11 %, respectively; P = 0.01). Pro-
spectively collected data on 907 biliary cannulations attempted phylactic pancreatic stenting was not used in any of the RCTs
by experienced endoscopists at 10 centers [115]. The authors mentioned above. Another RCT showed that prophylactic pancre-
found the incidence of PEP progressively increased with various atic stenting significantly decreased the incidence of PEP after
factors perceived as causing difficulty in cannulation. Any of the the PGW technique had been used [146]. In a retrospective study
following factors was associated with a PEP incidence of > 10 % that included 146 patients, prophylactic pancreatic stenting was
during wire-guided cannulation of a native papilla: cannulation always attempted after the PGW technique had been used, and
attempts of duration > 5 minutes, > 5 attempts, or 2 pancreatic failed prophylactic pancreatic stenting was the only independent
guidewire passages. The latter was also noted in another prospec- predictor of PEP [144]. In another retrospective study that in-
tive study [116]. volved 142 patients, the incidence of PEP decreased after the au-
For difficult cannulation, commonly used options include persist- thors changed their cannulation technique following PGW place-
ent attempts at cannulation using standard methods, pancreatic ment, from contrast-assisted to guidewire-assisted biliary can-
guidewire placement (with biliary cannulation attempted either nulation [147].
using a guidewire, the so-called double guidewire (DGW) tech-
nique, or using contrast medium injection), precut of various 7.2.3. Precut biliary sphincterotomy
types, repeat attempts at ERCP 24 48 hours later, and patient re- Statement 2010:
ferral to another endoscopist. Various techniques of precut biliary sphincterotomy have been
described; the fistulotomy technique may present a lower inci-
7.2.2. Pancreatic guidewire-assisted technique dence of PEP than standard needle-knife sphincterotomy but fur-
Statement 2010: ther RCTs are required to determine which technique is safer and
Data about the usefulness and safety of pancreatic guide wire more effective, based upon the papillary anatomy. There is no
placement to facilitate biliary cannulation in difficult cases are evidence that the success and complication rates of biliary precut
conflicting. Prophylactic pancreatic stent placement decreases are affected by the level of endoscopist experience in this tech-
the incidence of PEP with this technique (Evidence level 2 +). Pan- nique but published data only report on the experience of one
creatic guide wire assistance may facilitate biliary cannulation endoscopist (Evidence level 2 ). Prolonged cannulation attempts
mostly in the case of inadvertent but repeated cannulation of using standard techniques may impart a risk for PEP greater than
the pancreatic duct; if this method is used, a pancreatic stent the precut sphincterotomy itself (Evidence level 2 +). Precut
should be placed for PEP prophylaxis (Recommendation grade B). sphincterotomy should be performed by endoscopists with ex-
Statement 2014: pertise in standard cannulation techniques (Recommendation
In cases of difficult biliary cannulation, pancreatic guidewire grade D). The decision to perform precut biliary sphincterotomy,
(PGW) placement allows biliary cannulation in a proportion of the timing, and the technique, are based on anatomic findings,
cases similar to persistence in attempting cannulation with endoscopist preference, and procedural indication (Recommen-
standard cannulation techniques (or precut if it is used as a back- dation grade C).
up technique), but the risk of PEP is likely higher. In such circum- Statement 2014:
stances, PEP is effectively prevented by prophylactic pancreatic In cases of difficult biliary cannulation, early precut is associated
stenting (Evidence level 1 ). ESGE suggests restricting the use of with a lower PEP incidence than persistent attempts using the
a PGW as a backup technique to cases with repeated inadvertent standard approach but the overall success and complication rates
cannulation of the pancreatic duct; if this method is used, deep are similar with both approaches. Needle-knife fistulotomy
biliary cannulation should be attempted using a guidewire rather seems to be associated with fewer complications, including PEP,
than the contrast-assisted method and a prophylactic pancreatic compared with other precut techniques.
stent should be placed (Recommendation grade B). ESGE suggests that needle-knife fistulotomy should be the pre-
Background: ferred precut technique in patients with a bile duct dilated
In the PGW-assisted technique, a guidewire is inserted in the down to the papilla. Conventional precut and transpancreatic
main pancreatic duct to facilitate deep biliary cannulation by sphincterotomy present similar success and complication rates;
straightening the papillary anatomy and to prevent repeated can- if conventional precut is elected and pancreatic cannulation is ea-
nulation of the pancreatic duct [135, 136]. In two RCTs, compared sily obtained, ESGE suggests attempting to place a small-diame-
with persistence in applying the standard cannulation technique, ter (3-Fr or 5-Fr) pancreatic stent to guide the cut and leaving the
the PGW technique yielded overall similarly low success rates for pancreatic stent in place at the end of ERCP for a minimum of
biliary cannulation (means, 57 % vs. 56 %, respectively) and a non- 12 24 hours (Recommendation grade B).
significantly higher incidence of PEP (means, 14 % vs. 6 %, respec- Background:
tively) [137, 138]. Discordances between these RCTs in terms of Precut biliary sphincterotomy can be done by different tech-
cannulation success and of PEP incidence may be related to differ- niques: needle-knife precut starting at the orifice of the papilla
ences in the inclusion criteria (i. e., difficult biliary cannulation (conventional precut), needle-knife above the orifice (fistulot-
alone or combined with repeated unintended pancreatic cannu- omy), transpancreatic sphincterotomy (septotomy) and needle-
lation) and in the use of prophylactic pancreatic stenting. knife over a pancreatic stent. Compared with prolonged attempts
at biliary cannulation using standard techniques, the use of pre-
Guideline 809
Table 3 New studies evaluating pancreatic guidewire (PGW) placement for biliary cannulation in the case of difficult biliary cannulation.
First author, Design Additional Pancreatic Successful biliary PEP rate Note
year Patients, n inclusion criteria stenting cannulation rate
Xinopoulos, Retrospective Repeated uninten- No 44 % (vs. 81 % with 6.1 % (similar to Comparative study
2011 [139] 112 tional pancreatic precut in patients who group with easy
duct cannulation had no repeated un- biliary cannula-
intentional pancreatic tion [5.3 %] and to
duct cannulation) group with precut
in place of PGW
[7.5 %])
Grnroos, Prospective Repeated uninten- No 66 % 2% Authors advocate
2011 [140] 50 tional pancreatic to shift to other
duct cannulation technique if DGW is
cumbersome
Belverde, Retrospective Selective pancreat- No 97 % 2.6 %
2012 [141] 121 ic duct cannulation
achieved
Angsuwatcharakon, RCT No No PGW vs. precut: PGW vs. precut: Shorter cannula-
2012 [142] 44 74 % vs. 81 % (n.s.) 17.4 % vs. 9.5 % tion time with the
PGW vs. precut
technique
(172 s vs. 394 s
(P < 0.001)
Yoo, RCT Selective pancrea- No DGW vs. precut: DGW vs. precut:
2013 [143] 71 tic duct cannula- 91.2 % vs. 91.9 % (n.s.) 38 % vs. 11 %
tion achieved (P = 0.01)
Ito, Retrospective n.a. Attempted in all PGW: 70 %; PGW, 8 %; Independent
2013 [144]* 146 if failure with PGW, DGW, 4 % predictor of PEP:
DGW was successful in failed pancreatic
72 % stenting (OR 8.3;
95 %CI 2.3 30)
Tanaka, Retrospective Opacification of 40 /79 82 % (PGW) vs. 83 % 11 % (PGW) vs. 7 %
2013 [145] 1 79 the pancreatic duct (DGW) (DGW)
PEP, post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis; PGW, pancreatic guidewire; DGW, double guidewire; RCT, randomized controlled trial; n.s.,
not significant; n.a., not available; OR, odds ratio; CI, confidence interval
1
Biliary cannulation attempted by searching the bile duct through contrast medium injection with a guidewire in the main pancreatic duct (PGW technique), as opposed to
searching through manipulation of a guidewire inserted in a catheter (DGW technique).
cut sphincterotomy has long been thought to increase the success cess [152, 153]; they found no significant differences in terms of
of biliary cannulation and the incidence of PEP [6, 20]. PEP, overall complication and overall success rates.
New information since 2009: Needle-knife precut assisted by pancreatic stenting has been pro-
Two meta-analyses investigated the issue of timing of the precut posed for reducing PEP. One RCT found that, compared with stent
procedure in 6 RCTs [148, 149]. Aside from the definition of early removal at the end of the procedure, leaving the stent for 7 10
precut, differences between studies included the technique of days reduces the incidence and severity of PEP (P < 0.05 for both
precut and the randomization ratio (from 1:1 to 1:3). Endosco- comparisons) [111].
pists experienced in precut techniques performed all procedures.
The overall incidence of PEP was lower in patients allocated to 7.3. Specific therapeutic techniques
early precut than to persistence in the use of standard techniques 7.3.1. Balloon dilation as a substitute for endoscopic
(2.5 % vs. 5.3 %; OR 0.47; 95 %CI 0.24 0.91) but the overall cannu- sphincterotomy
lation and complication rates were similar in patients allocated to Statement 2010:
early precut or to persistence in the use of standard cannulation Compared with endoscopic sphincterotomy, endoscopic papil-
techniques. lary balloon dilation (EPBD) using small-caliber balloons ( 10
In a retrospective study comparing different precut techniques, mm) is associated with a significantly higher incidence of PEP
the risk of PEP was significantly lower after fistulotomy (2.6 %) and significantly less bleeding (Evidence level 1 ++). EPBD is not
compared with conventional precut (20.9 %) and pancreatic sep- recommended as an alternative to sphincterotomy in routine
totomy (22.4 %); the overall complication rate was also signifi- ERCP but may be useful in patients with coagulopathy and al-
cantly lower after fistulotomy vs. other precut techniques [150]. tered anatomy (e. g. Billroth II) (Recommendation grade A). If bal-
In another retrospective study of needle-knife fistulotomy per- loon dilation is performed in young patients, the placement of a
formed in 204 patients, complications (mostly PEP) progressively prophylactic pancreatic stent should be strongly considered (Evi-
increased with decreasing common bile duct (CBD) diameter, up dence level 4; Recommendation grade D).
to 14 % in patients with a CBD diameter < 4 mm [151]. Two retro- Statement 2014:
spective studies compared transpancreatic septotomy and nee- Compared with endoscopic sphincterotomy, endoscopic papil-
dle-knife precut (with pancreatic stenting or not) for biliary ac- lary balloon dilation (EPBD) using small-caliber balloons ( 10
mm) is associated with more PEP, less bleeding, and fewer late
810 Guideline
stone recurrences; the risk of PEP is inversely associated with the Statement 2014:
duration of EPBD (Evidence level 1 ++). ESGE does not recom- For the extraction of difficult biliary stones, endoscopic sphinc-
mend endoscopic papillary balloon dilation as an alternative to terotomy plus large-balloon dilation presents a risk of PEP similar
sphincterotomy in routine ERCP, but it may be advantageous in to that of endoscopic sphincterotomy alone; it presents a lower
selected patients; if this technique is used, the duration of dila- bleeding risk and, possibly, lower overall morbidity and requires
tion should be longer than 1 minute (Recommendation grade A). less use of mechanical lithotripsy. ESGE suggests performing
Background: endoscopic sphincterotomy plus large-balloon dilation in place
The use of EPBD may be advantageous compared with endo- of endoscopic sphincterotomy alone for the extraction of selected
scopic sphincterotomy, by decreasing clinically significant bleed- difficult biliary stones (Recommendation grade B).
ing in patients with coagulopathy, for preserving sphincter of Background:
Oddi function in younger patients [154], and in patients with al- In patients with a tapered distal bile duct or large biliary stones,
tered anatomy (Billroth II) where sphincterotomy is technically endoscopic sphincterotomy followed by biliary dilation using a
difficult. In two meta-analyses, the use of EPBD resulted in a low- large-diameter (12 20 mm) balloon has been proposed to facili-
er success rate than endoscopic sphincterotomy for the initial re- tate stone extraction [163]. This technique has been associated
moval of biliary stones, with a significantly higher incidence of with high success rates for stone extraction without the need for
PEP and significantly lower incidence of bleeding [155, 156]. mechanical lithotripsy and with acceptable complication rates in
New information since 2009: case series [164 167]; the single RCT that had compared this
A meta-analysis of 10 high quality RCTs (1451 patients) that com- method with endoscopic sphincterotomy at the time of publica-
pared EPBD vs. endoscopic sphincterotomy for biliary stone ex- tion of the first Guideline had found no differences in rates of suc-
traction found similar success rates of biliary stone extraction cessful stone clearance, need for mechanical lithotripsy, and
with both methods but did not bring new findings with regard complications [168].
to complications [157]; indeed it included fewer RCTs than the New information since 2009:
previously published Cochrane meta-analysis [156]. A meta-analysis of 7 RCTs that included 790 patients found that,
A meta-analysis that included 12 RCTs (1649 patients) indica- compared with endoscopic sphincterotomy alone, endoscopic
ted that duration of EPBD is inversely associated with the inci- sphincterotomy followed by large balloon dilation was associated
dence of PEP: short ( 1 minute) EPBD was associated with a with similar PEP rates but significantly fewer overall complica-
higher risk of PEP (OR 3.87; 95 %CI 1.08 13.84) compared tions and significantly less bleeding [169]. However in this
with endoscopic sphincterotomy (4 RCTs), but long EPBD infla- meta-analysis, studies which, according to their authors, were
tion time (> 1 minute) was not (OR 1.14; 95 %CI 0.56 2.35) (6 retrospective, were considered to be RCTs [170]. Two other
RCTs) [158]. A lower risk of PEP after long EPBD was also re- meta-analyses that included 3 RCTs and 4 6 retrospective stud-
ported in the single RCT that compared long (5-minute) vs. ies (including between 90 and 1295 patients) found similar inci-
short (1-minute) EPBD (RR 0.32; 95 %CI 0.11 0.93) [159]. The dences of PEP but significantly lower bleeding risk with endo-
authors suggested that the increased risk of PEP after short scopic sphincterotomy plus large balloon dilation vs. endoscopic
EPBD might be related to inadequate balloon expansion result- sphincterotomy [171, 172]. Additional differences in favor of
ing in a worsened compression of the pancreatic duct. endoscopic sphincterotomy plus large balloon dilation were
A meta-analysis that included 3 RCTs (496 patients) with a fol- mostly attributable to the results of retrospective studies; they
low-up longer than 1 year showed that stone recurrence was included a lower use of mechanical lithotripsy and a lower over-
less frequent after EPBD vs. endoscopic sphincterotomy (OR all complication rate [171, 172].
0.48; 95 %CI 0.26 0.90) [160]. Another RCT that was not included
in this meta-analysis and included 474 patients also reported 7.3.3. Sphincter of Oddi manometry
that, in patients with biliary stones 8 mm, overall late complica- Statement 2010:
tions and stone recurrence were less frequent after EPBD than In patients undergoing pancreatic sphincter of Oddi manometry,
after endoscopic sphincterotomy (5.3 % vs. 17.3 %, P = 0.009; 4.4 % use of the standard perfusion catheter without an aspiration port
vs. 12.7 %; P = 0.048, respectively) (mean follow-up, 55 months); has been shown to increase the risk of PEP compared with mod-
the difference was not significant for patients with stones > 8 ified water perfusion catheters (Evidence level 2 ++). Pancreatic
mm [161]. A retrospective cohort study with a median follow- sphincter of Oddi manometry should be done using a modified
up of 92 months also showed a lower incidence of common bile triple-lumen perfusion catheter with simultaneous aspiration or
duct stone recurrence after EPBD vs. endoscopic sphincterotomy a microtransducer catheter (non-water-perfused) (Recommen-
[162]. dation grade B).
Statement 2014:
7.3.2. Large-balloon dilation for extraction of ESGE recommends that all patients undergoing ERCP for known
difficult biliary stones or suspected sphincter of Oddi dysfunction (SOD) receive rectal
Statement 2010: NSAIDs combined with pancreatic stenting. Pancreatic sphincter
Potential advantages of performing large-balloon dilation in ad- of Oddi manometry should be done using a modified triple-lu-
dition to endoscopic sphincterotomy for extraction of difficult men perfusion catheter with simultaneous aspiration or a micro-
biliary stones remain unclear (Evidence level 3). Endoscopic transducer catheter (non-water-perfused) (Recommendation
sphincterotomy plus large-balloon dilation does not seem to in- grade B).
crease the risk of PEP and can avoid the need for mechanical li- Background:
thotripsy in selected patients, but not enough data are available It is well documented that patients undergoing ERCP for known
to recommend routine use over biliary sphincterotomy alone in or suspected SOD are at high risk of PEP, regardless of whether
conjunction to lithotripsy techniques (Recommendation grade sphincter of Oddi manometry (SOM) is performed [173]. Biliary
D). SOM does not appear to increase the risk of PEP [173]; pancreatic
Guideline 811
SOM is associated with an increased risk of PEP depending on the tors listed in
" Table 1 (definite or likely). Procedures and patient
technique used [174]. When water-perfused catheters are used conditions that do not fulfill these criteria are considered to re-
to measure pancreatic sphincter pressure, continuous aspiration present low risk for PEP.
of fluid from the main pancreatic duct through one of the three
manometry ports prevents overfilling of the duct [174], a known Competing interests: None of the authors reports financial com-
risk factor for PEP. A specialized aspiration manometry catheter is peting interests.
available for this purpose, though one port of a standard triple lu-
men catheter can be used for aspiration [174]. The use of solid- Institutions
1
state manometry catheters decreases the risk of PEP as there is Gedyt Endoscopy Center, Buenos Aires, Argentina
2
Division of Gastroenterology, Casa Sollievo Sofferemza Hospital, IRCCS,
no perfusion or filling of the pancreatic duct [175]. San Giovanni Rotondo, Italy
The results of SOM should not influence the decision of whether 3
Division of Gastroenterology, Medical University of South Carolina, Charles-
to institute measures for prevention of PEP. As mentioned, all pa- ton, South Carolina, USA
4
Division of Gastroenterology and Gastrointestinal Endoscopy, Vita-Salute
tients with known or suspected SOD are at high risk for PEP and San Raffaele University, Scientific Institute San Raffaele, Milan, Italy
should receive PEP prophylaxis [175]. Indeed one study showed 5
Department of Gastroenterology, HELIOS Albert-Schweitzer Klinik, Gttingen
that pancreatic stent placement reduced PEP in patients with an University Teaching Hospital, Northeim, Germany
6
Departments of Gastroenterology and Hepato-Pancreatology, Erasme
intact papilla undergoing SOM and when the manometry results University Hospital, Universit Libre de Bruxelles, Brussels, Belgium
were normal [176]. 7
Department of Gastroenterology, Silesian Academy of Medicine, Medykw,
New information since 2009: Katowice, Poland
8
Division of Gastroenterology and Hepatology, University of North Carolina,
Recent data suggest that rectal NSAIDs are at least as effective as Chapel Hill, North Carolina, USA
pancreatic stents in patients with SOD [34, 44, 107]. However, the 9
Digestive Endoscopy Unit, Catholic University, Rome, Italy
10
most evidence-based approach for preventing PEP in high risk Department of Gastroenterology and Hepatology, Elisabethinen Hospital,
Linz, Austria
cases remains the combination of rectal NSAIDs and prophylactic
pancreatic stenting. In the RCT mentioned above, patients who
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Guideline 799

Prophylaxis of post-ERCP pancreatitis:

Institutions Institutions are listed at the end of article.

4.2. Risk stratification New information since 2009:

First author, Studies, n PEP incidence OR NNT Comments

6. Pancreatic stent placement for PEP prophylaxis

7.1.3. Contrast medium (Evidence level 1 + + ). The wire-guided technique is recommen-

Background: New information since 2009:

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