risk factors associated to endoscopic retrograde
TRANSCRIPT
Department of Gastrointestinal Surgery, Abdominal Centre
Helsinki University Hospital
Helsinki, Finland
Doctoral Program in Clinical Research
University of Helsinki
Helsinki, Finland
RISK FACTORS ASSOCIATED TO ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY RELATED COMPLICATIONS
Shamel Ismail
ACADEMIC DISSERTATION
To be presented, with the permission of the Faculty of Medicine of the University of Helsinki, for public examination in
Lecture room 2, Haartman Institute, on 18 December 2020, at 12 noon.
Helsinki 2020
SUPERVISORS:
Docent Leena Kylänpää, M.D., Ph.D.
Department of Gastrointestinal Surgery, Abdominal Centre
Helsinki University Hospital and University of Helsinki
Helsinki, Finland
Docent Marianne Udd, M.D., Ph.D.
Department of Gastrointestinal Surgery, Abdominal Centre
Helsinki University Hospital and University of Helsinki
Helsinki, Finland
REVIEWERS: Professor Juha Saarnio M.D., Ph.D.
Department of Surgery
Cancer and Translational Medicine Research Unit
University of Oulu and Oulu University Hospital
Oulu, Finland
Professor Tuomo Rantanen M.D., Ph.D.
Faculty of Health Sciences
University of Eastern Finland
Kuopio, Finland
OPPONENT: Docent Urban Arnelo M.D., Ph.D.
Department of Surgery, Umeå University Hospital, Umeå, and
Division of Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden
ISBN 978-951-51-6883-2 (paperback)
ISBN 978-951-51-6884-9 (PDF)
http://ethesis.helsinki.fi
Unigrafia Oy
Helsinki 2020
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To Omar and Sami
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Table of Contents
ORIGINAL PUBLICATIONS ........................................................................................................................................... 6
1. ABSTRACT ............................................................................................................................................................... 7
2. ABBREVIATIONS ..................................................................................................................................................... 9
3. INTRODUCTION .................................................................................................................................................... 11
4. LITERATURE REVIEW ............................................................................................................................................. 12
4.1 INDICATIONS OF ERCP ................................................................................................................................................. 12
4.1.1 Primary sclerosing cholangitis (PSC) ............................................................................................................... 13
4.1.2 Familial adenomatous polyposis (FAP) ........................................................................................................... 14
4.2 BILIARY CANNULATION .................................................................................................................................................. 14
4.2.1 Primary technique ........................................................................................................................................... 14
4.2.2 Standard cannula or sphincterotome with a guidewire or contrast ............................................................... 14
4.2.3 Pancreatic guidewire-assisted biliary cannulation (PGW) .............................................................................. 15
4.2.4 Precut papillotomy .......................................................................................................................................... 16
4.2.5 Transpancreatic biliary sphincterotomy (TPBS) .............................................................................................. 17
4.2.6 The pancreatic duct stent technique ............................................................................................................... 18
4.2.7 Papillectomy as a cannulation technique ........................................................................................................ 18
4.3 PROCEDURES DURING ERCP .......................................................................................................................................... 18
4.3.1 Biliary procedures ............................................................................................................................................ 18
4.3.2 Pancreatic procedures ..................................................................................................................................... 20
4.3.3 Cannulation and Sphincterotomy of minor papilla ......................................................................................... 20
4.3.4 Papillectomy to treat ampullary adenomas .................................................................................................... 21
4.4 CLASSIFICATION OF ERCP COMPLICATIONS ....................................................................................................................... 22
4.5 POST ERCP PANCREATITIS (PEP) ................................................................................................................................... 24
4.5.1 Incidence ......................................................................................................................................................... 24
4.5.2 Pathophysiology .............................................................................................................................................. 24
4.5.3 Operator-related risk factors .......................................................................................................................... 24
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4.5.4 Patient related risk factors .............................................................................................................................. 25
4.5.5 Procedure-related risk factors ......................................................................................................................... 25
4.5.6 Prevention ....................................................................................................................................................... 26
4.6 TECHNIQUE MODIFICATION TO PREVENT PEP .................................................................................................................... 26
4.6.1 Guidewire vs. contrast into the pancreatic duct ............................................................................................. 26
4.6.2 Contrast medium ............................................................................................................................................. 27
4.6.3 Difficult cannulation ........................................................................................................................................ 27
4.6.4 Intraoperative CBD cannulation ...................................................................................................................... 28
4.6.5 Pancreatic stent placement for PEP prophylaxis ............................................................................................. 29
4.7 MEDICATIONS AND HYDRATION TO PREVENT PEP .............................................................................................................. 30
4.7.1 Nonsteroidal anti-inflammatory drugs (NSAIDs) ............................................................................................ 30
4.7.2 Somatostatin and octreotide .......................................................................................................................... 30
4.7.3 Other medications ........................................................................................................................................... 31
4.7.4 Hydration ........................................................................................................................................................ 32
4.8 BLEEDING................................................................................................................................................................... 33
4.8.1 An endoscopic papillary balloon dilatation (EPBD) as an alternative to sphincterotomy ............................... 34
4.9 CHOLANGITIS .............................................................................................................................................................. 35
4.10 PERFORATION ........................................................................................................................................................... 36
4.11 STENT RELATED COMPLICATIONS ................................................................................................................................... 39
4.12 PERFORMANCE MEASURES (PMS) FOR ERCP ................................................................................................................. 39
4.13 ROUTINE PREOPERATIVE LABORATORY TESTING (RPLT) ..................................................................................................... 40
5. AIMS OF THE STUDY ............................................................................................................................................. 42
6. MATERIALS AND METHODS .................................................................................................................................. 43
6.1 STUDY I ..................................................................................................................................................................... 43
6.2 STUDY II .................................................................................................................................................................... 44
6.3 STUDY III ................................................................................................................................................................... 46
6.4 STUDY IV ................................................................................................................................................................... 47
6.5 STATISTICAL ANALYSIS ................................................................................................................................................... 48
7. RESULTS ................................................................................................................................................................ 50
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7.1 STUDY I ..................................................................................................................................................................... 50
7.1.1 Cannulation success rate ................................................................................................................................. 50
7.1.2 PEP incidence, predicting and protective factors ............................................................................................ 50
7.1.3 Other complications ........................................................................................................................................ 51
7.2 STUDY II .................................................................................................................................................................... 52
7.2.1 Non FAP benign papillary tumours.................................................................................................................. 52
7.2.2 FAP related papillary tumours......................................................................................................................... 54
7.2.3 Ampullary cancer ............................................................................................................................................ 54
7.3 STUDY III ................................................................................................................................................................... 55
7.3.1 Primary and rescue cannulation methods ....................................................................................................... 55
7.3.2 PEP .................................................................................................................................................................. 57
7.3.3 Difficult cannulation ........................................................................................................................................ 57
7.3.4 TPBS as a rescue method ................................................................................................................................ 58
7.3.5 Other complications ........................................................................................................................................ 58
7.4 STUDY IV ................................................................................................................................................................... 58
7.4.1 Post-ERCP complications ................................................................................................................................. 59
7.4.2 Complications due to sedation ........................................................................................................................ 60
8. DISCUSSION .......................................................................................................................................................... 63
8.1 ERCP FOR PSC PATIENTS (I) .......................................................................................................................................... 63
8.2 ENDOSCOPIC PAPILLECTOMY (II) ..................................................................................................................................... 66
8.3 THE ROLE OF TPBS IN DIFFICULT CANNULATIONS (III) ......................................................................................................... 67
8.4 RPLT FOR ERCP (IV) ................................................................................................................................................... 69
8.5 LIMITATIONS OF THE STUDIES ......................................................................................................................................... 70
9. FUTURE ASPECTS .................................................................................................................................................. 71
10. SUMMARY AND CONCLUSIONS .......................................................................................................................... 73
11. ACKNOWLEDGEMENTS ....................................................................................................................................... 74
12. REFERENCES ........................................................................................................................................................ 76
13. ORIGINAL PUBLICATIONS .................................................................................................................................. 108
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Original publications
1. Ismail, S., Kylänpää, L., Mustonen, H., Halttunen, J., Lindström, O. K., Jokelainen, K., Färkkilä, M. A. (2012). Risk factors for complications of ERCP in primary sclerosing cholangitis. Endoscopy, 44(12), 1133-1138. https://doi.org/10.1055/s-0032-1325677
2. Ismail, S., Udd, M., Järvinen, H., Halttunen, J., & Kylänpää, M-L. (2014). Endoscopic papillectomy, single-centre experience. Surgical Endoscopy, 28(11), 3234-3239. https://doi.org/10.1007/s00464-014-3596-5
3. Ismail, S., Udd, M., Lindström, O., Rainio, M., Halttunen, J., & Kylänpää, L. (2019). Criteria for difficult biliary cannulation: start to count. European Journal of Gastroenterology and Hepatology, 31(10), 1200-1205. https://doi.org/10.1097/MEG.0000000000001515
4. Jokelainen, J., Ismail, S., Kylänpää, L., Udd, M., Mustonen, H., Lindström, O., & Pöyhiä, R. (2019). Effect and Predictive Value of Routine Preoperative Laboratory Testing for Endoscopic Retrograde Cholangiopancreatography. Scandinavian Journal of Surgery. https://doi.org/10.1177/1457496918822616
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1. Abstract
Endoscopic retrograde cholangiopancreatography (ERCP) is a minimally invasive procedure
for biliary and pancreatic disorders. It has evolved to predominantly therapeutic procedure
with the diagnosis of primary sclerosing cholangitis (PSC) being one of the main exceptions.
ERCP has the high potential for complications, like post ERCP pancreatitis (PEP), bleeding,
cholangitis and perforation. Therefore, the data concerning the risk factors of ERCP is
essential. The roles of preoperative laboratory testing and the new criteria of difficult biliary
cannulation are poorly studied. ERCP plays also the major role in the endoscopic removal of
papillary tumours (European Society of Gastrointestinal Endoscopy, European Association
for the Study of the Liver, 2017).
The main purpose of this study is to assess the safety of ERCP for different groups of
patients, and the adverse effects that can follow. Additionally, the study examines the effect
of using different tools during the procedure on the complication rate and the means to
minimize the complication rates in the future. The main complications after ERCP are post
ERCP pancreatitis (PEP), bleeding, cholangitis and perforation.
The risk factors of ERCP complications in 441 consecutive PCS patients were retrospectively
analysed. The outcome of 61 endoscopic papillectomies was retrospectively studied in study
II. In the prospective study (III) of 821 consecutive patients with native papilla were evaluated
the complication rates in difficult cannulation cases. To evaluate the relationship between
ERCP complications and the need for routine preoperative laboratory tests (RPLT) before
the ERCP procedure, we conducted prospective study (IV) with 1196 patients.
In PSC patients (study I) the PEP and cholangitis rates were 7 and 1.4 %, respectively. PEP
predictive factors are female sex (Odds ratio 2.6, p=0.015), and a guide wire slipping in the
pancreatic duct (PD) (Odds ratio 8.2, p<0.01). The risk of PEP is directly proportional to the
number of times the guide wire slips into the pancreatic duct. A previous endoscopic biliary
sphincterotomy (EST) was found to be a protective factor from PEP (Odds ratio 0.28, p=
0.02). In benign tumours of the papilla (study II), the recurrence rate after resection was
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25.5% (study II). Altogether 5 (9.5%) patients underwent a pancreaticoduodenectomy, and
46 out of 51 (90.5%) were treated endoscopically. Obstruction of the bile duct and jaundice
as a manifestation were risk factors for malignancy (p<0.001). PEP occurred in 6 cases
(9.8%). After a benign tumour resection and placing a stent, the PEP rate decreased
(p=0.045). The bleeding rate was 18%. In study (III), when the primary cannulation method
used to cannulate the bile duct succeeded, the PEP rate was 2.3%, but when the surgeon
used advanced methods to achieve the cannulation, the PEP rate increased up to 13.5%.
The primary cannulation success rate was 79% in the absence of difficult cannulation criteria
compared to 20.4% when at least one criteria was present (p<0.001). Broad RPLT could not
predict the adverse effects of ERCP in study (IV).
In conclusion, the new criteria of difficult biliary cannulation are important because the
complication risk increases with the complexity of cannulation. Endoscopic papillectomy for
benign tumours is feasible and relatively safe. The role of RPLT in safety of ERCP is minimal.
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2. Abbreviations
ASA American Society of Anaesthesiologists
ASGE American Society for Gastrointestinal Endoscopy
BBC Basic blood count
CBD Common bile duct
CI Confidence interval
CT Computed tomography
DGW Double guide wire
EPBD Endoscopic papillary balloon dilation
EPLBD Endoscopic papillary large-balloon dilation
ERC Endoscopic retrograde cholangiography
ERP Endoscopic retrograde pancreatography
ERCP Endoscopic retrograde cholangiopancreatography
EST Endoscopic sphincterotomy
ESGE European Society of Gastrointestinal Endoscopy
EUS Endoscopic ultrasound
FAP Familial adenomatous polyposis
ICU Intensive care unit
IPMN Intraductal papillary mucinous neoplasia
LRS Lactated Ringer’s solution
MRCP Magnetic resonance cholangiopancreatography
NSAID Nonsteroidal anti-inflammatory drug
NSS Normal saline solution
PD Pancreatic duct
PEP Post-ERCP pancreatitis
P-INR International normalized ratio
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PSC Primary sclerosing cholangitis
P-TT Thromboplastin time
PM Performance measures
RCT Randomized control trial
RPLT Routine preoperative laboratory testing
SEMS Self-expandable metal stent
SGW Single guidewire technique
SOD Sphincter of Oddi dysfunction
TPBS Transpancreatic biliary sphincterotomy
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3. Introduction
Endoscopic retrograde cholangiopancreatography (ERCP) is an endoscopic technique in
which a side-viewing upper endoscope is guided into the duodenum, allowing for instruments
to be passed into the bile and pancreatic ducts. Then a contrast injection is applied permitting
radiologic visualization and allowing for a variety of therapeutic interventions. ERCP is a
complex endoscopic procedure since it requires specialized equipment and requires a steep
learning curve to develop proficiency in its use. Its benefits in the minimally invasive
management of biliary and pancreatic disorders are challenged by a higher potential of
serious complications than any other standard endoscopic technique. ERCP is used primarily
to diagnose and treat conditions of the bile ducts and main pancreatic duct,
including gallstones, strictures, and leaks as result of surgery or trauma. In the past ERCP
was performed for diagnostic and therapeutic reasons, but now the ERCP is used rarely for
diagnostic reasons in the presence of safer and relatively non-invasive investigations such
as magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound. In
cases of primary sclerosing cholangitis (PSC), brush cytology is an important method used
to predict timing for transplantation (Vannas et al., 2017).
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4. Literature review
4.1 Indications of ERCP
Choledocholithiasis is the most common reason for undertaking ERCP (Wang, X. et al.,
2017). In pancreatic cancer, biliary obstruction is another common indication for the use of
ERCP (Gohil et al., 2017). When surgery is delayed, patients with pancreatic cancer and with
jaundice complications need preoperative biliary drainage (Singhirunnusorn et al., 2013).
ERCP is used in biliary strictures to obtain brush cytology and intraductal biopsies
(Navaneethan, Njei et al., 2015), and in the diagnosis and management of
cholangiocarcinoma (Fogel et al., 2006; Lindberg et al., 2006).
ERCP is essential in the evaluation and treatment of benign biliary strictures, postoperative
biliary strictures and anastomotic strictures after liver transplantation (Morelli et al., 2003;
Shah et al., 2004; Verdonk et al., 2006; Chang et al., 2016). ERCP should be performed as
first-line therapy for postoperative biliary leakage (Luigiano et al., 2016; Rainio et al., 2018).
Patients with acute biliary pancreatitis and concomitant cholangitis or biliary obstruction need
urgent ERCP (Tse et al., 2012; ASGE Standards of Practice Committee et al., 2019). ERCP
is used in the treatment of pancreatic pseudocysts and pancreatic fluid collections (Lehman,
2002; Tyberg et al., 2016). Additionally, ERCP is used in the treatment of symptomatic
dominant pancreatic duct strictures (Seza et al., 2011), and in case of pancreatic duct
leakage (Kim, S. et al., 2017). ERCP can be used in the treatment of pancreatic stones
following the extracorporeal shock wave lithotripsy in the case of large stones, or without for
small stones (Tandan et al., 2016). In patients with main pancreatic duct intraductal papillary
mucinous neoplasia (IPMN), ERCP is used for cytology (Yoshioka et al., 2016). ERCP with
empiric biliary or pancreatic sphincterotomy is an alternative in evaluation of idiopathic acute
recurrent pancreatitis (suspected type 2 pancreatic SOD) when the findings on an
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endoscopic ultrasound (EUS) or MRCP are normal and do not suggest suspected biliary
stones, sludge, or chronic pancreatitis (Rehman et al. 2013).
It is generally recommended that all patients not undergo routine preprocedure laboratory
testing, chest radiography, or electrocardiography prior to endoscopic procedures. Instead,
preprocedure testing should be used selectively based on the patient's medical history,
physical examination findings, and procedural risk factors (ASGE Standards of Practice
Committee et al., 2014).
We typically obtain laboratory tests prior to the procedure if an intervention is anticipated
(such as sphincterotomy) and blood tests have not been obtained as part of the patient's prior
evaluation. Such tests include a complete blood count and prothrombin time. Also, pregnancy
test for potential pregnancy, coagulation studies for patients with active bleeding and with an
increased risk of bleeding due to medication use, and in patients with prolonged biliary
obstruction. Chest radiograph for patients with new respiratory symptoms or decompensated
heart failure.
4.1.1 Primary sclerosing cholangitis (PSC)
Ampullary adenomas, can occur sporadically or in the context of genetic syndromes such as
FAP. Autopsy series has estimated the prevalence of sporadic ampullary adenoma to be
between 0,04 and 0,12% (Park, S. W. et al., 2000). Benign tumours of the ampulla of Vater
are rare and include lipomas, lymphangiomas, haemangiomas, leiomyofibromas, and
neurogenic tumours. Villous and tubulovillous adenomas, however, remain the most common
such benign lesions (Culver et al., 2011). The frequency of a malignant lesion in an adenoma
of the papilla figures around 11% (Alali et al., 2020).
PSC is a chronic, inflammatory bile duct disease. It may lead to stenosis of the internal and
external bile ducts and as it progresses it blocks the flow of bile and leads to cirrhosis of the
liver. PSC patients usually have underlying inflammatory bowel disease in 7-13% of cases.
Due to increased risk of cholangiocarcinoma (Boberg et al., 2002) the dysplasia surveillance
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using ERC and brush cytology essential to early detection of malignancy (Boyd et al., 2017;
Vannas et al., 2017).
4.1.2 Familial adenomatous polyposis (FAP)
FAP is an autosomal dominant inherited disease, in which hundreds or thousands of
adenomas develop in the colorectum, with a 100 percent risk of developing colorectal cancer.
The incidence of disease is about 2-3 per 100,000 inhabitants (Jarvinen, 1992; Bjork et al.,
1999). The incidence of ampullary tumours in FAP patients is 200-300 fold higher compared
to the general population, with a cumulative risk of up to 10% for carcinoma (Gluck et al.,
2015). The endoscopic papillectomy for benign adenomas is increasingly being performed
(Park, S. W. et al., 2000).
4.2 Biliary cannulation
4.2.1 Primary technique
Standard cannulas with or without a guidewire are limited in their ability to vary the angle of
approach to the papilla. A standard sphincterotome was originally used to allow variable
upward angulation for biliary cannulation. It was bowed to enter the biliary orifice, then
relaxed to achieve deep cannulation (Rossos et al., 1993).
4.2.2 Standard cannula or sphincterotome with a guidewire or contrast
The primary technique to commence ERCP is cannulation with a sphincterotome and
guidewire. Two methods of guidewire assisted cannulation have been used. In the first
method, the sphincterotome is inserted into the papillary orifice and the guidewire is
advanced under fluoroscopic guidance until it is observed to enter the bile duct. In the second
method, the guidewire is advanced 1-2 mm beyond the tip of the cannula and directly pushed
into the papillary orifice in the axis of the common bile duct under fluoroscopic guidance.
Contrast injection is not routinely administered prior to the advancement of the guidewire into
the common bile duct (CBD).
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For the contrast assisted biliary cannulation, the tip of the cannula or the sphincterotome is
inserted into the papillary orifice at the 11-o’clock position and a small volume of contrast is
injected under fluoroscopic guidance to define the anatomy of the CBD.
In 3 meta-analyses that include 4, 7 and 12 randomized control trials (RCT) comparing
contrast assisted and guidewire-assisted biliary cannulation, all favoured the guidewire
technique in terms of its significantly higher success rate. In the meta-analysis by Cheung et
al. the success rate of the guidewire-assisted technique compared to the contrast assisted
technique was 89% vs. 78%, respectively, RR1.19 (95% CI, 1.05-1.35), and in the meta-
analysis by Tse et al. the success rate was 83.6% vs. 77.3%, RR1.07 (95% CI, 1.00-1.15)
(Cheung et al., 2009; Tse et al., 2013).
4.2.3 Pancreatic guidewire-assisted biliary cannulation (PGW)
When the primary cannulation technique fails to achieve cannulation, rescue techniques are
used. PGW is used when the wire unintentionally enters the pancreatic duct (PD). The wire
that has been unintentionally placed in the PD is left in place and then the CBD is cannulated
by using a cannula/sphincterotome with a contrast medium injection. This technique is called
single guidewire technique (SGW). Alternatively, the procedure can be carried out by using
an additional guidewire, which is known as the double guidewire technique (DGW). The wire
in the PD straightens the PD and the common channel and stabilises the papilla and
increases the chances of cannulating the CBD (Freeman et al., 2005).
In one RCT that compared the DGW and persistent standard cannulation technique in difficult
cannulations found a significantly higher success cannulation rate in the DGW group (93%
vs. 54%, P<0.05), with no difference in PEP or other complications (Maeda et al., 2003;
Gronroos et al., 2011). Another RCT comparing DGW to the precut technique found a
significantly higher PEP rate in the DGW group (38% vs. 11%, p=0.01), although there was
no difference in successful cannulation rates (Yoo et al., 2013).
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In a systematic review of 7 RCTs with a total of 577 patients, comparing to other persistent
conventional contrast or guidewire assisted cannulations, the DGW technique was
associated with increased risk of PEP and there was no significant difference in CBD
cannulation success, or in the risk of other ERCP complications (Tse et al., 2017). However,
not all the studies in this meta-analysis were blinded. Additionally, most patients included in
the studies had no NSAID medication administered, and no prophylactic pancreatic stent
was applied. In one RCT the placing of a prophylactic pancreatic stent after DGW cannulation
significantly reduced the risk of PEP (Ito et al., 2010). In another retrospective study, in which
prophylactic pancreatic stenting was tried after every DGW-assisted attempt to cannulate the
CBD, applying the stent was successful in 86% of patients and the PEP incidence rate in this
group was significantly lower compared to the group in which the stenting failed (5% vs. 30%,
p =0.0073) (Ito et al., 2014). DGW is a rescue technique and should be reserved for cases
with difficult cannulation.
4.2.4 Precut papillotomy
Precut papillotomy is a commonly used technique to gain access to the CBD in difficult cases
(Liu, Y. et al., 2012). In one method (the conventional precut technique) a needle knife is
used to access the biliary orifice and a cut is made in the biliary orientation towards 11 o’clock.
Once the bile duct is visualized, cannulation is done through this opening using a needle
knife catheter, sphincterotome, or regular catheter. In the fistulotomy method, the needle
knife accesses the bile duct superior to the orifice in the 11 o’clock direction. A meta-analysis
of 6 RCTs with a total of 966 patients showed a significantly lower rate of PEP in the early
precut group than in the persistent attempt group (OR 0.47, 95% CI 0-24-0.91) (Cennamo et
al., 2010). Another meta-analysis that included 7 RCTs and a total of 1,039 patients, showed
a tendency of a decreased rate of PEP after an early precut, but this was not statistically
significant (3.9 % in the precut sphincterotomy vs. 6.1 % in the persistent attempts group;
OR 0.58, 95 % CI 0.32-1.05; P = 0.08) (Navaneethan et al., 2014). In a prospective,
multicentre trial, 375 patients were randomized in two groups: the early precut group and the
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late precut group. The group with an early precut was found to have a lower PEP rate
compared to the late precut group at 5.4% (10/185) vs. 14.1% (19/135) (Mariani et al., 2016).
A meta-analysis of six RCTs examined two precut techniques. Four RCTs used the
conventional precut method, whereas two RCTs used needle knife fistulotomy. The meta-
analysis showed that fistulotomy significantly reduced the odds of PEP (OR = 0.27, 95 % CI
0.09-0.82, P = 0.02). The overall cannulation rates were comparable between both precut
techniques (OR = 0.90, 95% CI 0.59-1.37, P = 0.62) (Choudhary et al., 2014). Both
techniques are safe and successful but should be performed by experts in high volume
centres.
4.2.5 Transpancreatic biliary sphincterotomy (TPBS)
Transpancreatic biliary sphincterotomy introduced by John S. Goff in 1995, is gaining
popularity as a rescue technique for difficult cannulations (Goff, 1995). After a guidewire
accidentally goes into PD, pancreatic sphincterotomy is done towards 11 o’clock. The
purpose is to make an incision through the septum between the pancreatic and biliary duct,
which exposes the bile duct orifice (Ahmed et al., 2017). This technique requires special
expertise. Three RCTs with a total of 364 patients and two prospective studies with more
than 300 patients suggest that the rate of successful biliary cannulation following TPBS
ranges from 85% to 100% (median 92.9%), and the rate of adverse events ranges from 3.5%
to 20.5% (median 13.1%), with PEP occurring in 3.5% to 22.4% of cases (median 10.4%)
(Catalano et al., 2004; Kahaleh et al., 2004; Yoo et al., 2013; Zang et al., 2014; Lee, Y. J. et
al., 2015). A meta-analysis that included five prospective and eight retrospective studies
comparing TPBS to the precut technique in terms of the success rate and complications
found that the success rate in the precut group was significantly lower (OR 0.50, P= 0.046),
and the bleeding rate was higher (OR 2.24, P= 0.02), with no difference in the PEP rate (OR
0.79, P = 0.24; RR 0.80, P = 0.19) (Pecsi et al., 2017).
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4.2.6 The pancreatic duct stent technique
The pancreatic duct stent technique is an adjunct to the double wire guided method where a
single stent (usually 5Fr x 2-8cm) is placed after an unintentional PD cannulation and then
the BD cannulation is carried out using a guide wire technique. The stent aids in adjusting
the orientation of the bile duct by straightening the distal choledochus to facilitate the biliary
cannulation. In a retrospective study of native papilla, pancreatic stent placement facilitated
bile duct cannulation in 78.9% (60/76) of cases when cannulation by the standard method
was not achieved (Davee et al., 2012).
4.2.7 Papillectomy as a cannulation technique
Farrell et al. described a novel technique in the case of a bulky ampulla. The large size of an
ampulla because of a tumour or overgrowth makes the cannulation of the CBD very difficult
to achieve. In this case, a polypectomy snare and diathermy in a coagulation current were
used to remove the bulky papilla, then the cannulation can be resumed (Farrell et al., 1996).
Ten patients with failed primary cannulations were included in the study. The cannulation
succeeded in all cases. One case of bleeding occurred, and there was no PEP or cholangitis.
However, a larger study is required to compare this technique to other cannulation methods
to assess its effectiveness and safety.
4.3 Procedures during ERCP
4.3.1 Biliary procedures
Biliary sphincterotomy is instrumental for removing bile duct stones, stricture dilation and for
the treatment of papillary stenosis, and in some cases when stent placement is needed
(Foutch, 1991).
Stone extraction from the CBD is the most common procedure during ERCP. In this
procedure a cannula or a sphincterotome is inserted into the CBD and a contrast medium is
injected to visualize the stones. In the case of a CBD stone, biliary sphincterotomy must be
19
done first. Then a balloon catheter or wire basket is used to extract the stone. Large stones
may require fragmentation before extraction. Dilatation and stent placement procedures are
used in cases of stenosis and obstruction of the CBD (Wang et al., 2017).
Using balloons, 6-10mm in diameter to dilatate the papilla up to the distal diameter of CBD,
with or without minor endoscopic sphincterotomy (EST) is a good alternative to EST alone
for patients with coagulopathy and for patients with altered anatomy. In a systematic review
and meta-analysis of 7 RCTs, a total of 369 patients underwent EPBD without EST, and 367
patients underwent EPBD with EST. There were no significant changes in the cannulation
success rate (OR 0.69, 95% CI= 0.44-10.19, p= 0.11), or in the PEP rate (OR 0.88, 95%
CI=0.43-1.78, p=0.72) (Liu, P. et al., 2019).
The only indication for an endoscopic papillary large-balloon dilation (EPLBD) is the
extraction of large choledochal stones. A systematic review of 15 RCTs involving 1,768
patients demonstrated significantly higher rates of PEP with EPLBD of an intact biliary
sphincter performed, compared with biliary sphincterotomy (RR 1.96, 95% CI, 1.34-2.89)
(Weinberg et al., 2006).
A papillectomy is possible to do endoscopically, but has an increased risk of PEP, which can
be reduced by PD stenting (Harewood et al., 2005).
In the case of biliary malignancy, brush cytology of the bile duct is the method of choice.
According to a recent study, the specificity of brush cytology is 90%, and the sensitivity is
56% (Geramizadeh et al., 2018). In the case of PSC, brush cytology is an important method
to determine the timing for transplantation (Vannas et al., 2017).
With per oral cholangioscopy it is possible to carry out manoeuvres under direct visualization
of the CBD. Cholangioscopy with or without directed lithotripsy can clear CBD stones with a
success rate of 73%-93% (Draganov et al., 2011; Kalaitzakis et al., 2012). Cholangioscopy
is also used for targeted biopsies of the bile and pancreatic ducts after undiagnostic brush
cytology or/and a biopsy during ERCP (Parsi, 2014; Navaneethan, Hasan et al., 2015).
20
The complication rate of cholangioscopy ranges between none up to 7.7% including
bleeding, pain and perforation of the bile duct (Lee, Y. N. et al., 2012; Farnik et al., 2014;
Korrapati et al., 2016). A large nationwide study of ERCP procedures with and without
cholangioscopy, showed that the rate of adverse events of ERCP with cholangioscopy was
higher than without it. The PEP rate in this study was 7.4% vs. 3.9% (P =0.003) respectively,
and the cholangitis rate was 4.4% vs. 2.7% (P=0.0332), respectively (Lubbe et al., 2015).
In patients with an altered anatomy (Roux-en-Y total gasterectomy, Billroth II,
pancreaticoduodenectomy, gastrojejunostomy with duodenal obstruction,
hepaticojejunostomy, gastric bypass), an enteroscopy-assisted ERCP (DB-ERCP) is the
recommended procedure. The cannulation success rate using DB-ERCP is up to 97% and
the cholangiogram success rate is 98% according to one study (Shimatani et al., 2009). In
another study of 712 patients with a Billroth II reconstruction, the biliopancreatic duct
cannulation was successful in 93.8% (Bove et al., 2015) of the cases.
4.3.2 Pancreatic procedures
Pancreatic sphincterotomy is used for further manipulations, such as stent placement in the
PD or for better access to the PD in cases of stricture. In cases of papilla stenosis, and in
cases such as the management of pancreas divisum related strictures, the cutting of the
minor papilla will ensure the normal flow of the pancreatic fluid (Sherman et al., 2001; Chacko
et al., 2008 Clarke et al., 2012). Chronic pancreatitis patients, with manifestations such as
pseudocysts and pancreatic fistulas can be treated by PD stenting (Larsen et al., 2014).
4.3.3 Cannulation and Sphincterotomy of minor papilla
In some patients with pancreas divisum, the identification of the minor papilla can be difficult.
As the pancreatic juice secretion increases, the orifice enlarges making the cannulation easy.
A multi-centre randomized controlled trial showed significantly higher successful cannulation
rates after a porcine secretin injection compared to a placebo (89.3% vs. 6.3%, P<0.001)
(Devereaux et al., 2003). A spray of methylene blue in the area the papilla minor is suspected
21
to be makes the identification of the papilla easier (Park, S. H. et al., 2003). In the case of
incomplete pancreatic divisum, an injection of a mixture of contrast media and methylene
blue into the major papilla can help to identify the minor papilla (Park et al., 2003).
There are two technical options for carrying out a pancreatic sphincterotomy of the minor
papilla. The first is a needle-knife cut over a plastic stent and the second is the standard pull-
type cut with a sphincterotome. In the retrospective study by Attwell et al. 133 patients
underwent needle-knife cut surgery and 51 patients underwent pull-type cut surgery. The
median follow-up for the needle-knife group was 6 years. Papillary stenosis for this group
was a rate of 24%. The median follow-up for the pull-type cut group was 5 years, with a
stenosis rate of 20%. The overall complication rates were similar in both groups (8.3% vs.
7.8%) (Attwell et al., 2006). Another technique described in a study by Maple et al. is wire
assisted access sphincterotomy. In this technique, the dorsal duct is deeply cannulated with
a guidewire, then the minor papilla cut is performed using a needle-knife, by cutting away
from the guidewire. This technique was compared with a pull-type cut with no significant
difference in complications (Maple et al., 2009).
4.3.4 Papillectomy to treat ampullary adenomas
A papillectomy is used to treat benign tumours of the papilla because it results in less
morbidity compared to surgery. Additionally, papillectomy is used to achieve a more accurate
diagnosis of the malignancy of ampullary tumours. As in colon cancer, the duodenal
adenoma tend to develop cancer in 30% of cases (Seifert et al., 1992). Although biopsies of
the papilla tumours are easy to obtain during an endoscopy, the accuracy of the biopsies in
cases of carcinoma within the adenoma are still low at 14%-66% (Hwang et al., 2008; Carter
et al., 2009), making the papillectomy of a whole tumour more accurate in order to achieve
a malignant diagnosis. However, in distinct malignant tumours surgery is the gold standard
(Irani et al., 2009). In a systematic review, and meta-analysis of five retrospectives, cohort
studies (446 patients) showed that an endoscopic resection was contraindicated when
malignancy manifestations were presented, such as ulcerations, duodenal infiltrations, lateral
22
spread, polyps sized more than 4 cm or an intraductal extension more than 1 cm (Mendonca
et al., 2016). The complication rate after a papillectomy ranges between 8% and 35% (Ito et
al., 2012; Moon et al., 2014).
4.4 Classification of ERCP complications
Two classifications are available to define the ERCP complications. The first one is the
consensus definition and grading by Cotton et al (Cotton et al., 1991) (Table 1). Another
classification is the revised Atlanta consensus classification of pancreatitis, which grades
pancreatitis into mild with no organ failure and local complications (acute fluid collection
around the pancreas, pseudocyst, acute necrotic collection, pleural effusion), and moderate
with transient organ failure that resolves in less than 48h, with or without local complications,
and severe pancreatitis with single or multiple persistent organ failure for more than 48h
(Banks et al., 2013).
23
Table 1. Consensus definition and grading of ERCP complications
Mild Moderate Severe Pancreatitis Clinical pancreatitis with
blood amylase levels more the 3 times normal and admission time up to 2-3 days
hospitalization time 4-10 days
Hospitalization time more than 10 days, pseudocyst, intervention needed
Bleeding Haemoglobin levels drop less than 3g, no transfusion needed
Transfusion needed (less than 4 units), but no invasive intervention needed (angiography, surgery)
Transfusion (5 units or more) and invasive intervention needed
Perforation Slight leak of contrast or fluid treated by fluids or suction for 3 days or less
Perforation treated medically for 4-10 days
Medical treatment for more than 10 days or percutaneous, surgical intervention needed
Infection Fever more than 38°c for 24-48h
Fever with more than 3 days hospitalisation or percutaneous intervention needed
Septic shock or surgery
(Cotton et al., 1991).
PEP is the most common and serious complication of ERCP with an incidence of 3.5% -9.7%
(Banks et al., 2013). Bleeding usually occurs as a result of sphincterotomy, with an incidence
of 0.3% - 9.6% (Cotton et al., 2010). Cholangitis is the most common infection complication
associated with ERCP. The incidence ranges between 0.5% and 3% (Masci et al., 2001;
Andriulli et al., 2007; Cotton et al., 2009). The incidence of duodenal perforation during the
ERCP is up to 0.6% (Masci et al., 2001; Cotton et al., 2009). Cardiopulmonary complications
are usually related to sedation during ERCP and include aspiration, hypoxia, cardiac
dysrhythmia and hypotension. The incidence of these complications ranges from 0.07% to
2.4% (Glomsaker et al., 2013; Jokelainen et al., 2017).
24
4.5 Post ERCP pancreatitis (PEP)
4.5.1 Incidence
In a systematic review of 21 prospective studies with 16,855 patients, PEP was the most
frequent adverse event following ERCP with an incidence of 3.47% (95% CI, 3.19%, 3.75%).
Of these 44.8% were graded mild, 43.8% moderate and 11.4% were graded severe.
Altogether 3% of patients with PEP died (Andriulli et al., 2007). In another systematic review
that included 13,296 patients, the incidence of PEP was 9.7% (95% CI, 8.6%-10.7%), of
which 5.7% of the cases were mild, 2.6% were moderate and 0.5% were severe. In high-risk
patients and procedures (e.g. involving pancreatic sphincterotomy or precut sphincterotomy,
SOD, or a difficult cannulation), the PEP incidence increased to 14.7% (95% CI, 11.8%-
17.7%), of which 8.6% of the cases were mild, 3.9% were moderate and 0.8% were severe.
The mortality rate was 0.2% (Kochar et al., 2015).
4.5.2 Pathophysiology
The mechanism that causes PEP is still poorly known. Mechanical injury of the papilla during
instrumentation, or hydrostatic injury from the contrast injection into the PD may be a reason.
Chemical and allergic injuries may occur from injections of contrast medium into the PD. A
thermal injury may occur from using electrocautery, which can cause an edema and
obstruction of the PD which disturbs the pancreatic secretion flow. An infection theory was
also suggested. These injuries can lead to the premature intracellular activation of proteolytic
enzymes inside acinar cells triggering an inflammatory cascade, resulting in the
autodigestion of the pancreatic tissue (Freeman et al., 2004; Cheng et al., 2006).
4.5.3 Operator-related risk factors
Operator-related risk factors, including prior experience, case volume, and trainee
participation, have been hypothesized to influence the risk of PEP, but this has been difficult
to evaluate because of confounding variables including the complexity of ERCP at high-
25
volume centres versus low-volume centres. In one prospective study, a total of 3,635
procedures were included, 2,838 (78%) ERCPs were performed in the 11 high-volume
centres (a median of 257 each) and 797 ERCPs were carried out in low-volume centres (a
median of 45 each). Overall, 3,331 ERCPs were carried out by expert operators and 304 by
less-skilled operators. There were significantly more grade 3 difficult procedures in the high-
volume centres than in the low-volume ones (P<0.0001). PEP occurred in 137 patients
(3.8%); the rates did not differ statistically between the high- and low-volume centres (3.9%
vs. 3.1%) and expert and non-expert operators (3.8% vs. 5.5%). However, in the high-volume
centres, there were 25% more patients with patient- and procedure-related risk factors, and
the PEP rate was one-third higher among non-expert operators (Testoni, P. A. et al., 2010).
4.5.4 Patient related risk factors
Patients-related factors include prior PEP, female sex, younger age, normal serum bilirubin
levels and history of acute recurrent pancreatitis and suspected SOD (Freeman et al., 1996;
Cotton et al., 2009; Moffatt et al., 2011; Ding, X. et al., 2015; Chen, J. J. et al., 2014). The
pancreas divisum is an anatomical variation, and by itself is not an independent risk factor
for PEP. However, minor papilla manipulations and sphincterotomies increase the PEP rate
(Moffatt et al., 2011).
4.5.5 Procedure-related risk factors
A difficult cannulation increases the risk of PEP. A difficult cannulation is defined as a
situation, where the procedure performing person, using his regularly used cannulation
technique fails to achieve a BD cannulation in 5 minutes from the first moment that the
guidewire touches the papilla, or after 5 attempts to cannulate the CBD, or after one
unintentional passage or contrast injection into the pancreatic duct (Halttunen et al., 2014).
The above definition of a difficult cannulation has been adopted by the European Society of
Gastrointestinal Endoscopy (ESGE) in their guideline (Testoni, Pier Alberto et al., 2016).
Before that, there was no consensus definition, and different studies adopted different
26
definitions of a difficult cannulation, which made the comparison of the studies very difficult.
In an easy cannulation, when in less than 5 attempts the cannulation of the BD is achieved,
the PEP rate is as low as 3%. In difficult cannulations the PEP rate increases up to 13-15%
(Freeman et al., 1996; Vandervoort et al., 2002). A pancreatic injection is another risk factor
for PEP (Ding et al., 2015).
4.5.6 Prevention
The indication of ERCP must be clear and the patients must be selected to prevent ERCP
complications. An ERCP should be performed on high-risk patients only after careful
consideration. Some of the high-risk groups are the SOD type III patients (patients with a
functional obstruction of the pancreaticobiliary flow at the level of the Oddi, with symptoms
such as right upper quadrant pain, dilated CBD and abnormality in liver enzymes in SOD
type I, pain and only one objective finding for SOD type II, and only pain in SOD type III). The
procedure should not be offered routinely to these patients (Cotton et al., 2014). There is a
surgical saying that the best way to avoid PEP is not to do an ERCP.
4.6 Technique modification to prevent PEP
4.6.1 Guidewire vs. contrast into the pancreatic duct
The guidewire assisted cannulation technique has less PEP compared to the contrast
assisted cannulation technique. In 2009 two meta-analysis of RCTs were published. In the
first, seven RCTs were included. The use of a guidewire in cannulation significantly reduced
the PEP compared to the contrast assisted cannulation group 3.2% vs. 8.7% (relative risk
RR 0.38%, 95% CI 0.19 – 0.76) (Cheung et al., 2009). The second meta-analysis of five
RCTs showed that the wire-guided technique reduced the PEP rate compared to the contrast
assisted group (OR 0.23, 95% CI, 0.13-0.43) (Cennamo et al., 2009). Two RCTs were later
published but did not confirm the above meta-analysis (Kawakami et al., 2012; Kobayashi et
al., 2013). However, in 2013, another meta-analysis was published that confirmed the
conclusions in Cheung et al. and Cennamo et al.’s meta-analyses. In a large systematic
27
review and meta-analysis by Tse et al. (2013) that included 12 RCTs, a total of 3,450 patients,
showed that the wire-guided technique significantly reduced PEP risks compared with the
contrast-assisted cannulation technique (RR 0.51, 95 % CI 0.32 - 0.82). In addition, the wire-
guided technique had greater primary success rates in CBD cannulations (RR 1.07, 95 % CI
1.00-1.15), fewer precut sphincterotomies (RR 0.75%, 95% CI 0.60-0.95), and no increase
in other ERCP related complications (Tse et al., 2013).
4.6.2 Contrast medium
Injecting a contrast medium into the PD must be avoided, however, if it is required, the dose
should be as low as possible. In the large meta-analysis by Masci et al. that included 15
prospective trials, the injection of a contrast medium into the PD was an independent risk
factor for PEP (RR 2.2, 95% CI 1.60-3.01) (Masci et al., 2003). In another large retrospective
study that included 14,331 ERCPs, the patients were divided into four groups: the first group
contained patients with a CBD injection alone, the second group were patients who had an
injection into the head part of the PD, the third group had an injection into the body part and
the fourth group had an injection up to the tail part of the PD. The results showed that the
risk of PEP was significantly higher in the last three groups compared to the first one (6.9%
vs. 0.8%, P<0.001) (Cheon et al., 2007).
4.6.3 Difficult cannulation
It is well documented that the PEP incidence increases significantly after a difficult
cannulation. The ESGE guideline definition of a difficult cannulation is based on prospective
study by Halttunen et al. and was published in 2014. Altogether 907 cannulations were
performed by expert operators in Scandinavian healthcare centres. The primary cannulation
was achieved in 75% of the patients, with a median time of 0.88 minute (53 sec) and with
maximum of two attempts and no PD passage or injection. The overall cannulation success
was 97.4%, and the PEP rate was 5.3%. The median time for successful cannulation was
1.55 minutes (0.02-94.2 minutes). If the primary cannulation succeeded, the PEP rate was
28
2.8%. After crossover to the second cannulation using different cannulation technique
depending on the choice of the operator, the PEP rate increased up to 11.5%. If the
cannulation was achieved within the first 5 minutes, the PEP rate was 2.6%. For procedures
that lasted longer than 5 minutes, the PEP rate was 11.8%. When the cannulation was
achieved in one attempt, the PEP rate was 0.6%, with two attempts 3.1%, with three to four
6.1%, and with five and more 11.9%. With one accidental PD passage the PEP rate was
3.7%, with two, it was 13.1% (Halttunen et al., 2014). Usually when the cannulation appeared
to be difficult, the operator chose to continue the cannulation with standard methods or
crossed over to another technique such as DGW, pre-cut techniques or TPBS. Another thing
to do if the cannulation fails, is to try later after 24-48 hours, or to ask a more experienced
surgeon to do the cannulation.
4.6.4 Intraoperative CBD cannulation
While the operator tries to achieve a cannulation of the CBD, the guidewire can cause injuries
to the papilla that increases the PEP incidence. Therefore, as few cannulation attempts as
possible are recommended. In a systematic review and meta-analysis by Wang et al. that
included five RCTs and a total of 631 patient with gallbladder and suspected CBD stones,
preoperative vs. intraoperative endoscopic sphincterotomies (rendezvous technique) were
compared. The meta-analysis showed that the PEP incidence was higher in the preoperative
endoscopic sphincterotomy group compared to intraoperative group (RR 2.27, 95 % CI 1.18-
4.40, p = 0.01), with no difference in the success rate of CDB stone clearance (RR 0.96, 95
% CI 0.91-1.01, p = 0.13) (Wang, B. et al., 2013). A prospective nationwide study from
Sweden came to the same conclusion that the intraoperative endoscopic technique reduced
the risk of PEP from 3.6% to 2.2% (OR 0.5, 95% CI 0.2-0.9, P=0.02 (Swahn et al., 2013).
Theoretically, every procedure that facilitates CBD access without causing any trauma to the
papilla, and without cannulation or opacification of the PD, should lower the PEP risk.
According to Swahn et al., the rendezvous technique provides cannulation over a guidewire
during laparoscopic cholecystectomy, avoiding trauma of the papilla, and unintentional PD
29
cannulation. However, intraoperative ERCP during a laparoscopic cholecystectomy prolongs
the operation time and may cause logistical problems.
4.6.5 Pancreatic stent placement for PEP prophylaxis
Two meta-analyses and controlled trials showed that using a pancreatic stent reduces the
PEP rate and severity (Andriulli et al., 2007; Mazaki et al., 2014). A meta-analysis by Mazki
et al. included 14 RCTs, with a total of 1,541 patients who were divided into two groups: the
first group had prophylactic pancreatic stents, and the second had none. The results showed
a significant reduction of PEP in the group with pancreatic stents (RR 0.39 95 % CI 0.29-
0.53, P < 0.001). A nationwide, register-based study of 43,545 ERCPs performed in Sweden
between 2006 and 2014 showed that the patients who received a pancreatic stent ≤ 5 Fr in
diameter had four times more PEP compared to patients who received pancreatic stent > 5
Fr in diameter (OR 3.58; 95% CI 1.40-11.07) (Olsson et al., 2017). In a study by Ito et al. 70
patients who had undergone a DGW assisted cannulation were randomized either to receive
prophylactic pancreatic stenting or not. Pancreatic stenting attempts were successful for 91%
of the patients and the stent had migrated at the end of procedure in 3% of the patients. The
frequency of PEP in the stent group was significantly lower than in the unstented group (3%
vs. 23%, p < 0.05) (Ito et al., 2014).To get the best results and prevent PEP, the stents must
remain in place 12-24 hours according to one randomized, prospective study (Cha et al.,
2013). However, placing a pancreatic stent can be challenging, and in case of failure the PEP
rate increases. A retrospective study which included 146 difficult cannulations showed that
the pancreatic stenting after DGW was successful only in 72% of the cases. The failed
pancreatic stenting cases had significantly higher rates of PEP (30% vs. 5%, P=0.0073) (Ito
et al., 2014). In their meta-analysis Wang et.al. included 23 retrospective cohort studies and
2 RCTs. A sensitivity analysis of the data showed that pancreatic stents significantly reduced
the PEP risk after a papillectomy (OR 0.44, 95% CI, 0.24-0.80, p = 0.007) (Wang, Y. et al.,
2019). Prophylactic pancreatic stenting can be useful in difficult cannulations and for high
risk patients (Berry et al., 2019). The recent ESGE guideline recommends using prophylactic
30
pancreatic stents in selected patients at high risk of PEP (unintentional guidewire insertion
into to the PD, DGW cannulation) (Dumonceau et al., 2020). Phillip et al. in their RCT (167
patients) showed that pancreatic stents significantly reduced the PEP in unselected patients
when an inadvertent cannulation of the PD occurred (OR 0.43; 95% Cl 0.19-0.98, P=0.04)
(Phillip et al., 2019).
4.7 Medications and hydration to prevent PEP
4.7.1 Nonsteroidal anti-inflammatory drugs (NSAIDs)
In a recent meta-analysis of 16 RCTs (6,458 patients), PEP occurred in 170 of 3,226 (5%)
patients in the NSAID group and in 317 of 3,232 (9.9%) patients in the placebo group. A dose
of 100mg of diclofenac or indomethacin was administered rectally immediately before or after
the procedure, and in one RCT an NSAID was administered during the procedure. NSAID
administration significantly reduced the PEP rate (RR = 0.55; 95%, 0.42-0.71; P<0.01). A
subgroup analysis showed that diclofenac was superior to indomethacin in preventing PEP
(RR = 0.32; 95%, 0.19–0.56, P < 0.01). Additionally, the NSAIDs administered rectally post-
ERCP were superior to NSAIDs that were administered pre-ERCP (RR = 0.39; 95% CI, 0.24–
0.63, P < 0.01) (Hou et al., 2017). However, in a multicentre, single-blinded, randomized
controlled trial of 2,600 patients undergoing ERCP, the PEP rate in the group with
indomethacin administered before the procedure was 4%, and in the other group with
indomethacin administered after the ERCP the PEP rate was 8% (RR 0.47; 95% CI, 0.34-
0.66; P< 0.0001) (Luo et al., 2016). Orally and intramuscularly administered diclofenac had
no effect in preventing PEP (Cheon et al., 2007; Park, S. W. et al., 2015). In high-volume,
low-PEP risk ERCP units, diclofenac seems to have no beneficial effect (Rainio et al., 2017).
4.7.2 Somatostatin and octreotide
A meta-analysis of 18 RCTs, and a total of 3,171 patients that compared octreotide vs. a
placebo found no significant difference in the PEP incidence (OR 0.77, 95% CI 0.56-1.05).
However, in a sub-group analysis of 6 RCTs (1470 patients), the dose of octreotide was
31
higher than 0.5 mg compared to the other 12 RCTs. With a high dose the OR of PEP dropped
to 0.45 (95% CI 0.28-0.73; NNT=25). When it came to giving the medication before or after
the procedure, the results were inconclusive (Zhang, Y. et al., 2009). In a more recent meta-
analysis of 11 RCTs, a total of 4,192 patients were divided into a somatostatin group and a
placebo group. In the somatostatin group, a decrease was observed in the incidence of PEP
and hyperamylasaemia (RR = 0.63, 95% CI, 0.40-0.98; P = 0.04) (RR = 0.75, 95% CI, 0.66-
0.84; P < 0.001) regardless of the way that the medication was administered (single bolus,
long-term infusion, or high dosage). When a subgroup analysis was performed according to
the area (6 RCTs in Asia and 5 RCTs in Europe), the six Asian studies showed a significant
decrease of PEP, compared to the studies from Europe (RR = 0.48, 95% CI 0.34-0.69; P <
0.001) (RR = 0.77, 95% CI, 0.37-1.61; P = 0.49), respectively (Hu et al., 2016). The results
in the above-mentioned studies are contradictory. Furthermore the use of somatostatin and
octreotide never became a common practice.
4.7.3 Other medications
A meta-analysis of six randomized controlled trials involving 2,448 patients, four out of six
trials administered corticosteroids intravenously, and the remaining two trials gave them
orally showed that the use of prophylactic corticosteroids did not prevent PEP (OR 1.13: 95%
CI 0.88-1.46) (Bai et al., 2008).
ERCP may activate the proteolytic enzymes of the pancreas, which may contribute to PEP.
Protease inhibitors can prevent enzyme activation and may reduce the PEP rate. According
to a meta-analysis of 18 RCTs evaluating the efficacy of protease inhibitors in reducing PEP,
when ulinastatin was administered in a high dose (equal or > 150,000 unit), the PEP risk
decreased (OR 0.39, 95% CI 0.19-0.81; NNT 6). Additionally, gabexate was effective in high
doses (equal or >150,000 units), and the PEP risk decreased (OR 0.44, 95% CI 0.25-0.79;
NNT7) (Zhang, Z. F. et al., 2010). However, in 2 other meta-analyses the administration of
ulinastatin and gabexate was not associated with a PEP decrease when they were
32
administered in doses of less than 15,000 units (Chen et al., 2010; Seta et al., 2011). The
use of protease inhibitors has not become a common practice.
There is no proof that the antibiotics are effective in PEP prophylaxis. In a systematic review
and network meta-analysis of 99 RCTs (25,313 patients), antibiotics were ranked in in fourth
position among 16 drugs for their effect in PEP prophylaxis (OR 0.46; 95% CI 0.15-1.07; NNT
21) (Akshintala et al., 2013). However, the difference between antibiotics and a placebo was
not statistically significant. Only 254 patients were included in the treatment arms of four
RCTs included in the meta-analysis (not 1,082 as stated in the meta-analysis), and two of
these RCTs did not have PEP prophylaxis as their primary study endpoint.
In patients with contraindications for NSAID and for aggressive hydration, the ESGE
guideline recommends using 5mg of sublingual glyceryl trinitrate before ERCP to prevent
PEP (Dumonceau et al., 2020). A meta-analysis of 11 RCTs (2,095 patients) showed that
the overall PEP incidence decreased in patients who had 2-5mg of glyceryl trinitrate (RR
0.67, 95%Cl 0.52-0.87) (Ding, J. et al., 2013).
4.7.4 Hydration
In patients with contraindications for NSAIDs, aggressive hydration during and after ERCP
may reduce the PEP rate. Contraindications to hydration are patients >80 years old, patients
with heart failure, advanced renal failure, and patients with advanced chronic obstructive
pulmonary disease. The amount of fluid used in hydration was 35-45ml/kg administered over
a period of 8–10h (Dumonceau et al., 2020). In a meta- analysis of three RCTs with a total
of 722 patients, the aggressively hydrated group had a lower incidence of PEP overall (OR
= 0.29, 95% CI 0.16-0.53), and a lower incidence of moderate and severe PEP (OR = 0.16,
95% Cl 0.03-0.96) (Wu et al., 2017). Another meta-analysis of 7 RCTs with a total of 1,047
patients showed that aggressive hydration using lactate Ringer’s solution (LRS) reduced the
PEP rates compared to a standard hydration group (OR = 0.47, 95% Cl 0.30-0.72, P=0.0006)
(Zhang, Z, et al., 2017). A recent RCT with a total of 395 patients reported a significant
33
decrease in PEP rates in an LRS group compared to a standard hydration group (3.0% vs.
11.6%, P=0.03) (Park, C. H. et al., 2018).
4.8 Bleeding
Bleeding is the second most common, serious complication of ERCP, with an estimated rate
of 0.3-2% depending on the definition adopted in the study. Bleeding after ERCP usually
occurs after biliary or/and pancreatic sphincterotomy (Freeman et al., 2001; Cotton et al.,
2009). The classification and grading of bleeding are set in the consensus document by
Cotton et al. based on the number of transfused blood units, and the need for angiographic
or surgical intervention. Mild bleeding is an event when clinical evidence of bleeding occurs
(melena, hematemesis) and the haemoglobin drops by less than 3g/dl, and there is no need
for a transfusion. Moderate bleeding is a situation where ≤ 4 units are needed for transfusion,
but there no need for angiographic or surgical intervention. In the severe form of bleeding ≥
4 transfusion units are needed, or angiographic or/and surgical intervention is involved
(Cotton et al., 1991) (Table 1). In a prospective study by Freeman et al., 2,347 patients
underwent ERCP, mainly for the removal of stones (85%). The incidence of bleeding was
2% (mild 0.6%, moderate 0.9%, severe 0.5%). Death from bleeding occurred in 2 cases with
Child-Pugh class C cirrhosis. The independent risk factors for bleeding included the presence
of coagulopathy (OR 3.32, P<0.001), active cholangitis (OR 2.59, P<0.001), anticoagulant
therapy during the next 3 days after ERCP (OR 5.11, P<0.001), and an endoscopist with one
or fewer ERCPs per week (OR 2.17, P=0.002). The use of Aspirin or NSAIDs were not risk
factors in a multivariable analysis (Freeman, 1997). Avoiding the risk factors mentioned will
probably reduce the risk of bleeding. In a multicentre, prospective study with 2,013 patients,
and a total of 2,444 procedures, the bleeding rate was 1.22%, and no death cases from
bleeding occurred. The only significant risk factors for bleeding were precut sphincterotomy
and a stenosis of the orifice of the papilla (Masci et al., 2001). A meta-analysis of four RCTs
shows that the bleeding risk is significantly higher in the pure cut group (28.9%, 95% CI 16.3-
41.4), compared to mixed current (9.4%, 95% CI 2.1%-16.8%) (Verma et al., 2007).
34
4.8.1 An endoscopic papillary balloon dilatation (EPBD) as an alternative to
sphincterotomy
The bleeding rate can be minimized by avoiding EST. EPBD is an alternative to EST when
there is no contraindication for EPBD. An EPBD preserves the function of the sphincter of
Oddi and prevents duodenobiliary reflux and the bacterial colonization of the bile duct, which
can cause stone recurrence and cholangitis (Isayama et al., 2003; Tsai et al., 2018). In a
meta-analysis by Liu et al. including 10 RCTs with a total of 1,451 ERCPs, the success rates
of stone removal in sphincterotomy and EPBD groups were similar (94.6% vs. 95.9%; OR
0.99, 95% CI 0.98-1.01). However, the EPBD group more frequently required mechanical
lithotripsy (35.0% vs. 26.2%; OR 1.31, 95% CI 1.13-1.51). Bleeding was significantly lower
in the EPBD group (0.1% vs. 4.2%, P <0.00001), but the PEP rate was higher (9.4% vs.
3.3%, P<0.00001) (Liu et al., 2012).
Another Meta-analysis with 14 RCTs (1,975 patients), showed that the bleeding rate was
significantly lower in an EPBD group comparing to a sphincterotomy group (0.2% vs. 3.4%,
P<0.01), and the PEP rate was higher (9.1% vs. 3.4%, P<0.0001). There were fewer
complete stone removals in the EPBD group (92.4% vs. 95.1%, OR 0.64, 95% CI 0.24-0.96),
and more frequent use of stone extraction baskets (OR 1.91, 95% CI 1.41-2.59), especially
when the stone diameter was larger than 8 mm. The stone recurrence rate in the EPBD group
was less than in the sphincterotomy group (6.6% vs.12.7%, OR 0.48, 95% CI 0.26-0.90)
(Zhao et al., 2013). A third meta-analysis separately compared four RCTs (923 patients) that
used balloon dilation for less than 1 minute (short EPBD) vs. sphincterotomy, and seven
RCTs that used balloon dilation for more than 1 minute (long EPBD) vs. sphincterotomy. The
overall adverse events rate was higher for the short EPBD group compared to long EPBD
group (OR 1.71, 95% CI 0.67-4.35) (OR 0.61, 95% CI 0.36-1.04), respectively. Compared to
EST group the PEP rate was higher in the short EPBD group (OR 3.87, 95% CI 1.08-13.84),
while the PEP rate was not higher in the long EPBD group (OR 1.14, 95% CI 0.56-2.35) (Liao
et al., 2012). In the above-mentioned meta-analysis, a study that compared 1-minute EPBD
35
vs. 5 minutes EPBD showed that the PEP rates were lower in the 5 minutes EPBD group
(4.8% vs.15.1%, P=0.038) (Liao et al., 2010).
4.9 Cholangitis
Cholangitis is the most common infectious post-ERCP adverse event. The definition of
cholangitis is based on the consensus definition by Cotton et al. In mild cholangitis, patients
have a fever of >38ºC for 24 to 48 hours. In moderate cholangitis febrile or septic illness
requires more than three days of hospital treatment or endoscopic or percutaneous
intervention. In severe cholangitis, septic shock emerges, or surgery is required (Cotton et
al., 1991) (Table 1). The symptoms of cholangitis are upper abdominal pain, fever, and
jaundice. The most common cause is a failure of complete drainage of the obstructed and
infected biliary system. The incidence of cholangitis ranges between 0.5-3% (Andriulli et al.,
2007; Cotton et al., 2009). In a malignant hilar obstruction of the bile duct, and in cases of
PSC, the risk of cholangitis rises because of the difficulty to achieve complete drainage
(Rerknimitr et al., 2002; Paik et al., 2009). In their study Freeman et al. identified three
significant risk factors in a univariate analysis: combined percutaneous-endoscopic
procedures (P< 0.001), malignant strictures stenting (P<0.001), failed biliary access or
drainage (P<0.001) (Freeman et al., 1996).
Prophylactic antibiotics must be considered before ERCP when bile duct obstruction is
suspected or incomplete biliary drainage is expected, and when extracorporeal shock wave
lithotripsy is used to clear a CBD stone (Manes et al., 2019). According to ESGE guidelines,
prophylactic antibiotics must be given before ERCP to all patients with biliary occlusion and
anticipated incomplete biliary drainage, also to patients with pancreatic pseudocysts, and
patients with a history of previous cholangitis (Dumonceau et al., 2020). In a meta-analysis
that included nine RCTs with a total of 1,573 patients, the fixed-effect meta-analyses
significantly favoured the use of prophylactic antibiotics in preventing cholangitis (RR 0.54,
95% CI 0.33-0.91), septicaemia (RR 0.35, 95% CI 0.11-1.11), and bacteraemia (RR 0.50,
36
95% CI 0.33-0.78) (Brand et al., 2010). In cases of malignancy, the unilateral drainage of the
biliary tree has higher rates of cholangitis compared to bilateral drainage (De Palma et al.,
2001), so it is recommended to use non-invasive imaging (MRCP) to plan selective guidewire
access before ERCP (Freeman et al., 2003). In cases of large stones in the bile duct, if stone
fragment clearance is not achieved, it is recommended to place a stent in the biliary tract to
reduce the cholangitis rate. Cholangitis can also be a delayed complication after a plastic or
metallic stent placement (Sawas et al., 2015). The stent obstruction can occur from sludge,
the growth of tumour tissue through the stent, migration of the stent, or from stone fragments.
The selection of the stent (metal, plastic) must depend on the aetiology and location of the
stricture, the patient survival, and the response to prior therapy (ASGE Technology
Assessment Committee et al., 2013). In cases of a malignant extrahepatic obstruction, the
ESGE recommends using a self-expandable metal stent to prevent the stent obstruction and
the possible cholangitis that can occur due to obstruction, which can delay the adjuvant
treatment later on (Dumonceau et al., 2018). Other infectious events such as cholecystitis,
duodenoscope-related transmission of infection, infective endocarditis, are less frequently
observed (Rahman et al., 2019).
4.10 Perforation
The incidence of perforation during ERCP is approximately 0.08 to 0.6% (Masci et al., 2001;
Cotton et al., 2009). A summary of 21 prospective studies with a total of 16,855 patients who
underwent ERCP, showed that the incidence rate of perforation was 0.6% (101 patients),
with 10 deaths (0.06%) (Andriulli et al., 2007).
Perforation is defined as the presence of air or contrast in the retroperitoneal space or in the
abdominal cavity that appears after the procedure. In the mild (defined) form of perforation,
a slight leak of contrast is observed and should be treated for 3 days conservatively. The
moderate (defined) form should be treated for 4-10 days conservatively, and the severe form
occurs when treated for more than 10 days and an intervention is needed (percutaneous or
37
surgical) (Cotton et al., 1991) (Table 1). Another classification that is based on the location
and the mechanism of the perforation is widely used (Stapfer et al., 2000) and divides
perforation into four types: A type I perforation is duodenal wall perforation caused usually
by the duodenoscope. A type II perforation is a retroperitoneal periampullary perforation after
biliary or pancreatic sphincterotomy and a type III is a perforation of the bile or pancreatic
duct caused by instrumentation, which can be noticed when the guidewire or contrast leak
out from the duct. A type IV perforation is when retroperitoneal air alone is the only
manifestation of complication.
In a retrospective study of 9,880 ERCPs, the perforation rate was 0.4% (44 patients), and
type II was the most common perforation 68% (30 patients) (Polydorou et al., 2011). Vezakes
et al. reviewed 18 mainly retrospective studies, performed in the 2000-2014 period, which
addressed only post-ERCP perforation. A total of 142,847 patients were included. The overall
incidence of perforation was 0.39% (95% CI 0.34-0.69), from which type I perforation
occurred in 25% of the cases, type II in 46% and type III in 22% of cases. The overall mortality
was 7.8% (95% CI 3.80-13.07) (Vezakis et al., 2015). The risk factors of perforation were
identified in a large retrospective study that included 9,314 procedures. Perforation occurred
in 33 cases. The risk factors for perforation according to a univariate analysis were EST (OR
9.0, 95% CI 3.2-28.1), SOD (OR 3.8, 95% CI 1.4-11.0), and dilated CBD (OR 4.07, 95% CI
1.63-10.18, P=0.003). In a multivariate analysis, other predictive factors were the duration of
the procedure (OR 1.021, 95% CI 1.006-1.036) and biliary stricture dilation (OR 7.2, 95% CI
1.84-28.11) (Enns et al., 2002).
The location of the perforation was in the periampullary area in 65% of the cases, in the bile
ducts in 25% of cases, and in the PD in 1.4% of cases (Paspatis et al., 2014).
Symptoms of perforation are severe epigastric and back pain, epigastric tenderness, fever
and tachycardia. Additionally, subcutaneous emphysema can occur. When retroperitoneal
air is present (Type IV) in the CT scan, but there are no symptoms, the patient needs no
38
further intervention (Vezakis et al., 2015). This kind of finding in the absence of symptoms
can be found in 13% - 29% of patients who have undergone EST (Genzlinger et al., 1999).
The diagnosis of perforation can be made during the ERCP. In a review of 437 cases from
15 studies, the diagnosis was made during the ERCP in 73% of cases (Vezakis et al., 2015).
In cases with a type I perforation, the diagnosis is usually obvious with symptoms of
peritonitis. In cases with severe pain after ERCP, a differential diagnosis between PEP and
perforation should be made. When perforation is suspected, a CT scan with oral contrast
should be considered (de Vries et al., 1997). If the perforation is discovered during the
procedure or within 12 h after the procedure, and the patient’s condition is stable, endoscopic
treatment should be considered using a stent. In type II cases, biliary drainage is essential
to prevent leakage of bile into the perforation site. In one study, 5 out of 13 cases of type II
perforation were managed successfully using a plastic biliary stent or percutaneous
transhepatic biliary drainage (Enns et al., 2002). In another study, 12 out of 30 cases had
nasobiliary drainage (Alfieri et al., 2013). Other studies reported the advantage of using the
fully covered self-expandable metallic stents which cover the laceration and permit free flow
of the bile into the duodenum (Park, W. Y. et al., 2012; Lee, S. M. et al., 2014; Odemis et al.,
2016). Vezakis et al. reviewed 11 studies with a total of 142,847 patients. After initial non-
surgical treatment for type II and type III patients, surgery was required later in 29/137 (21%)
cases for type II patients, with an overall mortality of 9.4%. The mortality rate for those
patients who underwent surgery was 38%. In surgery it is important to close the perforation,
and if necessary also carry out bile and gastric fluid diversion. For type III patients, non-
surgical treatment was successful for all of them (Vezakis et al., 2015). In another study, non-
surgical treatment was successful in 93% of type II and type III patients with a mortality rate
of 0.6% (Machado, 2012).
39
4.11 Stent related complications
The most common complications of stenting are occlusion and migration of the stent. The
migration rate is 5-10% and occurs predominantly distally (Bagul, P. et al., 2010). Distally
migrated stents rarely cause a problem, whereas proximally (into the duct) migrated stents
can be challenging to remove, and in a few cases surgical intervention may be needed. The
occlusion rate of migrated stents can be as high as 30-40% (Ferreira et al., 2010; Decker et
al., 2011). Although no equipment has been specially designed for stent retrieval
endoscopically, devices such as polypectomy snares, stone extraction baskets, dilating
balloons and foreign body retrieval forceps have been used to extract stents. Peroral
cholangioscopy and pancreatoscopy devices (biopsy forceps, snares and baskets) are
valuable tools when plastic stents are migrated intraductally. Uncovered self-expandable
metal stents (SEMSs) migrate less frequently (< 1%) because of the large diameter and the
tissue growth through the stent (Yang et al., 2009). In cases of malignant BD occlusion, the
use of SEMS results in longer stent patency, compared to plastic stents (Almadi et al., 2017;
Moole et al., 2017). Antimigration stent designs, such flared ends and anchoring flaps, have
been created to limit the migration of the covered SEMS. In pilot studies, antimigration stents
have yielded promising results in patients with benign strictures (Park, D. H. et al., 2011;
Hamada et al., 2015; Minaga et al., 2016).
4.12 Performance measures (PMs) for ERCP
PMs are the measures that should be followed to minimise the adverse effects of the
procedure and make it safer to the patient. These measures according to the ESGE are the
following:
1. A prophylactic antibiotic should be given only to selective patients, e.g.
immunosuppressive patients, or patients with hilar tumour or PSC. Routine antibiotic use
is not recommended (Dumonceau et al., 2020). A systematic review of nine RCTs
concluded that prophylactic antibiotics decreased the post ERCP cholangitis rate in cases
40
where an ERCP had failed to relieve the obstruction of the BD, but if the biliary obstruction
had been relieved there was no significant decrease in the cholangitis rate (Brand et al.,
2010), meaning that relieving the obstruction is the reason why patients did not have
cholangitis and did not require the use of antibiotics.
2. The successful cannulation of the BD should be achieved using all available tools and
techniques. Failure in BD cannulation increases the rate of adverse events (Bailey et al.,
2008).
3. In cases of biliary obstruction below the hilum, a successful stent placement reduces the
rate of adverse events (van Berkel et al., 2004).
4. For BD stones <10mm in size, the clearance rate should be at least 90%. Using the
available tools such as balloon/basket extractors and balloon dilatators for the papilla
increases the stone clearance success rate (Kuo et al., 2012; Oppong, Romagnuolo, &
Cotton, 2012). The cholangitis rate increases in cases of incomplete stone clearance.
5. PEP is the most common and serious complication; therefore, the PEP rate is a good
quality indicator of ERCP. According to the ESGE, the PEP rate should be below 10%
(Domagk et al., 2018). A systematic review of RCTs documented an overall PEP rate to
be 9.7% in low risk patients, and 14.7% for high risk patients (Kochar et al., 2015). Using
a rectally administered NSAID before the ERCP and placing a prophylactic stent in the
PD in high risk patients, reduces the risk of PEP.
4.13 Routine preoperative laboratory testing (RPLT)
Many studies have shown that RPLT is outdated, because of the small impact on the
perioperative outcomes. In one trial, 1,061 patients who underwent various ambulatory
surgeries were randomized into non RPLT and indicated RPLT groups. The RPLT test
battery included a complete blood count, electrolytes, blood glucose, creatinine, an
electrocardiogram, and chest radiograph according to the Ontario Preoperative Testing Grid.
There was no difference in the perioperative adverse effects, or in adverse effects over the
next 30 days after the procedure (Chung e al., 2009). From a national surgical quality
41
improvement programme, patients who underwent elective hernia repair, were collected
(N=73,596). For 63.8% of the patients, preoperative testing was performed. Of these
patients, at least one abnormality was recorded in 61.6% of the patients. In patients with no
solid indication for testing, 54% of them had at least one test. Neither the results of testing,
nor abnormal results were correlated with postoperative outcomes (Benarroch-Gampel et al.,
2012). However, for a selected group of patients with underlying diseases and for patients
with risk factors that can affect the procedure, selective testing is appropriate (Czoski-Murray
et al., 2012). For patients with chronic diseases (e.g., complicated diabetes mellitus, heart
failure, chronic kidney disease, liver disease), measuring of the electrolytes and creatinine
levels should be considered. A complete blood count is recommended for patients with
probable anemia (e.g., chronic kidney and liver diseases, chronic inflammatory conditions),
or for patients with clinical manifestations of anemia, or when there is a high risk of bleeding
during the procedure (Committee on Standards and Practice Parameters et al., 2012; O'Neill
et al., 2016). Coagulation testing should be reserved for patients with haematopoiesis
conditions, and patients on anticoagulants, or patients with history of underlying coagulation
disorders (Chee et al., 2008: ASGE Standards of Practice Committee et al., 2014).
Numerous studies and guidelines outline lack of evidence for benefit in routine preoperative
testing (e.g., chest X-ray, echocardiogram) in low risk surgical patients. Economic analyses
suggest significant potential cost savings from implementation of guidelines (Chung et al.,
2009; Benarroch-Gampel et al., 2012).
42
5. Aims of the study
The influencing factors of complications of ERCP were evaluated. The individual aims of the
study were the followings:
1. To evaluate the risk factors of complications of ERCP in patients with primary
sclerosing cholangitis (PSC).
2. To evaluate the outcomes, effectiveness and safety of the endoscopic resection of
papillary benign and malignant tumours.
3. To evaluate the adverse effects of biliary cannulation in patients with a native papilla.
4. To evaluate the association of Routine Preoperative Laboratory Testing (RLPTs) to
the risk factors of complications in ERCP.
43
6. Materials and Methods
All studies were designed in the Helsinki University Hospital, Abdominal Centre, in the
Department of Endoscopy at Meilahti Hospital. Studies I and II are retrospective studies.
Studies III and IV are prospective studies. The approval of the studies came from the local
Ethics Committee.
Prior to the procedure, 100 mg of diclofenac was given rectally to patients without
contraindications for diclofenac, which has been the general practice since September 2013.
The patients were in the prone position. All the patients were consciously sedated by an
anaesthesiologist. The ERCP related adverse events definition and grading were based on
the consensus criteria developed by Cotton et al. (Cotton et al., 1991).
6.1 Study I
In between 2007-2009, in the Helsinki University Central Hospital (known as the Helsinki
University Hospital, Abdominal Centre since 2015) 3,019 ERCPs were performed, 443 of
these (14.7%) with indications of PSC. In two patients (0.5%) the cannulation failed. The
primary tools used for the ERCPs conducted were a papillotomy knife (Jagtome RX; Boston
Scientific, Miami, Florida, USA) and a 0.035-in, 450 cm guide wire (Jagwire; Boston
Scientific) to gain access to the biliary duct. In cases of failed cannulations using the primary
tools, and in which the guide wire slipped unintentionally into the PD, a pancreatic
sphincterotomy was performed using the papillotomy knife over the guide wire. If cannulation
of the BD was still not achieved, then an oblique cut was made using a needle knife towards
10 o’clock, starting from the upper end of the pancreatic sphincterotomy cut. Once the
cannulation of the BD was achieved, a biliary sphincterotomy was performed in the same
direction. A successful cannulation was confirmed with fluoroscopy. Then a balloon catheter
was inserted into the CBD and the intrahepatic bile tree was filled with contrast. There was
no contrast filling of the PD. Balloon occlusion enhances the visualization of the bile ducts.
44
The strictures of the bile ducts were dilated when indicated, and brush cytology was collected
from the extra- and intrahepatic bile ducts, using 1-4 brushes. All ERCPs were performed by
a specialist. PSC imaging findings were scored according to the study by Ponsioen et al.
(Ponsioen et al., 2002).
The plasma amylase was measured in some cases before the procedure, and for all cases
4-6 hours after the procedure, and after 24 hours if the patient stayed overnight in the
hospital. The ERCP complications, PEP, cholangitis, bleeding, and perforation were
evaluated. The characteristics of the PSC patients are shown in Table 2.
Table 2. Characteristics of 441 patients undergoing ERCP for PSC Risk factors No. of patients Patient related factors Sex F/M 203/238 Age, years >50 115 >30-50 197 ≤30 129 Previous PEP Yes/No 23/418 Previous biliary sphincterotomy Yes/No 147/294 Radiological PSC score 3 89 2 77 1 44 0 227 (ERCP) endoscopic retrograde cholangiopancreatography, (PEP) post ERCP pancreatitis. (PSC) Primary sclerosing cholangitis.
6.2 Study II
Between 2000 and 2012, 61 papillectomies on tumours of the Vater of papilla were
performed. In 35 patients, the tumours were benign without FAP. Sixteen patients with FAP
had benign tumor and 10 patients had malignant tumor of the ampulla. The procedures were
performed by two experts with accumulated expertise of over 200 annual ERCPs. The
characteristics of the patients and tumours are presented in Table 3.
45
First, using a sphincterotome and guide wire the PD was cannulated and a small amount of
methylene blue was injected to mark the orifice and the end of the PD. Using a polypectomy
snare, the tumour was grasped and resected using a blended electrosurgical current (50-60
J). The goal was to perform an en-block resection of the tumour, but when necessary, a
piecemeal resection was performed. After the resection, a 5-7 Fr, 3-7 cm long plastic
pancreatic stent was inserted. The control duodenoscopy was planned after 1, 3 and 6
months. In the first control, the pancreatic stent was removed if still in place.
Table 3. Characteristics of patients and tumours
Benign tumour, FAP Cancer No FAP. n = 35 n = 16 n = 10 Male/female 24/11 9/7 5/5 ASA I 7 0 0 II 10 10 1 III 17 6 7 IV 1 0 2 ERCP Indications Incidental 18 16 0 Jaundice 7 0 9 Anaemia/bleeding 6 0 1 Pancreatitis 4 0 0 Abdominal pain 0 0 0 Tumour size in cm <1 1 0 0 1-2 23 15 5 2-4 7 1 5 >4 2 0 0 Unknown 2 0 0 Histologic diagnosis before resection Low grade dysplasia 24 13 2 High grade dysplasia 8 3 4 Adenocarcinoma 0 0 1
Histologic diagnosis after resection Low grade dysplasia 18 13 0 High grade dysplasia 14 13 0 Adenocarcinoma 0 0 10 Other 3 0 0 ASA: American Society of Anaesthesiology physical status classification. FAP: Familial adenomatous polyposis.
46
6.3 Study III
From March 2011 to September 2014, 1,626 patients with native papilla underwent ERCP.
291 patients were excluded because the primary target was to cannulate the PD. Another
620 patients without cannulation time records were also excluded. A total of 821 patients
were included in the study. The characteristics of the patients are presented in Table 4.
Table 4. Patient characteristics No of patients 821 Age (years) (median, range) 69 (8-102) Male/Female 437/384 BMI; kg/m2 (median, range) 25.7 (12.1-51.9) ASA I 51 (6.2%) II 159 (19.4%) III 424 (51.6%) IV 187 (22.8%) Procedure indication Stone 445 (54%) Stricture 310 (38%) Post cholecystectomy 33 (4%) Post liver transplant 19 (2.3%) Other 14 (1.7%) NSAID prophylaxis 256 (31%) Duodenal diverticulum 93 (11%) Biliary pancreatitis prior to ERCP 78 (9.5%) (BMI) Body mass index; (ASA) American Society of Anaesthesiology physical status classification. (NSAID) non-steroidal anti-inflammatory drug; (ERCP) endoscopic retrograde cholangiopancreatography
The primary cannulation tools were a sphincterotome (Ultratome Boston Scientific), and a
straight wire (Hydrosteer T Jude Medical). The cannulation time was defined as the time
between the first contact and the deep cannulation of the CBD, and this time was recorded.
Cannulation attempts were recorded, and every loss of contact and repositioning were
counted as a new attempt. Passages of the guide wire and injected contrast into the PD were
also counted. In case of difficult cannulations, TPBS was performed if the guide wire was in
the PD. In the TPBS, a pancreatic sphincterotomy incision was made toward the CBD
through the septum between the CBD and PD. If the CBD was still not accessible a needle
47
knife was used to continue the incision from the upper end of the pancreatic sphincterotomy
cut towards 10 o’clock. A difficult cannulation was defined according to the ESGE guidelines
(Testoni et al., 2016). Major adverse effects such as PEP, bleeding, cholangitis, and
perforation were evaluated.
6.4 Study IV
From March 2012 to February 2013, 1,228 patients underwent ERCP. 17 ERCPs performed
on patients under 18 years old were excluded from the study. Another 15 ERCPs performed
in the operation theatre were also excluded. The remaining 1,196 ERCPs were included. The
characteristics of the patients are shown in Table 5.
253 ERCPs were performed by two expert gastroenterologists when PSC was suspected or
was the indication for ERCP. The other 943 ERCPs were performed by 4 expert
gastrointestinal surgeons. Blood was collected for RPLT before the procedure. The RPLT
included basic blood count (BBC), electrolytes (P-NA, P-K), thromboplastin time (P-TT),
international normalized ratio (P-INR) and the plasma total amylase or pancreatic amylase.
4-6 hours after the procedure, the plasma amylase was collected again. If the patient stayed
in the hospital overnight, the amylase was collected again after 24 hours. Indications for the
procedure are shown in Table 5.
48
Table 5. Patients characteristics and indications for ERCP Patients and ERCP Number of ERCP (%) Indications Male/Female 529 (55%)/427 (45%) Median age; years 59 Median BMI; Kg/m2 24.6 Emergency procedures 299 (25%) ASA I 35 (2.9%) II 417 (34.8%) III 582 (48.7%) IV 160 (13.4%) Comorbidities Diabetes 256 (21.4%) Cardio- and cerebrovascular disease 663 (55.5%) COPD 43 (3.5%) Other lung diseases 70 (5.9%) Kidney failure 29 (2.4%) Liver diseases 331 (27.7%) Endocrinal diseases 41 (3.4%) Malignancy 89 (7.4%) Other 391 (32.7%) ERCP Indications Choledocholithiasis 254 (21%) Biliary Stricture 401 (34%) Primary Sclerosing Cholangitis 251 (21%) Chronic pancreatitis 123(10%) Pancreatic pseudocysts 77 (6%) Miscellaneous 41 (3%) ASA: American Society of Anaesthesiologists physical status classification. COPD: Chronic Obstructive Pulmonary Disease.
6.5 Statistical analysis
I. In the first study, the data was analysed using SPSS v 15.0 (IBM Corporation, Somers,
New Work, USA) and by Statexact v. 4.0 (Cytel Software Corporation, Cambridge,
Massachusetts, USA). To test for differences between categorical variables, Fisher’s exact
test was used. A logistic regression was used to calculate odds ratios and P values
(WALD𝑥2) for nominal and ordinal variables. To test for an association between the incidence
of PEP and an ordered categorical variable, the Cochran-Armitage trend test was used. A
nonparametric Wilcoxon-Mann-Whitney test was used to compare differences between
continuous and ordinal variables. The P value was considered statistically significant when it
49
was below 0.05. Professional statistician applied statistics in studies I and IV, and the
researcher applied statistics in studies II and III.
II. The statistical analysis in the second study was performed using IBM SPSS statistics
(version 19.0, Chicago, Illinois, USA) and the results were presented as the median and
range. A Mann-Whitney U test and Pearson’s 𝑥2 test were used to compare the results
between groups. P values below 0.05 were considered significant.
III. SPSS v 15.0 (IBM Corporation, Somers, NY) was used for the data analysis. A chi-square
test was used to test for the difference between categorical variables. A nonparametric
Wilcoxon-Mann-Whitney test was used to compare differences between continuous and
ordinal variables. P values < 0.05 were regarded as statistically significant.
IV. The statistical analysis in Study IV was generated using IBM SPSS Statistics 21
(International Business Machines Corporation, Endicott, NY, USA). The results were
reported as medians and interquartile ranges, or the number of patients and percentages. P
values <0.05 were regarded as statistically significant.
50
7. Results
7.1 Study I
After an ERCP the median length of stay in hospital was 1 day (range, 0-28).
7.1.1 Cannulation success rate
The success rate of the primary CBD cannulation was in 389/441 patients (88.2%). 147
patients (37.8%) had a prior biliary sphincterotomy, which made the cannulation easier. For
patients with native papilla, the primary cannulation rate was 82.3%, whereas for those with
a previous biliary sphincterotomy it was 100% (P<0.001). For 52 patients, the primary
cannulation failed, and in order to achieve the cannulation, TPBS was performed. In 11 cases
of these, a further cut using a needle knife was needed.
7.1.2 PEP incidence, predicting and protective factors
31 patients developed PEP (7%). In 18 cases the disease was mild, in 10 moderate and in 3
severe. One patient with severe PEP was treated in the intensive care unit for 3 days. No
cases of necrotizing pancreatitis were recorded. All patients were treated conservatively.
Patients with PEP, stayed in the hospital for a median of 4 days (range, 2-28). The evaluated
risk factors for PEP are presented in Table 6. From the patient-related factors, the female
sex was a risk factor (OR 2.6, P=0.015). The PEP rate in patients with native papilla was
9.2%. In patients, with a previously performed biliary sphincterotomy, the PEP rate
decreased to 2.7% (P=0.019), being therefore a protecting factor against PEP (OR 0.28,
P=0.02). Technique-related factors results showed that the accidental passage of the guide
wire into the PD was a risk factor (OR 8.2, P<0.01). With no accidental passage of the guide
wire into the PD, the rate of PEP was 2.6%. When the guide wire strayed into the PD twice,
the PEP rate was 20%, and if this occurred five times, the PEP incidence increased to 31.6%.
Contrast medium was injected into the PD in 15 patients. Only two of them developed PEP,
51
which is not statistically significant increase when compared to patients with no contrast in
the PD. The PEP rate increased when more complicated techniques had to be used to
achieve the CBD cannulation. When the cannulation was achieved without biliary
sphincterotomy, the PEP rate was 1.4%. When biliary sphincterotomy was performed alone,
the PEP rate was 6.8%. In cases of TPBS performed in order to gain access into the CBD,
the PEP rate increased to 25%, and with a combination of biliary sphincterotomy, the PEP
rate rose to 27%. In 9 cases with difficult cannulation where TPBS was performed in
combination with precut and biliary sphincterotomy, the PEP rate was 55.6%. The median
extrahepatic PSC score was lower in patients for whom TPBS was necessary (0, 0-6)
compared to the other patients without needing TPBS (1, 0-6, P<0.001).
7.1.3 Other complications
No bleeding cases after sphincterotomy were recorded. Six cases of cholangitis were
recorded (1.4%), one mild and five with a moderate form of disease. The patients that
developed cholangitis had the same procedure duration as others (median 40 min, range, 8-
50min) (27 min; range, 10-96min; P=0.096). All the cholangitis patients had a previous biliary
sphincterotomy. Cholangitis developed for 2% of patients with a previous biliary
sphincterotomy, versus 1% of patients without a biliary sphincterotomy (P=0.405). Three
perforations (0.6%) were recorded, one caused by the guide wire and the others occurred
after the sphincterotomy. All cases of perforation were treated conservatively in 5, 6 and 7
days, respectively. No deaths were recorded due to the procedure. The risk factors and
incidence of PEP are shown in Table 6.
52
Table 6. Risk factors and incidence of PEP in 441 patients undergoing ERCP for PSC
Risk factors No. PEP cases/ Odds ratio/ P value No. of patients (%) 95% CI Patient related factors Sex Female 21/203(10.3) 2.63(1.21-5.73) 0.015 Male 10/238(4.2) Age in years >50 7/115(6.1) 0.94(0.57-1.53) 0.799 30-50 15/197(7.6) ≤30 9/129(7.0) Previous PEP Yes 3/23(13.0) 2.09(0.59-7.46) 0.256 No 28/418(6.7) Previous biliary sphincterotomy Yes 4/147(2.7) 0.28(0.10-0.81) 0.010 No 27/294(9.2) PSC total radiological score 3 4/89(4.5%) 0.70(0.49-1.00) 0.053 2 3/77(3.9) 1 1/44(2.3) 0 22/227(9.7) Technique related factors Wire unintentionally in pancreatic duct Yes 23/129(17.8) 8.25(3.58-18.99) <0.001 No 8/312(2.6) Bile duct balloon dilation Yes 4/80(5.0) 0.65(0.22-1.92) 0.436 No 27/361(7.5) Duration of ERCP >30 min 13/138(9.4) 1.54(0.90-2.64) 0.120 20-30 min 14/185(7.6) ≤20 min 3/85(3.5) Precut + biliary and pancreatic 5/9(55.6) 87.5(15.4-498.5) <0.001 EST Biliary and pancreatic EST 10/37(27.0) 25.9(6.7-100.1) <0.001 Pancreatic EST alone 1/4(25.0) 23.3(1.9-294.1) 0.015 Biliary EST alone 12/176(6.8) 5.1(1.4-18.4) 0.012 Cannulation alone 3/213(1.4) (ERCP) endoscopic retrograde cholangiopancreatography, (PEP) post ERCP pancreatitis, (PSC) primary sclerosing cholangitis, (95% CI) 95% confidence Interval, (EST) endoscopic sphincterotomy.
7.2 Study II
7.2.1 Non FAP benign papillary tumours
Of the non FAP benign papillary tumours 18 out of 35 (51%) were found accidentally during
gastroscopy (14 patients), computed tomography (2 patients), or magnetic resonance
imaging (2 patients). The investigations started with seven patients (20%) because of
jaundice, in six patients because of bleeding episodes or anaemia, and for four patients
because of acute pancreatitis with an unknown aetiology. The concordance between a pre-
resection biopsy and resected specimen was 24 of 32 (57%), see Table 7.
53
Table 7. The ERCP procedures and the histologic diagnosis before and after the resection
Benign tumour, No FAP, n = 35
FAP n = 16
Cancer n =10
Histological diagnosis before resection Low grade dysplasia 24 13 2
High grade dysplasia 8 3 4 Adenocarcinoma 0 0 1 Histological diagnosis after resection Low grade dysplasia 18 13 0 High grade dysplasia 14 3 0 Adenocarcinoma 0 0 10 Other * 3 0 0 Procedures done during ERCP Biliary sphincterotomy 23 13 8 Pancreatic sphincterotomy 19 8 4 Pancreatic stenting 16 12 4 Coagulation of margins 23 15 9 *One amyloidosis, one paraganglioma, one inflammatory changes
An endoscopic ultrasound was performed in 12 cases before the papillectomy. Pancreatic
stenting was attempted for 17 patients and succeeded in 16 cases (94%). For 10 patients, a
pancreatic sphincterotomy was considered sufficient and prophylactic stenting was not
attempted. A biliary sphincterotomy was performed on 23 patients (66%). To prevent
bleeding after the papillectomy, resection margins were coagulated in 23 patients. PEP
developed in four patients (11%), three patients with a mild form of disease, and one with a
moderate form. Six patients suffered from bleeding and were treated endoscopically. Two
patients with a retroperitoneal perforation were treated conservatively. One patient
developed all three complications and was also treated conservatively. The median follow-
up was 14 months (range 1-91). During the follow-up, residual adenomas were found in ten
patients (29%), four of them underwent a pancreaticoduodenectomy. In patients who
underwent surgery, the pathologic report revealed an adenoma with high-grade dysplasia in
two patients, carcinoma in one patient, and no neoplasia in one patient, even if the pre-
operation biopsies reported a case of in-situ carcinoma.
54
7.2.2 FAP related papillary tumours
The papillary adenomas in FAP patients were discovered during the routine follow-up
endoscopy. The concordance between the pre-resection biopsy and the post-resection
specimen was 14 out of 16 (88%). No EUS was planned before the papillectomy. The use of
contrast was necessary in four patients during the procedure. In 12 out of 16 patients (75%)
methylene blue was inserted into the PD. Pancreatic stenting was successful in 12 out of 14
patients (86%), while in one case the stent was placed in the minor papilla. In one patient, a
pancreatic sphincterotomy was considered to be sufficient. A biliary sphincterotomy was
done for 13 out of 16 patients (81%). Two patients developed a moderate form of PEP and
were treated conservatively. Three patients had bleeding and were treated endoscopically.
The median follow-up time was 37 months (range 1-63). Three residual adenomas were
found during the follow-up. Two of these were minor lesions and were treated with
coagulation and biopsy. One patient underwent a pancreaticoduodenectomy, which revealed
a high-grade adenoma in the specimen. In one patient with residual multiple duodenal
adenomas, a pancreaticoduodenectomy was performed 4 years later, which revealed one
high grade and three low grade adenomas.
7.2.3 Ampullary cancer
The primary symptom of ampullary cancer was jaundice in nine patients and bleeding in one
patient. A CT scan or MRI was done for all patients and revealed a bile duct dilation for all
the patients and PD dilation for six of them. In two patients, methylene blue was inserted into
the PD. Pancreatic stenting was attempted in five patients and was successful in four (85%).
In two patients, a wide pancreatic sphincterotomy was carried out and stenting was not
necessary. A biliary sphincterotomy was performed for eight patients. In this group of patients
there was no PEP and no perforation. In two patients (20%) bleeding occurred. One patient
was treated endoscopically, and another needed a laparotomy and duodenotomy. During the
follow-up, three patients developed residual cancer (4 mm, 1 cm, 3 cm), and all of them
underwent a pancreaticoduodenectomy. A patient with a 3 cm tumour had also 6/16 lymph
55
node metastasis and died 14 months after the operation. The two other patients that
underwent surgery, have been followed up for 6 and 8.5 years without any sign of
malignancy. Five out of seven non-operated patients died 9-24 months later from ampullary
cancer, and one died due to pneumonia. The only patient that is still alive, is being monitored.
7.3 Study III
7.3.1 Primary and rescue cannulation methods
For primary cannulation in the native papilla, a sphincterotome with a straight guide wire was
used in all but in one case in which a regular cannula alone was used. After the primary
cannulation method, the success rate was 73%. After the second rescue cannulation method,
the success rate was 91%, after the third 98.7%, and after the fourth it was 99.1%. In 7
patients (0.91%) cannulation failed. The median success time was 1.1 minutes (range 0.02-
19.67), with a median of 2 (range 0-15) cannulation attempts. An intrusion into PD was rare
(median 0, range 0-8), and the injection of contrast into the PD was also rare (median 0,
range 0-1). 80% of all successful primary cannulations were achieved in 3.5 minutes, and
91% in 5 minutes. When the endoscopist found that the primary cannulation was not going
to be successful, he adapted a rescue cannulation method in a median time of 4.8 minutes
(range 0.3-28). After 5 minutes, only 9% of the primary cannulations succeeded. The most
common rescue cannulation methods were TPBS alone, or combined with needle knife
precut, and sphincterotome precut. In total, within 10 minutes, 85% (691 patients) of the
successful cannulations were performed. Details of the ERCP and adverse events are shown
in Table 8. For the rescue methods used in cases of failed primary cannulation methods, see
Tables 9, 10, and 11.
56
Table 8. ERCP details, adverse events and mortality ERCP details Procedure length, min (median, range) 18 (5-110) Biliary sphincterotomy 803 (97.8%) Biliary cytology 209 (25.5%) Biliary duct dilatation 77 (9.4%) Common bile duct stone extraction 358 (43.8%) Biliary stent placement 286 (34.8%) Pancreatic sphincterotomy 145 (17.7%) Prophylactic pancreatic stent 5 (0.6%) Adverse events Post-ERCP pancreatitis 33 (4%) Mild 19 (45%) Moderate 20 (48%) Severe 3 (7%) Bleeding 20 (2.4%) Perforation 4 (0.5%) Cholangitis 10 (1.2%) 30-day mortality 42 (5%) ERCP: endoscopic retrograde cholangiopancreatography
Table 9. Rescue methods used in the second attempt, when the first attempt methods failed
The second cannulation Total Success Failure Attempt methods n=222 n=144 (65%) n=77 (35%) No second attempt 1 TPBS 156 107 (69%) 49 (31%) Sphincterotome precut 44 29 (66%) 15 (34%) Needle knife precut 13 7 (54%) 6 (46%) Double wire technique 5 1 (20%) 4 (80%) Pancreatic stent 2 0 2 (100%) Regular cannula alone 1 0 1 (100%)
TPBS: Transpancreatic biliary sphincterotomy.
Table 10. Rescue methods used in the third attempt, when the second attempt methods failed
The third cannulation Total Success Failure Attempt methods n=74 n=67 (91%) n=7 (9%) No third attempt 3 TPBS + NK 49 44 (90%) 5 (10%) TPBS 8 7 (88%) 1 (12%) NK 8 8 (100%) 0 Papillectomy 4 4 (100%) 0 Double wire technique 2 1 1 Sphincterotome precut 1 1 0 Sphincterotome with straight wire 1 1 0 Sphincterotome with J-tip wire 1 1 0
TPBS: Transpancreatic biliary sphincterotomy, NK: Needle knife precut.
57
Table 11. Rescue methods used in the fourth attempt, when the third attempt methods failed
The fourth cannulation Total Success Failure Attempt methods n=4 n=4 n=0 Papillectomy 3 3 0 Sphincterotome with a straight wire 1 1 0
7.3.2 PEP
A total of 33 patients (4.0%) developed PEP. When the primary cannulation succeeded, only
14 patients (2.3%) had PEP. After using the second cannulation method, 9 patients (6.3%)
developed PEP, and after further cannulation methods the PEP increased up to 13.5% (10
patients). When the successful cannulation was achieved within 5 minutes of the beginning
of the procedure, the PEP rate was 2.1% (12 patients), but if the cannulation was prolonged
for more than 5 minutes, the PEP rate increased up to 8.7% (21 patients), p<0.001.
In patients who required a maximum of 5 attempts to achieve the successful cannulation, the
PEP rate was 2.1% (12 patients), with more than 5 attempts, the PEP increased to 8.8% (21
patients), p<0.001. If the guide wire slipped into the PD once, the PEP rate was 3.3% (18
patients), for more than once, the PEP was 6.4% (15 patients), p=0.048.
Contrast was injected into the PD in 29 patients (3.5%) and the PEP rate for this group was
10% (n=3), compared to 3.8% (n=30) in patients with no contrast injection, p=0.106. The
presence of a trainee did not affect the PEP rate, with 4 cases of PEP (5.8%) vs. 29 cases
without PEP (3.9%), p= 0.35.
7.3.3 Difficult cannulation
A total of 599 patients had a successful primary cannulation, and 477 of this group (79.6%)
had an easy cannulation with the absence of any of the difficult cannulation criteria mentioned
in the ESGE guidelines (Testoni et al., 2016). 311 patients out of 821 (37.9%) had at least
one difficult cannulation criteria (cannulation >5 minutes in 152 patients, more than five
cannulation attempts in 141 patients, and unintended PD passages in 234 patients). For
58
these patients, the PEP rate was 7.1% (n=22), and if no criteria presented, the PEP rate was
2.2% (n=11), p=0.001. With only one difficult cannulation criteria presented, the PEP rate
was 6.9% (n=11), and with the presence of all criteria, the PEP rate was 12.3% (n=8).
7.3.4 TPBS as a rescue method
A TPBS was the preferred rescue method in 156 cases (70.6%), whereas other rescue
methods were used in 65 cases (29.4%). When a TPBS ± needle knife precut was used as
rescue method the PEP rate was 8.9% (n = 15), and when other rescue methods were used,
the PEP rate was 2.8% (n = 18), p =0.001.
7.3.5 Other complications
49 patients had adverse events. 33 patients (4%) had PEP, 20 patients (2.4%) had bleeding,
four patients (0.5%) had perforations, and 10 patients (1.2%) had cholangitis. In cases of
difficult cannulations, the rate of complications was 9.3% (n=29), whereas in the easy
cannulation group the complication rate was 3.9% (n=20), p=0.002. After excluding PEP,
there were no more significant differences in complications between the two groups 11
(3.5%) vs. 12 (2.4%), p=0.384.
7.4 Study IV
In 33 cases out of 1196, the cannulation failed. This was because the papilla could not be
reached due to previous surgery (gastric resection, pancreaticoduodenectomy) in 5 cases, a
proximal obstruction to the papilla in six cases, edema of the descending duodenum in eight
cases, and in 13 cases, a deep cannulation of the bile duct could not be achieved. In one
case the ERCP was not performed because of the patient's allergic reaction to sedatives.
Procedures done during the ERCP are listed in Table 12.
59
Table 12. Procedures during the ERCP
ERCP procedures Number of ERCPs (n=1196)
Biliary cytology 416 (35%) Biliary sphincterotomy 562 (47%) Stone extraction from the CBD 345 (29%) Biliary dilatation 164 (14%) Biliary stent 357 (30%) Pancreatic sphincterotomy 207 (17%) Pancreatic cytology 35 (3%) Pancreatic dilatation 101 (8%) Pancreatic stent 216 (18%) Pseudocyst gastrostomy or 24 (2%) duodenostomy Per oral cholangioscopy 21 (2%) Double balloon ERCP 8 (1%) ERCP: Endoscopic retrograde cholangiopancreatography. CBD: Common bile duct.
7.4.1 Post-ERCP complications
PEP developed in 43 (3.6%) patients. The ERCP-related and sedation related complications
are listed in Table 13, and a univariate and multivariate analysis of PEP risk factors are listed
in Table 14.
Table 13. ERCP related and sedation related adverse events in 1196 ERCPs performed to 956 patients
Adverse events Count (%)
ERCP-related 102 (8.5) Pancreatitis 43 (3.6) Mild 24 (2) Moderate 14 (1.2) Severe 5 (0.4) Bleeding 17 (1.4) Cholangitis 17 (1.4) Perforation 6 (0.5) Miscellaneous 19 (1.6) Sedation-related 214 (17.9) Respiratory depression 128 (10.7) Cardiovascular depression 86 (7.2)
60
Table 14. Univariate and multivariate analysis of PEP risk factors
Univariate Odds p-value 95% CI Diabetes, insulin treatment 0.140 (0.19-1024) 0.053 Diabetes, oral medication 0.216 (0.030-1.587) 0.132 Hypertension 0.431 (0.198-0.937) 0.034 Cardiovascular disease 0.625 (0.243-1.607) 0.329 Opioid use 1.494 (0.615-3.632) 0.376 Anticoagulant use 0.695 (0.290-1.669) 0.416 Smoker 0.481 (0.169-1.372) 0.171 Hospitalized patient 0.770 (0.362-1.636) 0.497 Outpatient case 1.336 (0.629-2.839) 0.451 P-tromb < 150 0.154 (0.021-1.125) 0.065 P-TT <70% 0.206 (0.049-0.860) 0.206 Abnormal ECG 0.596 (0.291-1.222) 0.158 Hyponatremia 0.506 (0.211-1.212) 0.127 Hypokalemia 1.837 (0.547-6.162) 0.325 Hyperkalemia 3.837 (0.468-32.400) 0.208 ASA 1-2 vs 3,4,5 0.51 (0.28-0.95) 0.033 Age 0.97 (0.96-0.99) 0.004 Age > 60 years 0.44 (0.23-0.86) 0.016 Female vs male 0.70 (0.37-1.32) 0.264 Anaemia 0.67 (0.34-1.29) 0.231 Multivariate analysis Odds 95% CI P-value
Age > 60 years old 0.525 (0.261-1.054) 0.070 Female vs male 0.714 (0.370-1.375) 0.313 Diabetes, insulin treatment 0.138 (0.019-1.020) 0.052 P-TT<70% 0.244 (0.57-1.037) 0.056
ECG: Electrocardiogram, ASA American Society of Anaesthesiologists.
The bleeding and perforation cases were treated conservatively. Nineteen miscellaneous
complications were reported, e.g. pseudocyst infection, stent migration, peptic ulcer bleeding,
air embolism. Two deaths happened the same day that the ERCP was performed, one due
to an air embolism, and another due to a myocardial infarction. Eleven deaths happened
within one week after ERCP, and 44 deaths during the next 30 days after the procedure.
7.4.2 Complications due to sedation
Respiratory depression occurred in 128 patients (11%). During the procedure, mask
ventilation was needed 20 times (1.7% of patients), and the ERCP was paused. Three
patients were intubated because of resuscitation due to an air embolism, second due to a
laryngobronchospasm and third due to septic cholecystitis.
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There was no association between respiratory depression and the RPLT in the multivariate
analysis (Table 15).
Table 15. Univariate and multivariate analysis of respiratory depression risk factors
Univariate Odds ratio P-Value 95% CI Diabetes insulin treatment 1.477 (0.916-2.380) 0.110 Hypertension 1.139 (0.778-1.668) 0.502 Cardiovascular disease 1.721 (1.117-2.651) 0.014 COPD 0.405 (0.097-1.695) 0.216 Kidney failure 0.609 (0.143-2.590) 0.502 Endocrinal disease 1.753 (0.760-4.044) 0.188 Opioid use 0.688 (0351-1.350) 0.277 Anticoagulant use 1.210 (0.769-1.904) 0.409 Hospitalized patient 0.760 (0.488-1.183) 0.223 Outpatient case 1.518 (0.957-2.407) 0.076 P-TT <70% 1.264 (0.812-1.967) 0.300 P-INR >2 0.648 (0.219-1.914) 0.432 Abnormal ECG 1.229 (0.841-1797) 0.287 ASA 1-2 vs 3-5 1.32 (0.98-1.95) 0.169 Age >60 1.13 (0.78-1.63) 0.506 Female vs male 1.27 (0.88-1.83) 0.205 Anemia 0.44 (0.29-0.68) <0.001 Multivariate all patients Cardiovascular disease 2.07 (129-3.34) 0.003 Anemia 0.39 (0.25-0.61) 0.000 Patients without cardiovascular disease Anemia 0.26 (0.14-0.48) 0.000 Patients with cardiovascular disease Female vs male 1.34 (0.59-3.02) 0.483
COPD: Chronic obstructive pulmonary disease, ECG: Electrocardiogram, ASA American Society of Anaesthesiologists.
In this multivariate analysis, an interaction between anemia and cardiovascular disease was
found in the statistical model. Upon further investigation, anemia was found to be a stronger
protective factor if the patient had no cardiovascular disease (OR 0.26, p<0.001).
In 86 patients (7.2%) cardiovascular depression occurred. The multivariate analysis showed
that cardiovascular depression was increased in cases of hyponatremia, thrombocytopenia,
or in patients over 60 years old. In this statistical model, an association was found between
62
gender and hyponatremia, in which hyponatremia was associated with cardiovascular
depression slightly more in men than in women (Table 16).
Table 16. Univariate and multivariate analysis of cardiovascular depression risk factors Univariate Odds ratio P-value 95%CI Diabetes insulin treatment 1.316 (0.735-2.357) 0.355 Diabetes oral medication 1.432 (0.736-2.781) 0.291 Hypertension 1.363 (0.871-2.134) 0.175 Cardiovascular disease 2.854 (1.780-4.576) 0.000 Cerebrovascular disease 2.183 (0.630-7.566) 0.218 Atherosclerosis 3.664 (1.542-8.704) 0.003 COPD 3.219 (1.441-7.190) 0.004 Kidney failure 2.874 (1.065-7.760) 0.037 Endocrinal disease 1.835 (0.700-4.816) 0.217 Opioid use 1.56 (0.648-2.434) 0.500 Anticoagulant use 2.162 (1.335-3.502) 0.002 Benzodiazepam use Chemotherapy< 30days ago Smoker 1.585 (0.874-2.874) 0.130 Hospitalized patient 1.516 (0.925-2.414) 0.080 Outpatient case 0.706 (0.441-1.129) 0.146 P-Tromb <150% 2.194 (1.289-3.734) 0.004 P-TT <70% 2.151 (1.325-3.492) 0.002 P-INR >2 0.367 (0.123-1.096) 0.072 Abnormal ECG 2.121 (1.365-3.297) 0.001 Hyponatremia 2.641 (1.684-4.142) 0.000 Hypernatremia Hypokalemia 1.522 (0.587-3.947) 0.388 Hyperkalemia ASA 1-2 vs 3-5 3.70 (2.02-6.75) 0.000 Age >60 4.06 (2.41-6.85) 0.000 Anemia 1.89 (1.22-2.94) 0.005 Multivariate analysis of all patients Age >60yrs old 3.34 (1.95-5.72) 0.000 Female vs male 0.84 (0.53-1.34) 0.468 Atherosclerosis 2.41 (0.99-5.89) 0.053 P-tromb <150 1.87 (1.08-3.25) 0.025 Hyponatremia 2.22 (1.40-3.52) 0.001 Male patients Age >60yrs old 4.79 (2.23-10.30) 0.000 Atherosclerosis 2.58 (0.87-7.70) 0.088 P-Tromb <150 1.69 (0.81-3.53) 0.164 Hyponatremia 3.66 (1.98-6.75) 0.000 Female patients Age >60yrs old 2.14 (1.00-460) 0.050 Atherosclerosis 2.53 (0.50-12.89) 0.263 P-tromb <150 2.14 (0.92-4.99) 0.078
A split analysis was performed according to gender because a significant interaction was found between gender and hyponatremia.
63
8. Discussion
In the last years, ERCP has evolved from a diagnostic to a predominantly therapeutic
procedure, and the use of this tool seems to be increasing. ERCP is still one of the most
technically complicated and challenging procedures since it requires a steep learning curve
to increase the success of the cannulation rate and to reduce the adverse events of the
procedure. PEP is the most common and severe complication of an ERCP. Other adverse
events include bleeding, cholangitis, and perforation.
8.1 ERCP for PSC patients (I)
For PSC patients the incidence of developing abdominal malignancies is high compared to
the general population. The lifetime incidence of cholangiocarcinoma in PSC patients is 20%,
while for hepatocellular carcinoma the lifetime incidence is 0.3%-2.8%, and for gallbladder
carcinoma it is 1-3.5% (Fung et al., 2019). In fact, 40%-50% of the mortality in PSC patients
occurs due to malignancies (Folseraas et al., 2016). ERCP is a sensitive and specific tool for
primary diagnosis and follow up of the progression of PSC. In the Helsinki University Hospital,
a PSC diagnosis is always confirmed by an ERCP and liver biopsy. In patients without PSC,
the adverse events associated with ERC have been reported to range from 4% to 16% (Etzel
et al., 2008; Bangarulingam et al, 2009; Cotton et al., 2009). The overall adverse events for
PSC patients have varied in different studies between 1.8% up to 18.4 {{261 European
Society of Gastrointestinal Endoscopy 2017}}. In our study, the overall complication rate was
9%.
Some studies that compare complication rates between PSC and non-PSC patients have
shown that the two groups have differed neither in the overall complication rate, nor in the
risks of PEP, perforation, or bleeding (Etzel et al., 2008; Bangarulingam et al., 2009). In their
study Bangarulingam et al. reported a higher rate of cholangitis in the PSC group (4% vs.
0.2%, p 0.0002). Additionally, the ERCP duration was longer for PSC patients who developed
64
cholangitis. The differences between the reported complication rates can be explained by the
number of interventions carried out during the ERCP procedure. In our study, the cholangitis
rate was 1.4%, and no association was found between the procedure time and the
development of cholangitis. A previous biliary sphincterotomy did not affect the cholangitis
rate. The regular use of prophylactic antibiotics can explain these findings in our study. There
were no procedure-related deaths in this study, unlike in other studies that reported a
mortality rate of 0.4% (Freeman et al., 1996). The fact that the PSC patients were usually
young and had no severe comorbidities, may explain the absence of deaths in our study. For
instance, in the study by Freeman et al., half of the deceased were over 70 years old, and
the other half had severe comorbidities. Additionally, in our study, we could not find any
association between young age and PEP, which was reported in other studies (Freeman et
al., 1996; Wang, P. et al., 2009).
In our unit, the PEP rate for patients with native papilla was 4.8% for non-PSC patients, and
7% for PSC patients with native papilla. This is can be explained because the balloon
catheter insertion and several brushings and dilations, that take place in an ERC for PSC
patients are known to increase the overall risk of complications. The PEP rate in our study of
7% is slightly less than in previous studies (Etzel et al., 2008; Bangarulingam et al., 2009),
which can be attributed to the guidewire technique we used instead of a contrast injection.
Navaneethan et al. reported a rate of PEP as low as 1.2% and explained the likely reason to
be routine stenting of the PD after cannulation or injection in the PD (Navaneethan,
Jegadeesan et al., 2015), which we did not do routinely in our unit. The history of PEP was
not a risk factor in the present study. Female sex was associated with an increased risk of
PEP, which has also been reported in previous studies (Cotton et al., 1991; Wang et al.,
2009). However, there are studies that have found no association between sex and an
increased risk of PEP (Cheng et al., 2006; Etzel et al., 2008). An uninitiated wire insertion
into the PD increased the PEP. Having had a previous papillotomy was a protective factor
against PEP, which could probably be attributed to the ease of cannulating the bile duct,
65
which reduces the mechanical irritation of the papilla. The accidental insertion of the
guidewire into the PD has been reported in many studies to be a risk factor for PEP (Cheng
et al., 2006; Cotton et al., 2009; Halttunen et al., 2014). However, one study has reported
that this is not a risk factor (Lella et al., 2004). The difference between the surveys can be
attributed to the difference in the PEP definition. In the study by Artifon et al., an amylase
level of five times the normal level was necessary for a PEP diagnosis, whereas in our study
it was three times the normal level. Still, in the study by Atrifon et al., an accidental guidewire
insertion into the PD did not cause PEP (Artifon et al., 2007).
The precut technique is a valuable method which can increase the cannulation success rates
up to 95% (Siege et al., 1989), but many studies have reported that a precut increased the
PEP rates (Freeman et al., 1996; Loperfido et al., 1998; Testoni et al., 2010). However, recent
meta-analyses showed that when an early precut was performed, the PEP rates were
significantly lower than in the late precut group (Cennamo et al., 2010; Mariani et al., 2016).
In our study, the precut technique was used in the most difficult cannulation cases. A previous
study from our unit showed that TPBS was safe, with a high cannulation success rate (97%)
compared to precut rates (71%), with no difference in the complication rates (Halttunen et
al., 2009). An additional precut after TPBS was needed in 42% of the cases in our previous
study (Halttunen et al., 2009), but in the present study it was 21%. The difference in the need
for a precut procedure after TPBS in the two studies could stem from the fact that in the
present study all the patients had PSC. However, the PSC score was no higher in the group
that needed TPBS. Thus, the difficulty of BD access cannot be entirely explained by the
stricture of the extrahepatic bile duct. A biliary sphincterotomy was associated with a 6.8%
risk of PEP (Freeman et al., 1996). A previously performed sphincterotomy was a significant
protective factor against PEP in our study. For this reason, we recommend to perform a
biliary sphincterotomy for PSC patients if repeat procedures are expected.
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8.2 Endoscopic papillectomy (II)
Jaundice and bile duct dilation are definite risk factors of malignant periampullary tumors, yet
in the present study, for benign tumours, jaundice was also present in 14% of patients.
Patients with cancer that survived were those who were operated and had no lymph node
metastasis. It is very hard with cancer patients to estimate complete endoscopic removal,
and the case in this study is a good example. With clean findings after a papillectomy, still, a
4 mm cancer was found in the pancreaticoduodenectomy specimen. A previous study
showed that pre-resection biopsies were unreliable in many cases (Irani et al., 2009). In the
present study, we came to the same conclusion since the biopsies revealed cancer in only
one case out of 10 cancer cases, and the papillectomy specimen was needed for diagnosis.
In the case of a papillary carcinoma, pancreaticoduodenectomy is the treatment of choice. In
this study, we saw that in spite of the follow-up, a small amount of cancer could be missed;
for this reason, many experts consider even high-grade adenomas to be an indication of
surgery (Beger et al., 1999; Kim, J. H. et al., 2009).
The frequency of ampullary tumours in FAP patients is 200-300 times higher compared to
the general population, with a risk of carcinoma up to 10% (Gluck et al., 2015). In the present
study, during the follow-up, none of the FAP patients developed cancer, and the concordance
between pre-resection and papillectomy specimens was up to 88%. The endoscopic
surveillance of FAP patients can delay the surgery, which can help patients with a high risk
of malignancy. With the lack of randomized controlled studies, the timing of the surgery is
still not clear. Additionally, adenomas can develop after surgery, which makes the decision
whether to operate or not, more complicated. In the present study, the PEP rate after a
papillectomy was 9.8% with mild and moderate forms. The use of a prophylactic stent
reduced the PEP rate, which was confirmed by previous research (Napoleon et al., 2013),
but locating the PD for stenting can be challenging. Some operators use a guidewire or
contrast to determine the PD. In our institution, we use methylene blue to identify the PD,
which is a safe technique (Catalano et al., 2004; Udd et al., 2010). Some prefer to perform a
67
pancreatic papillotomy before a papillectomy to ensure pancreatic stenting afterwards
(Testoni, P. A., 2007). In this series, when a pancreatic papillotomy was performed without a
stent, the risk of PEP increased noticeably. By changing our policy and using prophylactic
stents every time after the PD was reached, we should be able to reduce the PEP rates. Non-
steroidal anti-inflammatory drugs (NSAIDs) can be more effective in preventing PEP than the
prophylactic stents (Akbar et al., 2013). Additional studies are needed to show whether both
NSAIDs and PD stents work synergistically or not, and until then, both can be used.
According to Napoleon et al., post-papillectomy adverse events include PEP (5-19%),
perforation (0-5%), bleeding (0-18%) and cholangitis (0-4%) (Napoleon et al., 2013). We had
a relatively high overall complication rate of 24.6%. Of these PEP accounted for 9.8%,
bleeding for 18%, perforation for 3.3%, and there was no cholangitis. All but one patient was
treated conservatively. Three deaths which were non-procedure related were reported. A
high bleeding percentage can be from our policy to perform a duodenoscopy as soon as any
suspicion appears. Coagulation of the resection margins after the papillectomy did not
prevent bleeding. However, this may be due to the retrospective nature of the study. Using
haemostatic agents in the papilla area can be dangerous, if they obstruct the pancreatic
orifice. Using haemostatic clips after pancreatic stenting could be one option to reduce the
bleeding rate.
8.3 The role of TPBS in difficult cannulations (III)
The guidewire-assisted cannulation technique was shown to be associated with greater
primary cannulation success and reduced PEP risk compared to contrast assisted
cannulations in one large systematic review (Tse et al., 2012). In the present study, the
difficult cannulation rate was 37%. As a first rescue cannulation technique, we used the TPBS
technique with a final success rate of 99% and a PEP rate of 4%. The high final success rate
can be attributed to our policy of attempting to obey the 5-5-2 rule and move to the rescue
method quickly as it was in the present study, in a median of 4.8 minutes.
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In a multicentre prospective study by Wang et al., the guidewire passage to the PD was an
independent risk factor for PEP (Wang et al., 2009). In the present study, the risk of PEP was
6.4% if the wire slipped more than once into the pancreatic duct. According to one meta-
analysis, a contrast injection into the pancreatic duct is a risk factor for PEP (Ding et al.,
2015), unlike in our study, which could not confirm the same. This can be attributed to the
fact that we used guide wire cannulation and hardly used contrast injections because usually
it is easy to assess the location of the guidewire using only a fluoroscope.
TPBS was first described by Goff et al. (Goff, 1999). It was described as a safe and effective
method for gaining access to the CBD in difficult cannulations, with a success rate range
between 86-100%, and acceptable PEP rates (3.5-10.4%) (Goff, 1999; Weber et al., 2008;
Halttunen et al., 2009; Kim, S. J. et al., 2015). In our previous study, the success rate of
TPBS was 97% in difficult cannulations. The PEP rate was 9.3%, and when an additional
needle-knife cut was performed, the PEP rate was 8.2%. When only a needle-knife cut was
performed, the PEP rate was 5.1%. In a previous study from our unit, the BD cannulation
success rate of the needle knife group was lower compared to the TPBS group (71.3% vs.
97.3%, p<0.001) (Halttunen et al., 2009).
DGW cannulation is another rescue technique that needs additional guidewire in the PD to
straighten the BD, to make the cannulation of the BD easier. In cases of a tight tumour
stricture, the additional guidewire may hamper the cannulation and even block access.
Although when the first guidewire is placed already in the PD, the second guidewire can still
easily enter the PD. In a study comparing DGW and TPBS techniques as rescue methods,
the cannulation time for the DGW group was 7.8 +/- 1.7 minutes, and for the TPBS group it
was 3.7 +/-2.3 minutes (p<0.001), and the complication rate was 2.19% vs. 7.04%, (p=0.04)
respectively. It is noteworthy that the primary cannulations in this study succeeded in only
23.8% of the cases (Huang et al., 2015), which differs from other studies with primary
successful cannulation rates of 75-90% (Ito et al., 2014; Kim et al., 2015) . Another study that
compared DGW with needle knife techniques after the failure of a primary cannulation, found
69
that the success rate was 44.8% in the DGW group and 79.1% in the needle knife group.
The cannulation time was 312 seconds vs. 257 seconds, and the PEP rate was 14.9% vs.
4.5%, respectively (Kim et al., 2015). It is essential to register the data during the ERCP,
concerning the cannulation time, the number of attempts and the number of passages into
the PD, to monitor the rate of difficult cannulation criteria in clinical practice.
8.4 RPLT for ERCP (IV)
The average utilization of ERCP increased over time up to 105 ERCPs /100,000 person/year
driven by therapeutic procedures (Coelho-Prabhu et al., 2013). The need for ERCP will most
likely rise more in the future. This means that the cost of the preoperative testing will also
rise. In our institution, an RPTL package costs about 41€ per one elective patient, and 66€
in emergency cases. Many studies previously showed an excessive RPLT to have no true
effect on clinical decisions (Pasternak, 2004; Czoski-Murray et al., 2012; ASGE Standards
of Practice Committee et al., 2014). Although the majority of these studies focused on RPTLs
for patients undergoing surgery, we can assume that ERCP as the less invasive procedure
needs even fewer RPTLs than surgical patients. The rate of the adverse events in the present
study was similar to other studies (Cohen et al., 1996; Andriulli et al., 2007). We found that
none of the RPTLs that were used were directly associated with any complications of ERCP.
Still an association was found with thrombocytopenia, hyponatremia, and cardiovascular
depression. However, the reason for this association is unclear, and further studies are
needed. Usually, hyponatremia and thrombocytopenia are causes of other health-related
issues, which most likely is the reason for hypotension during sedation. Correcting these
values probably would not alleviate the problem. Still, a clinical assessment of the patient
before the procedure may inform the anaesthesiologist of the cardiovascular depression risk,
even without RPTLs. This does not mean that we should abandon the preoperative testing
completely, but to focus on patients that would benefit from them. In the present study,
anemia was found to be a protective factor for respiratory depression caused by sedation,
especially for patients without cardiovascular disease, which the sensitization to hypoxemia
70
that anemia causes could explain. However, the clinical utilization of this finding is difficult,
since anemia is an issue to be avoided in clinical practice.
8.5 Limitations of the studies
In study I, we included a large cohort of PSC patients who underwent ERCP for primary
diagnosis, surveillance of progression, and therapeutic purposes. For PSC cases,
prophylactic pancreatic stents were not used routinely in difficult cannulations. In high-risk
patients, prophylactic placement of a pancreatic stent decreases the risk of PEP. As in our
series there was a high PEP rate in patients with the most difficult cannulations, placement
of a pancreatic stent could be beneficial in such cases.
For papillectomy cases, a prophylactic pancreatic stent was used more often, but not for all
patients (Study II). Additionally, we did not have specific instructions on when we crossed
over to the rescue method in Study III. The use of diclofenac before the ERCP began in
September 2013 during the data collection phase of the studies. In cases of difficult
procedures, the change to a more experienced endoscopist was not documented.
Additionally, we did not collect the difficult cannulation criteria for every patient because of
the busy daily practice. We rarely used DGW as a rescue method because it has been quite
unreliable in our hands. Instead, we used TPBS as the first rescue method.
In Study IV the relatively small number of complications made it difficult to draw reliable
conclusions. However, the study is still a good foundation for additional studies on the
subject.
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9. Future aspects
Although advances have been made, we still need to reduce the rate of PEP. The
combination between more than one prophylactic procedure (e.g. diclofenac, pancreatic
stent, aggressive hydration) can reduce the rate of PEP. In our institution we are going to
begin a study in which we compare the using of diclofenac suppository prior to native papilla
ERC in the same time with using of pancreatic stent after PD sphincterotomy, and compare
it to using of only diclofenac, and compare the impact on PEP developing.
Avoidance of unnecessary ERCP is the best way to reduce the number of complications.
Professional practice guidelines inform the appropriateness of preoperative noninvasive
imaging or preoperative ERCP, respectively, before cholecystectomy based on pretest
probability of retained BD stone. Institutional adoption of a standard algorithm for
management of such patients may minimize redundant investigations, including ERCP.
Compared with cholangiography, EUS is highly sensitive and specific in the diagnosis of
choledocholithiasis, and has predominant role in defining pancreaticobiliary lesions because
of its relative safety and its superiority over ERCP in tissue acquisition. Endoscopists
performing ERCP may also be skilled in EUS. It would also be beneficial to have randomized,
controlled trials comparing ERCP- vs. EUS -facilitated biliary drainage in patients with
unresectable malignant obstructive jaundice.
Duodenoscopes should be redesigned to eliminate or minimize infections resulting from
difficult to clean elevators. Transmission of multi- drug resistant organisms by
duodenoscopes is not novel occurrence, with prior reports including transmission of
Pseudomonas aeruginosa and Klebsiella pneumoniae occurring in the setting of known
significant breach in endoscope reprocessing.
It would be great to expand the capabilities of ERCP to allow for something to be placed in
the pancreatic duct that could dissolve stones instead of using electrohydraulic, laser, or
extracorporeal shockwave lithotripsy. The potential injection of litholytic agents into the
72
pancreas for chronic calcific pancreatitis, and directed infusion of chemotherapeutic or
immunomodulatory agents into the pancreaticobiliary tree may be a potential future scenario.
73
10. Summary and conclusions
The following conclusions can be drawn from this study:
1. ERC for PSC patients is accompanied with a fairly low risk of severe adverse events and
no mortality. For PSC patients undergoing dysplasia surveillance with repeated ERC, we
recommend biliary sphincterotomy during the first ERC to prevent PEP after the next
procedures. Biliary sphincterotomy is not associated with ERCP-associated cholangitis.
2. For benign tumours, endoscopic ampullectomy is a relatively safe and effective
treatment. Jaundice and bile duct dilation are risk factors for malignancy. Although
residual adenomas occur frequently, they can be treated endoscopically or
conservatively. Malignant tumors should be treated surgically. Prophylactic pancreatic
stenting reduces the risk of PEP.
3. To monitor difficult cannulation cases, the cannulation attempts, and cannulation time
must be recorded; also, the number of guidewire passages into the PD must be counted.
This will help in the timing of crossover to another cannulation method. TPBS is an
efficient and safe rescue method.
4. Routine RPLTs often fail to predict adverse effects of ERCP. The RPLTs that should be
considered before ERCP are: a basic blood count, creatinine, P-NA, P-K, in patients with
ASA 4-5, and with coronary artery disease, atherosclerosis, kidney failure, or patients
consuming diuretics. If the patient takes oral anticoagulants, then P-INR must be
checked. Additional RPLTs should be considered according to the patient's health status.
For young, healthy patients RPLTs are not needed.
74
11. Acknowledgements
This study was carried out at the Department of Surgery, University of Helsinki, and Helsinki University
Hospital, during the years of 2000-2020.
I want to express my sincere gratitude and respect to the academic head of the department, Professor
Pauli Puolakkainen, for the opportunity to carry out this thesis and for creating an inspiring and
supportive academic environment to work.
I owe my deepest gratitude to my supervisors Docent Leena Kylänpää and Docent Marianne Udd, for
not losing faith in me, for always being available and tirelessly helping me through the demanding
phases in the process. My first steps in the field of clinical research were not smooth, without their
never-ending optimism and vast knowledge in the clinical field, it would have been impossible to
accomplish this thesis. I truly admire both of them.
I sincerely thank my reviewers Professor Tuomo Rantanen and Professor Juha Saarnio for their
excellent and constructive comments. I also thank Docent Urban Arnelo for agreeing to be my
opponent. My present superiors, Docent Esko Kemppainen, Docent Leena Halme, are sincerely
acknowledged for their kind support.
All of my co-authors are thanked for their invaluable help: Professor Martti Färkkilä, Professor Heikki
Järvinen, Docent Jorma Halttunen, Docent Kalle Jokelainen, Docent Reino Pöyhiä, Dr Outi Lindström,
Dr Mia Rainio and Dr Jarno Jokelainen. I am deeply indebted for Harri Mustonen for his help with
statistical analysis.
I warmly thank Elina Aspiala for her kindness and for the effort she took to make the thesis appear in
this way. I also warmly thank Docent Arno Nordin for his niceness and support.
My deepest thanks to my lovely wife Nina and our dear children Omar and Sami. You are the most
important people in my life.
Helsinki, December 2020
Shamel
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I
Risk factors for complications of ERCP in primarysclerosing cholangitis
Authors S. Ismail1, L. Kylänpää1, H. Mustonen1, J. Halttunen1, O. Lindström1, K. Jokelainen2, M. Udd1, M. Färkkilä2,3
Institutions 1 Department of Gastrointestinal and General Surgery, Helsinki University Central Hospital, Helsinki, Finland2 Department of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland3 Helsinki University, Institute of Clinical Medicine, Department of Medicine, Clinic of Gastroenterology, Helsinki, Finland
submitted14. December 2011accepted after revision18. June 2012
BibliographyDOI http://dx.doi.org/10.1055/s-0032-1325677Published online: 29.10.2012Endoscopy 2012; 44: 1133–1138© Georg Thieme Verlag KGStuttgart · New YorkISSN 0013-726X
Corresponding authorL. Kylänpää, MD, PhDDepartment of Gastrointestinaland General SurgeryHelsinki University CentralHospitalHaartmaninkatu 4PL34000029 [email protected]
Original article 1133
Introduction!
Primary sclerosing cholangitis (PSC) is a chronicprogressive disease of the biliary tract character-ized by diffuse inflammation and fibrosis andstrictures of both intrahepatic and extrahepaticbile ducts [1, 2]. The disease is slowly progressiveand may eventually lead to cirrhosis, but the mostfeared complication is cholangiocarcinoma. Non-invasive diagnostic methods such as magneticresonance cholangiography (MRC) have largelysuperseded diagnostic endoscopic retrogradecholangiopancreatography (ERCP) for many indi-cations. However, diagnosis of PSC in its earlyphase, especially when intrahepatic, is impossiblewith even the best MRC. ERCP done with the bal-loon occlusion technique using adequate contrastfilling is still the gold standard for diagnosing PSC,and is the only option for collecting cytologicalmaterial from bile ducts for dysplasia screeningand surveillance. Early diagnosis of PSC is essen-
tial, as it has great impact on both the surveillanceof the liver disease and the associated colitis. Atpresent, detection of biliary dysplasia with ERCPis the only way of diagnosing cholangiocarcinomain its early, curable stage. Using DNA flow cyto-metry combined with brush cytology with Papa-nicolaou stain, we have previously shown in con-secutive patients with PSC that an aneuploid DNAcontent was found in 19% of patients and cellssuspected of malignancy in 21% during dysplasiasurveillance in PSC [3]. The brush cytology andbiopsies obtained during ERCP in combinationwith advanced cytology techniques, such as fluor-escence in situ hybridization (FISH), are the mostsensitivemethods for early detection of the devel-opment of cholangiocarcinoma [4]. At our unit,repeated ERCP procedures are used for the dila-tion of dominant strictures and for dysplasia sur-veillance of the biliary tract in patients with PSC.The reported incidence of complications afterERCP in patients with PSC ranges from 4% to
Ismail S et al. Risk factors for complications of ERCP in primary sclerosing cholangitis… Endoscopy 2012; 44: 1133–1138
Background and study aims: Endoscopic retro-grade cholangiographic pancreatography (ERCP)is the most accurate technique for surveillance ofpatients with primary sclerosing cholangitis(PSC). Our aim was to evaluate risk factors forcomplications of ERCP in patients with PSC.Patients and methods: In 2007–2009 we per-formed 441 ERCPs in patients with PSC. The pri-mary tools for ERCP were a guide wire and papil-lotomy knife to gain access into the biliary duct. Ifthe primary cannulation failed, and the wire wentonly into the pancreatic duct, pancreatic sphinc-terotomy was performed. If necessary, a furtheroblique cut with a needle knife was done in orderto expose the biliary duct.Results: Primary cannulation was successful in389 patients (88.2%). Of these, 147 (37.8%) hadhad biliary sphincterotomy performed previous-ly. In the group with failed primary cannulation,access into the biliary duct was achieved after
pancreatic sphincterotomy in 52 patients. In 11of these, a further cut with a needle knife was per-formed. Post-ERCP pancreatitis (PEP) was diag-nosed in 31 patients (7.0%). Factors predictingPEP were female sex (odds ratio [OR] 2.6, P=0.015) and a guide wire in the pancreatic duct(OR 8.2, P<0.01). Previous biliary sphincterotomywas a protective factor (OR 0.28, P=0.02). The riskof PEP increased with the number of times thewire accidentally passed into the pancreatic duct(P<0.001). Cholangitis developed in 6 patients(1.4%).Conclusions: In patients with PSC the incidence ofERCP complications remained relatively low. Thecomplication risk increased with the complexityof cannulation. In a patient with PSC in whom fol-low-up ERCP is planned, biliary sphincterotomyshould be considered, as it may protect againstPEP.
15.9% [5–9], post-ERCP pancreatitis (PEP) being the most fre-quent and dreaded complication. Its prevalence ranges from 1%to 7% [4], average 3.47% (CI 3.19%–3.75%), in a large systematicsurvey of prospective studies involving 16 855 patients [7].Known patient-related risk factors for PEP include younger age,female sex, suspected sphincter of Oddi dysfunction (SOD), andprevious PEP. Difficult cannulation, needle knife precut, frequentcontrast injections into the pancreatic duct, and pancreaticsphincterotomy are the most commonly reported procedure-related factors. Although in most cases PEP is mild, 20% of pa-tients with PEP suffer from a moderate or severe form of the dis-ease, with prolonged hospitalization and even PEP-related organfailure and death. The other ERCP-related complications are cho-langitis, bleeding, and retroperitoneal duodenal perforation,usually following therapeutic procedures. Understanding whatfactors increase the complication rates could help to reducethem to the minimum. Patients with PSC undergo repeatedERCP examinations with multiple therapeutic interventions dur-ing the procedures, such as brushing, biopsies, and dilations, andso form a special group of patients at high risk of complications ofERCP. The aim of the present study was to identify patient- andprocedure-related risk factors for complications of ERCP in pa-tients with PSC.
Patients and methods!
In the years 2007–2009, 3019 ERCPs were performed in HelsinkiUniversity Central Hospital. In 443 of these (14.7%) the indicationfor ERCP was PSC. The patient records were retrospectively re-viewed. In two patients (0.5%) biliary cannulation had failed. Nei-ther of them developed PEP and the biliary cannulation succeed-ed in the second ERCP session. For these patients, the data of thesecond, successful cannulation are included in the analysis. Thepatient group was made up of 441 consecutive patients withPSC. PSC imaging findings were scored according to Ponsioen etal. [10]. All the procedures were performed by an expert (M.F.),who performs all ERCPs for patients with PSC at Helsinki Univer-sity Hospital. All patients received oral levofloxacillin 500mg as aprophylactic antibiotic, within 1 hour prior to ERCP.The primary tools for ERCP were a papillotomy knife (JagtomeRX; Boston Scientific, Miami, Florida, USA) and a 0.035-in, 450-cm guide wire (Jagwire; Boston Scientific) to gain access into thebiliary duct. If the primary cannulation failed, and the guide wireslipped only into the pancreatic duct, pancreatic sphincterotomywas performed with the papillotomy knife over the guide wire. Ifnecessary, a further oblique cut with a needle knife towards 10o’clock starting from the upper end of the pancreatic sphincterot-omy cut was performed in order to gain biliary access. After suc-cessful biliary cannulation a sphincterotomy was performed alsoin that direction. The presence of the guide wire in the pancreaticduct was assessed by the position in fluoroscopy; no contrast wasinjected into the pancreatic duct for the purpose. After cannula-tion of the biliary tract with the papillotomy knife and guidewire, a balloon catheter was inserted into the common hepaticduct and the intrahepatic bile ducts were filled with contrastusing the balloon occlusion technique to ensure adequate visua-lization of the bile ducts. In all ERCP procedures brush cytologyspecimens were collected from intrahepatic and extrahepaticbile ducts using between one and four brushes. In addition, dila-tion of dominant hilar and extrahepatic strictures was performedwhen indicated: i. e., in the presence of pruritus, cholestasis, sig-
nificant prestenotic dilatation, or inability to pass the cytologybrush.Plasma total amylase or pancreatic amylase was measured beforeand 4–6 hours after ERCP. If the patient stayed overnight in thehospital, plasma amylase was checked on the following morning.If a complication occurred, the patient stayed in the hospital untilhe or she recovered.Themain aimwas to evaluate the frequency of complications, i. e.,PEP, cholangitis, bleeding, and perforation. PEP was defined asplasma amylase elevated to three times the upper reference limitor more, and the presence of abdominal pain persisting 24 hoursafter the procedure. Cholangitis was defined as fever requiringintravenous or intramuscular antibiotics occurring within 2days after ERCP. Bleeding was defined as a need for repeat endos-copy due to melena or blood transfusion within 1 week afterERCP. Perforation was diagnosed as an extravasation of contrastduring ERCP or retroperitoneal air on computed tomographyafter the procedure. The severity of the complications was de-fined according to consensus criteria [11].Five patient-related risk factors were recorded: sex, age, historyof previous PEP, radiological scoring of PSC, and previously per-formed biliary sphincterotomy. Six procedure-related risk factorswere included: the number of accidental passes of the guide wireinto the pancreatic duct, pancreatic sphincterotomy, biliarysphincterotomy, precut with a needle knife, balloon dilation ofthe biliary tract, and the duration of ERCP.Data are presented as the median (range) or number of patientsand percentages. Odds ratios are presented with 95%Wald confi-dence intervals (CI). The data were analyzed using SPSS v. 15.0(IBM Corporation, Somers, New York USA) and by Statexact v.4.0 (Cytel Software Corporation, Cambridge, Massachusetts,USA). Fisher’s exact test was used to test for differences betweencategorical variables. Logistic regression was used to calculateodds ratios and P values (Wald χ2) for nominal and ordinal vari-ables. Multivariate logistic regressionwas used to obtain adjustedodds ratios. Age and sex were included in the model as well asrisk factors with a univariate P value of less than 0.1.The risk fac-tors in●" Table1 and contrast agent in the pancreatic duct wereconsidered as risk factors for multivariate analysis. Interactionterms were considered. The Cochran–Armitage trend test wasused to test for an association between the incidence of PEP andan ordered categorical variable. The nonparametric Wilcoxon–Mann–Whitney test was used to compare differences in contin-uous and ordinal variables. Probabilities were regarded as statis-tically significant when they were below the 0.05 level.
Results!
Themedian age of the patients was 38 years (range, 5–80); 46.0%were females. Themedian lengthof hospital staywas 1day (range,0–28) after ERCP. Primary cannulationwas successful in 389/441patients (88.2%). Of these, 147 (37.8%) had undergone a prior bili-ary sphincterotomy. In patients with a naïve papilla, the primarycannulation rate was 82.3%, whereas in those with a previoussphincterotomy it was 100% (P<0.001). In the group with failedcannulation, access to the biliary duct was achieved in 52 cases byfirst performingpancreatic sphincterotomy.Of these, a further cutwith a needle knifewas performed in 11 cases.PEP was seen in 31 patients (7.0%). It was graded as mild in 18,moderate in 10, and severe in 3.One patient with severe PEPwas treated in the intensive care unit for 3 days. No case of necro-
Ismail S et al. Risk factors for complications of ERCP in primary sclerosing cholangitis… Endoscopy 2012; 44: 1133–1138
Original article1134
tizing pancreatitis was diagnosed. All the patients with PEP weretreated conservatively. The median length of hospital stay for PEPpatients was 4 days (range, 2–28 days). Evaluated risk factors forPEP are presented in●" Table1. Factors predicting PEP were fe-male sex (OR 2.6, P=0.015) and accidental passage of the guidewire into the pancreatic duct (OR 8.2, P<0.01). In cases wherethe pancreatic duct remained untouched, the incidence of PEPwas 2.6%. If the wire was twice passed accidentally into the pan-creatic duct, the incidencewas 20%, and if five times it was 31.6%(●" Fig.1; P<0.001 for a trend). Contrast agent was seen in thepancreatic duct in 15 patients. Two of them developed PEP, whichwas not a statistically significant figure (P=0.342).The PEP rate for patients with naïve papillas was 9.2%, whereasfor those with previous sphincterotomy it was 2.7% (P=0.01).Previously performed biliary sphincterotomy was a protectivefactor against PEP (OR 0.28, P=0.02). The risk for PEP increasedas more complicated techniques had to be used for successful ac-cess to the biliary tract. If only cannulation was performed, with-out sphincterotomy, the risk of PEP was 1.4%. If biliary sphincter-otomy was performed alone, the risk for PEP was 6.8%. Whenpancreatic sphincterotomy had to be performed in order to gainaccess into the biliary tract, the PEP ratewas 25%, andwith an ad-ditional biliary sphincterotomy the rate was 27%. In the caseswhere cannulation was most difficult (pancreatic sphincterot-omy, precut, and biliary sphincterotomy, n=9), the rate of PEP
Table 1 Risk factors and incidence of post-ERCP pancreatitis in 441 patients undergoing ERCP for primary sclerosing cholangitis.
Variable No.of PEP cases/No.of patients (%) Odds ratio 95% confidence interval P
SexFemaleMale
21 /203 (10.3)10 /238 (4.2)
2.63 1.21–5.73 0.015
Age, years> 50> 30–50≤30
7 /115 (6.1)15 /197 (7.6)9 /129 (7.0)
0.94 0.57–1.53 0.799
Previous PEPYesNo
3 /23 (13.0)28 /418 (6.7)
2.09 0.59–7.46 0.256
Previous biliary sphincterotomyYesNo
4 /147 (2.7)27 /294 (9.2)
0.28 0.10–0.81 0.010
Wire accidentally in pancreatic ductYesNo
23 /129 (17.8)8 /312 (2.6)
8.25 3.58–18.99 < 0.001
Bile duct balloon dilationYesNo
4 /80 (5.0)27 /361 (7.5)
0.65 0.22–1.92 0.436
Duration of ERCP, minutes> 30> 20–30≤20
13 /138 (9.4)14 /185 (7.6)3 /85 (3.5)
1.54 0.90–2.64 0.120
Radiological PSC score3210
4 /89 (4.5 )3 /77 (3.9)1 /44 (2.3)
22 /227 (9.7)
0.70 0.49–1.00 0.053
TechniquePrecut + biliary and pancreatic sphinc.Biliary and pancreatic sphinc.Pancreatic sphinc.Biliary sphinc.Cannulation
5 /9 (55.6)10 /37 (27.0)1 /4 (25.0)
12 /176 (6.8)3 /213 (1.4)
87.525.923.35.1
15.4–498.56.7–100.11.9–294.11.4–18.4
< 0.001< 0.0010.0150.012
ERCP, endoscopic retrograde cholangiopancreatography; PEP, post-ERCP pancreatitis; sphinc., sphincterotomy.For odds ratios, the last category is used as a reference category.
50
45
40
35
30
25
20
15
10
5
0
Post
ERC
P pa
ncre
atiti
s rat
e (%
)
N = 312
0
N = 33
2–3No of accidental passes of guide wire in pancreatic duct
N = 30
4–6
N = 43
1
Fig.1 The risk of pancreatitis after endoscopic retrograde cholangiopan-creatography increases as the number of times the wire accidentally passesinto the pancreatic duct increases (P<0.001, Cochran–Armitage trendtest; data are presented with exact 95% confidence intervals). N, totalnumber of patients in each group.
Ismail S et al. Risk factors for complications of ERCP in primary sclerosing cholangitis… Endoscopy 2012; 44: 1133–1138
Original article 1135
rose as high as 55.6%. Intrahepatic, extrahepatic, and total PSCscores were slightly lower in patients who developed PEP thanin others (●" Table2). The extrahepatic score was lower in pa-tients in whom performance of a pancreatic sphincterotomywas necessary (0, 0-6) than in other patients (1, 0-6, P<0,001).Patient age and history of PEP, dilation of biliary tract, and dura-tion of ERCP each had no influence on the development of PEP(●" Table1). In multivariate analysis the risk for PEP increasedwith the complication of technique (●" Table3). Another factorpredicting PEP was female sex. Patients in whom biliary sphinc-terotomy had previously been performed always had easy cannu-lations (85% with cannulation only and the rest with biliarysphincterotomy), and so their risk of PEP was not different fromthat of the reference group (reference group: male, age≤30 years,cannulation, no wire in pancreas, radiological score=0).There were no cases of post-sphincterotomy bleeding. Six pa-tients (1.4%) suffered from cholangitis after ERCP. One of themhad mild and the others moderate disease. Patients who devel-oped cholangitis did not have a longer duration of ERCP (median,40 min; range, 18–50min) than the rest of the patients (median,27 min; range, 10–96 min; P=0.096). Three of the six patientswith cholangitis had had a previous biliary sphincterotomy. Cho-langitis developed in 2% of patients with sphincterotomy and in1% of those without (P=0.405). So, there is no evidence that pre-vious biliary sphincterotomy increases the risk of ascending cho-langitis.There were three perforations (0.6%), one due to guide wire per-foration and two related to the sphincterotomy. None of themwas life threatening, and the patients were all successfully treat-ed conservatively. The three patients with a perforation stayed inthe hospital for 5, 6, and 7 days respectively. There were no pro-cedure-related deaths.
Discussion!
ERCP performed with the balloon occlusion technique remainsthe most sensitive and specific method for primary diagnosisand follow-up of the progression of PSC. Diagnosis of small-ductPSC cannot be done without high-quality ERCP. Moreover, for de-tection and surveillance of biliary dysplasia and dilation of domi-nant strictures, ERC is an irreplaceable diagnostic and therapeu-tic tool. However, the risks related to the procedure must alwaysbe weighed up against the benefits for the patient. The compli-cation rate associated with ERCP has been reported to rangefrom 4% to 15.9% in patients without PSC, and up to 14% in pa-tients with PSC [12–14]. Some studies comparing complicationsin PSC and non-PSC patients show that neither the overall com-plication rate nor the risks of PEP, perforation, and bleeding differbetween the two groups [8, 12]. In the authors’ unit, the PEP ratein naïve papillas is 4.8% in indications other than PSC, whichtends to be somewhat lower than in patients with PSC with a na-ïve papilla (9.2%). In a recent study, the incidence of post-ERCPcholangitis was reported to be higher in patients with PSC thanin the control group of non-PSC patients [8]. The study also foundthe duration of ERCP to be longer in those patients who devel-oped cholangitis. One explanatory factor for the differences be-tween the reported complication rates is the number of interven-tions carried out during the ERCP procedure. Cholangitis was nota common complication in the present study and no associationwas found between a prolonged procedure time and the develop-ment of cholangitis, neither did previous biliary sphincterotomyincrease the risk of ERCP-associated cholangitis. These findingsmay partly be explained by the prophylactic antibiotic regularlyused in this study.In the present study, we included a large cohort of patients withPSC who underwent ERCP for primary diagnosis, therapeuticpurposes, or surveillance of disease progression and biliary dys-plasia. In our unit, a diagnosis of PSC is always confirmed by ERCPand liver biopsy. All patients who are potential candidates for liv-
Table 2 Scoring of primary scle-rosing cholangitis (PSC) and inci-dence of post-ERCP pancreatitis in441 patients.
1
Intrahepatic score Extrahepatic score Total score N
Median Range Median Range Median Range
Min. Max. Min. Max. Min. Max.
No PEP 3 0 6 1 0 6 4 0 11 410PEP 2 0 5 0 0 6 2 0 10 31P 0.022 0.030 0.005
ERCP, endoscopic retrograde cholangiopancreatography; PEP, post-ERCP pancreatitis.1 Scoring according to Ponsioen et al. [10].
Table 3 Multivariate analysis ofrisk factors of post-ERCP pancrea-titis in 441 patients undergoingERCP for primary sclerosing cho-langitis.
Variable Odds ratio 95% confidence interval P
Sex, female/male 2.4 1.0–5.8 0.046Age, years, > 50 / > 30–50 / ≤30 0.9 0.5–1.6 0.726TechniquePrecut + biliary and pancreatic sphinc.Biliary and pancreatic sphinc.Pancreatic sphinc.Biliary sphinc.Cannulation (reference category)
46.313.112.94.7
5.0–430.01.9–90.30.8–221.51.05–21.15
0.0010.0090.0780.046
No. of times wire in pancreas, 5–0 (0 reference category) 1.2 0.97–1.61 0.088Previous biliary sphincterotomy, yes/no 1.5 0.4–5.9 0.561Radiological score PSC, 3 /2 /1 /0 0.85 0.58–1.26 0.417
ERCP, endoscopic retrograde cholangiopancreatography; sphinc., sphincterotomy.For odds ratios, the last category is used as a reference category. No significant interactions were found.
Ismail S et al. Risk factors for complications of ERCP in primary sclerosing cholangitis… Endoscopy 2012; 44: 1133–1138
Original article1136
er transplantation undergo regular screening and surveillance forbiliary dysplasia with repeated ERCPs and multiple brushings ofintrahepatic and extrahepatic bile ducts. With this strategy, ana-lyzing DNA ploidy and Papanicolaou stain from brush cytology,we have been able to demonstrate a sensitivity of 72% and a spe-cificity of 82%, with a positive predictive value of 86% and a neg-ative predictive value of 67% for biliary malignancy [3].However, multiple interventions in bile ducts have been shownto increase the complication rate [8]. Since most patients areasymptomatic when they come to ERCP, safety and technical suc-cess must be optimized. In the present study, the success rate ofbiliary cannulation was high.
Complication rate and mortalityThe overall complication rate of 9% after ERCP is a little less thanin some previously published reports of patients with PSC [8, 12],which may be due to the guide wire cannulation technique weuse. On the other hand, the patients underwent multiple proce-dures during the ERCP, including balloon catheter insertion andseveral brush instruments and dilations, which are known to in-crease the overall risk of complications. All the complicationscaused prolonged hospitalization, but it was possible to treatthem conservatively. There were no procedure-related deaths.In one study with a large number of ERCP patients, the overallmortality rate was 0.4%, and half of the deceased were over 70years of age and another half had serious co-morbidities [6].Most patients with PSC are young and have no serious coexistingmedical condition, which explains the absence of mortality.Probably for the same reason, we could not find any associationbetween age and risk of PEP, although there are studies reportingthat young age is associated with a high PEP rate [6,15,16].
PancreatitisPEP occurred in 31 cases, in three of which it was graded as se-vere. Unlike in some other studies [17,18], in the present studya history of PEP was not a risk factor for new PEP. The PEP rate infemale patients was more than twice that in male patients. Fe-male sex has been related to increased risk of post-ERCP compli-cations [11,16,19–21]. However, there are many studies whichfind no association between sex and increased complications[5, 8,15,18,22]. Accidental wire insertion into the pancreaticduct was a risk factor for PEP, and the risk increased with multi-ple passes. Previous papillotomy was a protective factor for PEP;this can be explained by the fact that cannulation is technicallyeasier and also that accidental slipping of the wire into the pan-creatic duct is less probable. These results relating to the techni-cal part of the procedure suggest that mechanical irritation of thepapilla has a significant effect on the risk of PEP.Many studies show that contrast agent in the pancreatic duct in-creases the risk of PEP [5,15,17,18,23]. In the technique of pan-creatic sphincterotomy, the position of the wire in the pancreaticduct is usually clearly distinguishable without contrast injectionunder fluoroscopy. However, in our previous study, the presenceof contrast agent in the pancreatic duct was not a risk factor forPEP [9]. In the study of Lella et al. [24], accidental insertion ofthe guide wire into the main pancreatic duct a median of twotimes happened in 82/200 patients (41%) without any adverseeffect. The difference in these results may be due to differencesin PEP diagnosis: an amylase level five times the upper referencelimit was needed to diagnose PEP in their study compared withthree times the upper reference limit in the present study. Still,
in the study of Artifon et al. [23], accidental guide wire insertioninto the pancreatic duct did not cause PEP.Precutting is a valuable tool which increases the success rate oftherapeutic ERCP to over 90–95% [25,26]. In many studies, pre-cutting has been related to an increased complication rate [6,18,22]. Freeman et al. reported that precutting increased the risk ofPEP [6], while Loperfido et al. showed it to increase the risk ofduodenal perforation [22]. There are, however, other studiesshowing that this technique is nomore harmful than convention-al sphincterotomy [8,26–29]. In our data set precutting was per-formed only if cannulation was unsuccessful after pancreaticsphincterotomy. So, in nearly all cases where precut was used,the wire had slipped into the pancreatic duct many times, andalso pancreatic and biliary sphincterotomy were performed,forming the most difficult cannulation cases of the series– thusexplaining the high PEP rate. In high-risk patients, prophylacticplacement of a pancreatic stent decreases the risk of PEP [30]. Asin our series there was a high PEP rate in patients with the mostdifficult cannulations, placement of a pancreatic stent could bebeneficial in such cases.We have previously compared pancreaticsphincterotomywith the precut technique in difficult biliary can-nulations [9]. In our experience, pancreatic sphincterotomy issafe and results in a high cannulation success rate. Catalano et al.also found the complication rate to be lower with pancreaticsphincterotomy than with the precut technique [31]. In our pre-vious study [9], the need for the additional precut after pan-creatic sphincterotomy was 42%, while in the present study itwas 21%. Cannulation technique may vary according to individ-ual endoscopists. The dissimilarity may also be due to the factthat in the present study the patient group consisted only ofthose with PSC. However, the extrahepatic PSC score was nohigher in patients requiring pancreatic sphincterotomy than inthose who did not. Thus, a stricture of the extrahepatic bile ductdoes not completely explain the difficulty of biliary access.Difficult cannulation increased the risk of PEP [6,17,19]. Biliarysphincterotomy has also been associated with an increased riskof PEP; in one large prospective study the odds ratio (OR) for PEPwas 1.21 (range, 0.91–1.60) [6]. In our study, biliary sphincterot-omy was associated with a 6.8% risk of PEP, but in consecutiveERCP procedures a previously performed biliary sphincterotomywas a significantly protective factor (OR 0.28, P=0.01). For thisreason, we recommend that biliary sphincterotomy be per-formed for patients with PSC in whom long-term follow-up withERCP is planned.In conclusion, PSC has previously been shown to increase the riskof cholangiocarcinoma by up to 161 times. As the development ofcholangiocarcinoma is unpredictable on the basis of clinicalsymptoms, ERCP, or magnetic resonance cholangiographic find-ings, ERCP with brush cytology is an indispensable diagnosticand therapeutic tool for detecting biliary dysplasia in patientswith PSC with fairly low risk of severe complications and no mor-tality. We recommend endoscopic sphincterotomy to preventPEP in patients with PSC undergoing dysplasia surveillance withrepeated ERCPs. Endoscopic sphincterotomy is not associatedwith an increased risk of ERCP-associated cholangitis.
Competing interests: None
Ismail S et al. Risk factors for complications of ERCP in primary sclerosing cholangitis… Endoscopy 2012; 44: 1133–1138
Original article 1137
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Ismail S et al. Risk factors for complications of ERCP in primary sclerosing cholangitis… Endoscopy 2012; 44: 1133–1138
Original article1138
II
Endoscopic papillectomy, single-centre experience
Shamel Ismail • Udd Marianne • Jarvinen Heikki •
Halttunen Jorma • Kylanpaa Leena
Received: 3 January 2014 / Accepted: 29 April 2014! Springer Science+Business Media New York 2014
AbstractBackground Endoscopic removal of benign tumours of
papilla is increasing. Our aim was to evaluate the outcome
of endoscopic resection of papillary tumours.Methods In the years 2000–2012, 61 papillectomies were
performed in Helsinki University Central Hospital. The
cases were analysed retrospectively.Results There were 35 patients with benign tumour of
papilla without familial adenomatous polyposis (FAP), 16
patients with FAP and 10 patients with ampullary cancer.Jaundice and bile duct dilation were risk factors for malig-
nancy (p \ 0.001). In benign tumours, the recurrence rate was
25.5 %. In 5/51 benign tumour cases (9.8 %), a pancreatico-duodenectomy was performed. The remaining cases were
treated endoscopically. Neither tumour size, resection in one
piece or piecemeal technique, nor coagulation of resectionmargins had an effect on the development of residual tumour.
The total complication rate was 24.6 %. Pancreatitis devel-
oped in six patients (9.8 %, 3 mild and 3 moderate). In benigntumour cases, pancreatic stent decreased pancreatitis rate
(p = 0.045). In cases where only a pancreatic sphincterotomywas performed, the risk of pancreatitis was high 4/7 (57 %).
Bleeding was the most common complication (18 %). Only
one patient was operated due to complication, a post-papil-lectomy bleeding. In six out of seven non-operated cancer
patients, the disease progressed.
Conclusion Endoscopic papillectomy is an effectiveprocedure for treating benign papillary tumours. Jaundice
and bile duct dilation are more common in malignant
tumours. Pancreatic stent decreases the risk of post-papil-lectomy pancreatitis. Pancreatic sphincterotomy without
stenting carries a high risk of pancreatitis. For papillary
cancer, surgery is recommended.
Keywords Ampulla of Vater ! Papillectomy ! Adenoma !Carcinoma ! Familial adenomatous polyposis
The most common benign lesions in the ampulla of Vater
are villous and tubulovillous adenomas [1, 2]. Benign
ampullary adenomas have premalignant potential [3].These adenomas may occur sporadically or in the setting of
familial adenomatous polyposis (FAP). Autopsy series
have estimated the prevalence of ampullary adenoma to bebetween 0.04 and 0.12 % [4, 5]. In FAP, duodenal ade-
nomas occur in nearly all patients with time, the most
commonly at the area of the papilla [6, 7]. With theincreasing use of endoscopy, especially endoscopic retro-
grade cholangiopancreatography (ERCP), tumours of the
papilla are being progressively more recognised.The treatment of the adenomas of the major duodenal
papilla can be either surgical (pancreaticoduodenectomy or
local excision) or endoscopic resection. To eliminate the riskof histologic progression and to exclude foci of carcinoma
within the adenoma, pancreaticoduodenectomy remains the
only choice of treatment, but is associated with significantmorbidity and mortality. In pancreaticoduodenectomy, a
perioperative mortality rate of between 2 and 5 % and a sig-
nificant rate of postoperative complications (up to 41 %) havebeen reported [8, 9]. Local excision has lower mortality and
morbidity rates, but is associated with the risk of recurrence
[10, 11]. Currently, endoscopic papillectomy with curativeintent is increasingly performed for benign papillary tumours.
A systematic review estimated that success rates for
S. Ismail ! U. Marianne ! J. Heikki ! H. Jorma ! K. Leena (&)Department of Gastrointestinal and General Surgery, HelsinkiUniversity Central Hospital, P.O. Box 340, 00029 HUS Helsinki,Finlande-mail: [email protected]
123
Surg Endosc
DOI 10.1007/s00464-014-3596-5
and Other Interventional Techniques
endoscopic removal of ampullary adenomas range from 46 to
92 %, while recurrence rates range from 0 to 33 % [12].This study evaluates the safety of endoscopic resection
of papilla in benign and malignant tumours, and patient
outcomes under surveillance.
Patients and methods
In the years 2000–2012, a total of 61 papillectomies for
tumours of the papilla of Vater were performed at HelsinkiUniversity Central Hospital, in the Department of Gastro-
intestinal and General Surgery. All the procedures were
performed by the two experts who perform over 200ERCPs annually. All the patients received 500 mg of oral
levofloxacillin as a prophylactic antibiotic within 1 h prior
to the ERCP. The patient material consisted of 35 patientswith a benign papilla tumour without FAP, 16 patients with
FAP and 10 patients with ampullary cancer. No formal
Research Ethics Board approval was applied due to theretrospective nature of the study. However, institutional
research permission was granted for the study protocol.
Papillectomy
Papillectomy was performed under fluoroscopic guidanceand with a side-viewing duodenoscope. The patient was in
a prone position. An anaesthesiologist sedated and moni-tored the patient throughout the procedure.
The pancreatic duct was identified and cannulated with a
sphincterotome and a guide wire. Using the sphinctero-tome, a minimal dose of methylene blue was injected into
the pancreatic duct to mark the orifice and end of the duct.
The tumour was grasped with a polypectomy snare andresected using blended electrosurgical current (50–60 J).
En bloc resection was attempted, and piecemeal resection
was performed when necessary. After the papillectomy, theaim was to insert a 5–7 Fr, 3–7 cm pancreatic stent. A
pathologist examined the resected specimen.
Follow-up
Control examinations using a side-viewing endoscope after1, 3 and 6 months were planned. Complications were divi-
ded into pancreatitis, bleeding, perforation and cholangitis.
The severity of complications was graded by the consensusdefinition by Cotton et al. [13]. Data about the patients were
collected retrospectively from the patient files.
Statistical analysis
Statistical analysis was performed using IBM SPSS Sta-tistics (version 19.0, Chicago, Ilinois, USA).The results are
presented as median and range. Comparison of the results
between groups was made using the Mann–Whitney U testand Pearson’s v2 test, as appropriate. A p value below 0.05
was considered significant.
Results
Patient characteristics are presented in Table 1. Lesion size
was determined by pathologic reports. The median age ofthe cancer patients was higher (77 years, 67–91) than the
age the patients with benign lesions (58 years, 28–79,
p \ 0.001). The ampullary cancer patients had jaundicemore often than the patients with benign tumours (90 vs.
14 %, p \ 0.001). Similarly, bile duct dilation was more
frequent in the cancer patients (100 vs. 27 %, p \ 0.001).The median hospital length of stay was 1 day (0–45).
Benign papillary tumours: no FAP
Of benign papillary adenomas in patients without FAP, 18
of 35 (51 %) were found incidentally in gastroscopy(n = 14), computed tomography (CT, n = 2) or magnetic
resonance imaging (MRI, n = 2). Seven of the patients
(20 %) had jaundice as a symptom. Six patients underwentinvestigations due to bleeding episodes or anaemia. Four
patients had ERCP due to acute pancreatitis with unknown
aetiology. The concordance between pre-resection biopsyand the resected specimen was 24 of 32 (75 %, Table 1).
Endoscopic ultrasound (EUS) was performed on 12
patients before papillectomy. In ERCP, contrast was nec-essary in only 10 patients, while the position of the wire in
pancreatic duct could be confirmed in fluoroscopy. During
the endoscopy, methylene blue was inserted into the pan-creatic duct in 6 out of 35 patients. Pancreatic stenting was
attempted for 17 patients. For 10 patients, stenting was not
attempted because pancreatic endoscopic papillotomy(EPT) was considered sufficient. Thus, pancreatic stenting
was successful in 16 of 17 patients (94 %). EPT for the bile
duct was performed for 23 patients (66 %). After thepapillectomy, resection margins were coagulated in 23
patients in order to prevent bleeding.
Post-papillectomy complications developed in ninepatients (25.7 %, Table 1). Post-ERCP pancreatitis devel-
oped for four patients (11 %, 3 mild cases, 1 moderate). Six
patients had bleeding and were treated endoscopically.There were two retroperitoneal perforations which were
treated conservatively. One patient with a large adenoma
had all the three complications.The follow-up time was 14 months (range 1–91). Ten
patients (29 %) had residual adenomas. Four of them
received pancreaticoduodenectomy, which revealed anadenoma with high-grade dysplasia in two patients and a
Surg Endosc
123
carcinoma in one patient. One patient had a carcinoma
in situ in follow-up biopsies, but in the pancreaticoduo-denectomy specimen there was no neoplasm. The rest of
the residual cases could be treated endoscopically.
FAP
All papillary adenomas in FAP patients were found inroutine endoscopic follow-up (Table 1). The concordance
between pre-resection biopsy and the resected specimenwas 14/16 (88 %). EUS was not planned before papillec-
tomy. During the procedure, contrast was necessary in only
four patients. Methylene blue was inserted into the pan-creatic duct in 12 of 16 patients (75 %). Pancreatic stenting
was attempted for 14 of 16 patients. For one patient, pan-
creatic EPT only was considered sufficient. Thus, pancre-atic stenting was successful in 12 of 14 patients (86 %).
One of them had the stent placed in the minor papilla. A
bile duct EPT was done for 13 of 16 patients (81 %,Table 1).
Four patients (25 %) developed complications. Post-
ERCP pancreatitis with moderate severity developed intwo patients. Three patients (19 %) had a bleeding com-
plication which could be treated endoscopically. The fol-
low-up time is 37 months (range 1–63). Three patients(19 %) had residual adenomas. In two of them they were
minor lesions, which could be treated with biopsy forceps
and coagulation. A pancreaticoduodenectomy was per-formed on the third patient, which revealed an adenoma
with high-grade dysplasia in the specimen. One of the FAP
patients had a pancreaticoduodenectomy 4 years after thepapillectomy because of multiple duodenal adenomas
which were distant from the papilla (1 high grade and 3 low
grade).
Ampullary cancer
Of the patients, nine out of ten had jaundice as the primary
symptom. One patient had a gastroscopy because of a
bleeding episode. The pre-resection biopsies revealedcancer in only one patient. In four patients, the result was
an adenoma with high-grade dysplasia, and two patients
had low-grade dysplasia (Table 1). EUS was performed forfour patients before the papillectomy. In three of them, the
tumour was considered to be resectable endoscopically. In
one patient, the tumour infiltrated through the duodenalwall but the biopsies revealed only adenoma with high-
grade dysplasia and not cancer. CT or MRI scans were
performed on all the patients before papillectomy. Bileduct dilation was present in all the cases and dilation of the
pancreatic duct was ascertained in six of them. During the
Table 1 Characteristics of the patients and the procedure
Benign tumour,no FAP
FAP Cancer
n = 35 n = 16 n = 10
Male/female 24/11 9/7 5/5
ASA
I 7 0 0
II 10 10 1
III 17 6 7
IV 1 0 2
Concomitant diseases
Coronary heart disease 8 0 3
Pulmonary disease 8 1 3
Diabetes 6 0 0
Other 31 0 9
Indications of ERCP
Incidental finding/surveillance 18 16 0
Jaundice 7 0 9
GI bleeding or anaemia 6 0 1
Pancreatitis 4 0 0
Abdominal pain 0 0 0
The size of tumour
\1 cm 1 0 0
1–2 cm 23 15 5
2.1–4 cm 7 1 5
[4 cm 2 0 0
Unknown 2 0 0
Pre-resection histologic diagnosis
Low-grade dysplasia 24 13 2
High-grade dysplasia 8 3 4
Adenocarcinoma 0 0 1
Other 0 0 0
Post-resection histologic diagnosis
Low-grade dysplasia 18 13 0
High-grade dysplasia 14 3 0
Adenocarcinoma 0 0 10
Othera 3 0 0
Procedure
Biliary sphincterotomy 23 13 8
Pancreatic sphincterotomy 19 8 4
Pancreatic stenting 16 12 4
Coagulation of margins 23 15 9
Complications
Pancreatitis 4 2 0
Mild 3 0
Moderate 1 2
Bleeding 6 3 2
Extraperitoneal perforation 2 0 0
a One amyloidosis, one paraganglioma, one inflammatory changes
Surg Endosc
123
procedure, methylene blue was inserted into the pancreatic
duct in two patients. Pancreatic stenting was not performedfor two patients because of wide pancreatic EPT. Pancre-
atic stenting was successful in four of the five cases in
which it was attempted (85 %). Biliary sphincterotomy wasperformed for eight patients.
There were no cases of post-papillectomy pancreatitis or
perforation. Two patients (20 %) developed bleeding as acomplication, despite coagulation during the papillectomy.
One was treated endoscopically, but the other needed alaparotomy and duodenotomy.
Three patients ended up undergoing a pancreaticoduo-
denectomy. In all of them, a residual cancer (4 mm, 1 cm,3 cm) was found in the resected specimen. The patient with
the 3 cm tumour also had 6/16 lymph node metastasis. The
patient with the 4 mm residual cancer had undergone acontrol duodenoscopy before the operation, which did not
reveal any tumour at the papillectomy site. The two
patients without lymph node metastasis, who were operatedon, have now been followed up for 6 and 8.5 years,
respectively, without any signs of malignancy. The patient
with lymph node metastasis died 14 months after theoperation due to cancer. Two out of 7 non-operated
patients needed endoscopic stenting due to biliary
obstruction. Six of the 7 non-operated patients died9–28 months after papillectomy. Three of them died due to
ampullary cancer and one due to pneumonia. The patient
who is still alive has now been followed up for 5 months.
Procedure and complications
In total, 15 patients out of 61 (24.6 %) had complications.
In benign tumours there were 13 patients out of 51
(25.5 %) with residual adenomas in follow-up. The numberwas the same regardless of whether the papillectomy was
performed en bloc or in piecemeal. The size or grade of the
adenoma did not have an effect on the development ofresidual adenoma, neither did coagulation of the resection
margins decrease the risk of residual adenomas (p = ns).
Post-papillectomy pancreatitis developed in 6 of 61patients (9.8 %). Contrast was inserted into the pancreatic
duct in only 18 patients (30 %), but the pancreatitis risk did
not increase for them (n = 1). Among patients with benigntumour, the patients with a prophylactic pancreatic stent
(n = 28) had only one case of pancreatitis. The patients
without a stent (n = 23) had five pancreatitis cases(p = 0.045). In cases where only pancreatic EPT was
performed without inserting a stent (n = 7), the rate of
pancreatitis was high (n = 4, 57 %, p = 0.002). Resectionmargins were coagulated in 47 patients (77 %), but this did
not prevent the risk of bleeding, since 10 out of 11 bleeding
complications happened in these cases.
Discussion
Cancer
Jaundice as a symptom and bile duct dilation are clear riskfactors of malignancy. Still, in the present series, in the
benign tumour cases, 14 % of patients presented jaundice
as a symptom. The only cases that survived the cancer werethose who were operated on and had no lymph node
metastasis. In cancer patients, especially, it is hard to
estimate complete endoscopic removal, which was under-lined in the case with a clean post-papillectomy finding in
the duodenoscopy but a 4 mm cancer in the pancreatico-
duodenectomy specimen. Of course, the most commonreason not to operate is that the patient is unfit for surgery.
Pre-resection biopsy has been shown to be unreliable in
many cases [14]. Similarly, in the present series, biopsiesrevealed cancer in only one patient and the papillectomy
specimen was needed for diagnosis. Pancreaticoduoden-
ectomy is the treatment of choice for papillary cancer.Many experts consider even the adenomas with high-grade
dysplasia to be an indication for surgery [10, 15, 16]. As
was shown here, even a thorough follow-up may miss asmall cancer. By radical surgery the outcome of the patient
is favourable. If the cancer diagnosis is made before pap-
illectomy, palliative biliary stenting would probably be anappropriate procedure for patients unfit for surgery. In
bleeding tumours, papillectomy could still be helpful.
FAP
In FAP patients, duodenal adenomas are common and they
often occur in the papilla [17]. Surveillance seems to be
beneficial, since none of the FAP patients in the presentseries developed cancer. In addition, the concordance
between pre-resection biopsies and papillectomy speci-
mens was high. By endoscopic it is possible to postponesurgery, which should be reserved for patients with a high
risk of malignancy. The timing of the operation is not clear,
since randomised controlled studies are lacking. The factthat adenomas also develop after surgery, especially near
hepaticojejunal anastomosis, makes the decision about
whether to operate even more complex.
Pancreatitis and pancreatic stent
The post-papillectomy pancreatitis rate in our series was
9.8 %, which is acceptable. There were no cases of the
severe form of disease. The use of a prophylactic pancre-atic stent decreased the risk of pancreatitis, as has also been
shown in previous studies [18–21]. Using the guide-wire
cannulation technique, injection of contrast into the pan-creatic duct is not necessary to ensure correct positioning
Surg Endosc
123
of the guide wire. Some endoscopists perform pancreatic
EPT before a papillectomy to ensure pancreatic stentingafterwards. The technique using methylene blue minimises
the risk of not locating the pancreatic duct orifice. In the few
cases where the pancreatic duct was not found with standardtechniques, administering secretin to the patient was helpful.
In our unit, we use pancreatic sphincterotomy in difficult
biliary cannulation, and it has been shown to be a safetechnique [22, 23]. However, in the present series, pancre-
atic EPT without a pancreatic stent was not sufficient toprevent pancreatitis; on the contrary, the risk increased
markedly in papillectomy. By changing our policy to insert a
pancreatic stent every time when the pancreatic duct isreached, we should be able to reduce our pancreatitis risk to
a lower level. It seems that ampullary cancer patients have
minimal risk of pancreatitis, but the explanation for this isunknown. Recently, it was suggested that non-steroidal anti-
inflammatory drugs (NSAIDs) would be more efficient than
a pancreatic stent in preventing post-ERCP pancreatitis [24],but NSAIDs and pancreatic stenting could also act syner-
gistically [25]. While papillectomy is a high-risk procedure,
both NSAIDs and pancreatic stenting may be needed untilthere is stronger evidence for either of them from prospec-
tive randomised studies.
Complications
If endoscopic treatment has acceptable morbidity, mortal-ity and recurrence rates, the procedure could be considered
to be the treatment of choice for benign tumours of the
duodenum. Post-papillectomy complications include pan-creatitis (5–19 %), perforation 0–5 %, bleeding 0–18 %
and cholangitis 0–4 % [21]. We had 11 cases of bleeding
(18 %), six of pancreatitis (9.8 %), two perforations(3.3 %) and no cholangitis. Our total complication rate of
24.6 % of patients is relatively high. However, among
these there were three patients with mild pancreatitisrequiring only 2 days of hospitalisation. In addition, all but
one patient could be treated conservatively, and there were
no procedure-related deaths. In treating FAP patients inparticular with papillectomy, safety is the most important
factor to be considered. The complication rate of FAP
patients was no higher than in other benign tumours, whichdiffers from the study by Irani et al. [14], where the pan-
creatitis rate was significantly higher in FAP patients.
Bleeding
Post-papillectomy bleeding happened in 18 % of thepatients. One explanation for the high percentage may be that
our policy is to do a duodenoscopy quickly, if there is any
suspicion of bleeding. Interestingly, coagulation of theresection margins during the papillectomy did not prevent
bleeding. This may, however, be due to the retrospective
nature of the study. Perhaps the patients with the greatest riskof bleeding were coagulated. Still, it is hard to find a means of
reducing the risk of bleeding, since using haemostatic agents
next to the pancreatic duct seems to be a risky option. Hae-mostatic clips placed after pancreatic stenting could be one
option to reduce bleeding complications.
In summary, the endoscopic ampullectomy is a safe andeffective treatment for benign ampullary tumours and
should be considered as the initial intervention. Jaundiceand bile duct dilation are risk factors for malignancy.
Residual adenomas occur frequently but are mostly treated
endoscopically. The risk of complications is high, but theycan usually be treated endoscopically or conservatively.
Pancreatic stenting decreases the risk of pancreatitis. It is
recommended to treat cancer surgically whenever possible.
Disclosures Drs. Shamel I, Udd M, Jarvinen H, Halttunen J andKylanpaa L have no conflicts of interest or financial ties to disclose.
Funding The manuscript has no funding.
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0954-691X Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MEG.0000000000001515 1200
Original article
Criteria for difficult biliary cannulation: start to countShamel Ismail, Marianne Udd, Outi Lindström, Mia Rainio, Jorma Halttunen and Leena Kylänpää
Introduction
The primary biliary cannulation with sphincterotome and guidewire or catheter fails in 15–35% of patients [1–3]. The risk of post-endoscopic retrograde cholangiopancrea-tography (ERCP) pancreatitis (PEP) varies between 3 and 15%, and is increased in high-risk patient groups [4, 5]. Difficult cannulation, needle-knife precut, frequent injec-tions into the pancreatic duct (PD), transpancreatic bil-iary sphincterotomy (TPBS) and balloon dilatation of the intact biliary sphincter are reported to be procedure-re-lated factors that are responsible for the PEP risk [6, 7].
The definition of difficult biliary cannulation [8] is more than five contacts with the papilla; more than 5 min cannulation time following touching of the papilla; more than one unintended PD guidewire passage. This defini-tion is based on a Nordic multicenter study [9].
Aim of the study is to confirm these criteria for difficult cannulation with regard to the PEP rate, and to study the final cannulation success, when primary cannulation meth-ods and advanced cannulation methods like TPBS with or without needle-knife precut sphincterotome precut (SPH),
needle-knife precut, double guidewire cannulation (DGW) and papillectomy were used.
Methods
Analysis of routinely collected data in the Helsinki University Hospital was undertaken during March 2011 to September 2014. Four gastrointestinal surgeons under-took 3272 ERCPs, including 1723 cases with native papilla. After every ERCP, an endoscopist had to fill an excel file with details of patient demographics, indication, cannulation details, performed procedures. We excluded 322 patients where the PD was the target and 580 patients without a complete recorded cannulation time and details. These included altogether 6–18 variables (method: cannu-lation time, number of papilla contacts, number of pancre-atic guidewire passages and contrast injections) depending on the needed cannulation methods to gain success. The number of patients with the recorded cannulation details increased from 37.8% in year 2011 to 69.3% in year 2014, P < 0.001. The study group comprised 821 patients. The study was approved by the hospital ethics committee.
Peroral levofloxacin 500 mg was administered. After September 2013, protocol to administer rectal diclofenac (100 mg) before ERCP was started, and during this period, 256 patients underwent ERCP. Of them, 181 (71%) had rectal diclofenac and 75 did not receive it (elevated cre-atinine: n = 42; allergy: n = 7; miscellaneous reasons: n = 9; reason not known: n = 17). All in all, 22.1% of the patients had rectal diclofenac. Patients were in left lat-eral decubitus position and an anesthesiologist provided conscious sedation with propofol. During perioperative period, patients received standard hydration. We did not have aggressive hydration policy [10].
European Journal of Gastroenterology & Hepatology, 2019 31:1200–1205
Keywords: adverse event, biliary sphincterotomy, difficult cannulation, ERCP, mortality, needle-knife precut, post-ERCP pancreatitis, sphincterotome precut, transpancreatic biliary sphincterotomy
Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Correspondence to Marianne Udd, MD, PhD, University of Helsinki and Helsinki University Hospital, P.O. Box 340, HUS 00029, Finland
Tel: +358504270182; fax: +3580947174688; e-mail: [email protected]
Received 10 April 2019 Accepted 18 June 2019
Objective In European Society of Gastrointestinal Endoscopy guidelines, biliary cannulation of native papilla is defined as difficult in the presence of >5 papilla contacts, >5 min cannulation time or >1 unintended pancreatic duct cannulation (5-5-2). The aim is to test 5-5-2-criteria in a single-center practice predicting the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), and to study the efficacy of transpancreatic biliary sphincterotomy (TPBS) as an advanced method for biliary cannulation.Methods Prospectively collected data of 821 patients with native papilla were analyzed. Primary cannulation was the first method chosen for cannulation (sphincterotome and a guidewire). Advanced cannulation method was endoscopist-chosen cannulation method after failed primary cannulation.Results Primary cannulation succeeded in 599 (73%) patients in a median of 2 min. TPBS ± needle knife resulted in a 90% success rate. The final cannulation success was 814 (99.1%) cases in a median of 5.3 min. PEP risk was 4.0%. When primary cannulation succeeded, the PEP rate was 2.3%. When advanced methods were needed, the PEP rate increased to 13.5%. Altogether 311 (37.9%) patients fulfilled at least one 5-5-2-criterion. In patients without 5-5-2-criteria, the primary cannulation succeeded in 79.6% (n = 477), compared to 20.4% (n = 122) with the criteria, P < 0.001, indicating the need to exchange the cannulation method instead of persistence. If all the 5-5-2-criteria were present, the risk of PEP was 12.7%.Conclusion The results support the use of the 5-5-2-criteria for difficult cannulation. TPBS is an effective advanced cannulation method with an acceptable complication rate. Eur J Gastroenterol Hepatol 31: 1200–1205Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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www.eurojgh.com 1201Criteria for difficult biliary cannulation Ismail et al.
Definitions
The cannulation time was defined as the period between the first contact with the papilla and the deep biliary cannulation. An attempt was defined as each continu-ous contact with the papilla. Loss of contact and repo-sitioning counted as a new attempt. Contrast injections and passages with a guidewire into the PD were counted. Total procedure time was a period between insertion and removal of duodenoscope.
Primary cannulation was defined as the first cannu-lation method (cannulation with sphincterotome and a straight guidewire) as used. After primary cannulation, second, third and fourth methods were advanced can-nulation methods chosen by an endoscopist. Advanced cannulation methods were TPBS, SPH, needle knife (NK) precut, DGW and papillectomy. In TPBS, with the guide-wire in the PD, an incision is directed toward the bile duct through the septum between the two ducts. Then the bil-iary duct opens and cannulation can be attempted with sphincterotome and guidewire; or the wall of the duct becomes visible and can be opened with a NK and then, cannulation with sphincterotome and a guidewire is possi-ble [11, 12]. In sphincterotomy precut, papillary orifice is cut with sphincterotome inside papilla, then, cannulation could be attempted. In NK technique, papillary orifice was cut with NK until the underlying biliary sphincter visual-ized and cannulation can be attempted. In papillectomy, papillary mucosa is resected with snare to visualize bil-iary duct orifice to help cannulation of the biliary duct. In DGW technique, with the guidewire in the PD, biliary cannulation is attempted with the second guidewire. We did not routinely place prophylactic pancreatic stents after advanced cannulation.
Successful cannulation was defined as a biliary cannu-lation with the guidewire inside the common bile duct. Failed cannulation was a situation when no access to bil-iary duct was achieved during ERCP procedure. Difficult cannulation was defined according to the European Society of Gastrointestinal Endoscopy guidelines (5-5-2 criteria) [8]. Easy cannulation was defined as cannulation not fulfilling the difficult cannulation criteria. Adverse events were defined and graded according to the modified Cotton consensus [13].
Mild PEP was defined as a state with clinical pancreati-tis, amylase at least three times normal at more than 24 h after the procedure, requiring admission or prolongation of planned admission to 2–3 days, moderate pancreatitis as pancreatitis requiring hospitalization of 4–10 days and severe pancreatitis as pancreatitis requiring hospitaliza-tion for more than 10 days, or hemorrhagic pancreatitis, phlegmon, or pseudocyst, or intervention (percutaneous drainage or surgery). Bleeding was graded as mild (clinical bleeding was present with no need of transfusion), moder-ate [need of transfusion (4 units or less), no angiographic intervention or surgery] and severe (need of transfusion 5 units or more, or angiographic/surgical intervention). Perforation was graded as mild (slight leak of fluid or contrast, treatable by fluids and suction for 3 days or less), moderate (any definite perforation treated medically for 4–10 days) or severe (hospital stay for more than 10 days, or percutaneous or surgical intervention needed). Cholangitis was graded as mild (fever >38ºC, 24–48 h),
moderate (fever or sepsis requiring more than 3 days of hospital stay or endoscopic or percutaneous intervention) or severe (septic shock or surgery).
SPSS v 15.0 (IBM Corporation, Somers, New York) was used for data analysis. The χ2 test was used to test for a difference between categorical variables. A nonparamet-ric Wilcoxon-Mann–Whitney test was used to compare differences in continuous and ordinal variables. P-values <0.05 (two-sided) were regarded as being statistically significant.
Results
Cannulation details in 821 patients
Data of 821 patients with recorded cannulation time are presented in Table 1. The total cannulation time was median 2 min (range 0.02–89.5 min) in 814 patients with final cannulation success. The final cannulation success method was 99.1%. In seven (0.91%) patients, biliary cannulation failed. Of the successful primary cannula-tions, 49% could be performed in a minute and 91% in 5 min. The most common advanced cannulation method in 221 cases was TPBS in 70.6% (n = 156). SPH was the second most common in 20% (n = 44) of the cases. In total, TPBS was used in 76.5% (n = 169) of the cases. Flow chart of cannulation methods in 821 native papilla patients is presented in Fig. 1.
Table 1. Baseline characteristics of 821 patients and endoscopic retrograde cholangiopancreatography procedures
Age (years) (median, range) 69 (8–102)
Male/female 437 (53%)/384 (47%)BMI (kg/m2) (median, range) 25.7 (12.1–51.9)ASA class I–I 210 (25.6%)ASA class III–IV 611 (74.4%)Elective/emergency procedure 420 (51%)/401 (49%)Indication: stone 445 (54%)Indication: stricture 310 (38%)Indication: postcholecystectomy, liver transplant,
other66 (8%)
Diclofenac prophylaxis (starting Oct 2013) 181 (71%)Duodenal diverticula 93 (11%)Biliary pancreatitis before ERCP 78 (9.5%)Primary cannulation success 599 (73) Time for success (min) (median, range) 1.1 (0.02–19.67) Cannulation attempts (median, range) 2 (0–15) Unintended PD cannulations (median, range) 0 (0–8) Contrast injections to PD (median, range) 0 (0–1)Second method attempted after (min) (median, range) 4.8 (0.3–28)Cannulation time with the second method (min)
(median, range)4.2 (0.3–56)
Secondary cannulation success 144 Time for success with the second method (min)
(median, range)3 (0.33–56)
Third method attempted after (min) (median, range) 7 (1–56) Cannulation time with the third method; min
(median, range)5 (0.3–39.3)
Cannulation time, total min (median, range) 2 (0.02–89.5)Total procedure time (min) (median, range) 18 (5–110)Biliary sphincterotomy 803 (97.8%)Biliary cytology 209 (25.5%)Biliary duct dilatation 77 (9.4%)Common bile duct stone extraction 358 (43.6%)Biliary stent application 286 (34.8%)Pancreatic sphincterotomy 169 (20.5%)Protective pancreatic stent 5 (0.6 %)
ASA, Data of Physical Status Classification of the American Society of Anesthesiologists ASA class; ERCP, endoscopic retrograde cholangiopancreatography.
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1202 European Journal of Gastroenterology & Hepatology October 2019 • Volume 31 • Number 10
Difficult cannulation
The primary cannulation time was more than 5 min in 152 patients (18.5%), at least five cannulation attempts were needed in 141 (17.2%) patients and unintended pancreatic passages occurred in 234 (28.5%) patients. Altogether, 311 out of 821 (37.9%) patients met at least one 5-5-2-criterion. If there were no 5-5-2-criteria present, 2.2% (n = 11) had PEP, if 5-5-2-criteria were present, the risk was 7.1% (n = 22), P = 0.001. If one criterion was present, the PEP rate was 6.9% (n = 11) and if all the criteria were present, 12.3% (n = 8) suffered from PEP. Difficult cannulation criteria were present significantly more often with biliary stricture than with other indica-tions, 46.3% (n = 152) vs. 32.3% (n = 159); P < 0.001. Accordingly, primary cannulation failed significantly more often with this indication compared to other indications, 36.9% (n = 121) vs. 20.5% (n = 101); P < 0.001. The flow chart of 821 native papilla patients with easy and difficult cannulation is presented in Fig. 2.
Unsuccessful cannulation
In seven patients, access to biliary duct was not achieved. In them, cannulation was attempted for median of 48 min (range 1.00–81.00). There were three patients with com-mon bile duct (CBD) stones (one patient had successful repeat ERCP, one patient underwent repeat magnetic reso-nance cholangiopancreatography with finding of no CBD stones and one moribund patient did not undergo repeat ERCP) and four cases with malignant strictures (one patient had successful repeat ERCP and three patients had percutaneous transhepatic biliary drainage).
Post-ERCP pancreatitis
Thirty-three (4.0%) patients developed PEP. It was mild in 19, moderate in 20 and severe in three patients. When primary cannulation succeeded, 14 (2.3%) patients had PEP. After the second cannulation method, the PEP rate was 6.3% (nine patients) and after the third and following
Fig. 1. The flow chart of different cannulation methods in 821 native papilla patients. DGW, double guidewire cannulation; NK, needle knife precut; PD, pancreatic duct; SPH, sphincterotome precut; TPBS, transpancreatic biliary sphincterotomy.
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www.eurojgh.com 1203Criteria for difficult biliary cannulation Ismail et al.
cannulation methods, the risk of PEP was 13.5% (10 patients).
If the biliary duct was cannulated in 5 min, 2.1% (12 patients) had PEP, if it took more than 5 min, the PEP rate increased to 8.7% (21 patients), P < 0.001. The PEP risk was 2.1% (12 patients) if a maximum of five cannulation attempts was needed for biliary cannulation, but increased to 8.8% (21 patients) with additional attempts, P < 0.001. If PD was not cannulated at all, the PEP risk was 2.8% (13 patients). If PD was cannulated up to one (0–1) time, the PEP risk was 3.3% (18 patients) compared to PD cannu-lation more than once: 6.4% (15 patients); P = 0.048. In 29 (3.5%) patients, contrast was injected in to the PD. In them, the risk of PEP was 10% (n = 3) compared to 3.8% (n = 30), in patient without contrast injection, P = 0.106. The presence of a trainee did not affect the PEP rate, four patients (5.8%) with trainees vs. 29 patients (3.9%) with-out them, P = 0.35. In patients with biliary pancreatitis, there was no exacerbation of pancreatitis after ERCP.
With TPBS ± NK method, the PEP rate was 8.9%; n = 15, compared to situation when this was not used 2.8%, n = 18, P < 0.001.
After September 2013, the protocol to administer rectal diclofenac to prevent PEP was started. There was no sig-nificant difference in PEP rate without or with diclofenac, [28 (4.4%) vs. 5(2.8%); P = 0.31].
Other adverse events
A total of 49 patients (6%) had adverse events: PEP in 33 (4%) patients, bleeding in 20 (2.4%), perforation in four (0.5%) and cholangitis in 10 (1.2%) patients. In cases of difficult cannulation, the rate of adverse events was 9.3% (n = 29), but in cases of easy cannulation, the rate was 3.9% (n = 20), P = 0.002. After excluding PEP complication, there was no differences in complication rates between patients with 5-5-2-criteria and easy cannu-lation; 11 (3.5%) vs. 12 (2.4%), P = 0.384. TPBS did not
Patients
n = 821
Easy cannulation
n = 510
Difficult cannulation
n = 311
Primarycannulation
success477(93.5%)
Primary cannulation
failure33(6.5%)
Primary cannulation
success122(39.7%)
Primary cannulation
failure189(60.8%)
2nd methodsuccess
24(72.7%)
2nd methodfailure
8(14.3%)
2nd methodsuccess
141(74.6%)
2nd methodfailure
48(25.4%)
3rd methodsuccess
8(100%)
3rd methodfailure
0
3rd methodsuccess
38(79.1%)
3rd method failure4(8.3%)
4th method success4(100%)
No attempt, final failure
1(3%)
No attempt, final failure6(12.5%)
Fig. 2. The flow chart of 821 native papilla patients with easy and difficult cannulation.
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1204 European Journal of Gastroenterology & Hepatology October 2019 • Volume 31 • Number 10
adversely affect the rate of other complications, 3% (n = 5), versus 2.8% (n = 18) without the procedure, P = 0.89.
30-day mortality
Total 30-day mortality was 5% (n = 42). There was no difference in patients with and without PEP, (3/9% vs. 39/4.9%, P = 0.235) or in patients with difficult and easy cannulation (21/6.8% vs. 21/4.1%, P = 0.104); or when TPBS or other rescue methods were necessary [(13/8.3% vs. 4/6.2%); P = 0.58]. Deaths were mostly related to underlying disease (malignancy in 70.4%), and not directly to complications.
Discussion
The study results support the use of the 5-5-2 criteria for difficult cannulation [9] as it predicts the risk of PEP. Our preferred advanced cannulation method was TPBS in 70.6% of the cases. Altogether 37% had difficult cannu-lation criteria in the present series, and advanced cannula-tion methods were used in 27% of the cases. TPBS as our preferred advanced cannulation method ended in a final success rate of over 99% and a PEP rate of 4%.
Transpancreatic biliary sphincterotomy
TPBS as a rescue method for deep biliary cannulation by Goff et al. [11] succeeds in 86–100% of the cases and has acceptable PEP rates (3.5–10.4%) [11, 12, 14–18]. Previously, in our unit, the biliary cannulation success was less common after a NK precut (71.3%) than after the TPBS (97.3%; P < 0.001) with PEP rates of 5.1% and 9.3%, respectively. When TPBS was combined to NK precut, the PEP rate was 8.2% [12]. In present series, the PEP rate with TPBS is similar, 8.9%.
Other rescue techniques
With TPBS, we had similarly high success rate (97.6%) as in the literature. In difficult cannulation, DGW and TPBS were compared in a prospective randomized study of 34 patients in each group. TPBS had higher success rate of 94% compared to 58% in DGW group. PEP rate in both groups were 2.9% [19]. When DGW technique and TPBS as a rescue method after a failed primary cannulation in 10 min were compared, the cannulation time was 7.8 ± 1.7 min and 3.7 ± 2.3 min, P < 0.001, respectively, with similar PEP risks, 1.8% [3]. The adverse events rate was 2.19% in the DGW group and 7.04% in the TPBS group, P = 0.04. In this study, however, primary cannulation suc-ceeded in only 23.8% of the 366 patients and is much lower than in other studies with 75–90% success rates of primary cannulation.
Early NK precut has also been effective. After an unsuc-cessful biliary cannulation in native papilla patients, the suc-cess rate with an early NK was 79.1%, and with the DGW technique, it was only 44.8%. The PEP rates were 4.5% and 14.9%, respectively [16]. We seldom used DGW technique. DGW cannulation needs an additional guidewire in the PD to straighten the biliary duct. Sometimes an additional guide-wire blocks the access, especially in cases of a tight tumor stricture. In DGW cannulation, an additional guidewire still easily enters the pancreatic and not biliary duct.
A competent ERCP-endoscopist should be able to can-nulate the duct of interest in at least 90% of procedures [20]. However, risk of PEP increases with repeated can-nulation attempts, when papilla is manipulated and espe-cially with multiple guidewire passages to PD. Keeping this in mind, endoscopist must be aware of the time spent to cannulate. The frequency of 5-5-2-criteria should be routinely recorded. It will assist in decision making when to change the cannulation method or endoscopist or post-pone ERCP. In the present study, when difficult criterion was fulfilled, primary method success rate was only 20.4%. Early exchange of cannulation method enhances cannula-tion success with lower PEP rates compared persistence in cannulation with sphincterotome and guidewire.
Limitations
We were not able to collect data of 5-5-2-criteria in con-secutive patients with native papilla due to busy clinical practice. Intention was to routinely collect cannulation data to guide clinical decision making. The ratio of patients with complete data increased during the study period. Cannulation time, pancreatic passages and papilla contacts were monitored with numerous patients. Aggressive hydra-tion with lactated Ringer solution decreased the incidence of PEP in a meta-analysis, but needs further evaluation [10]. We had standard hydration policy. The use of preven-tive techniques for PEP was not uniform, rectal non-ste-roidal anti-inflammatory drug administration to prevent PEP was started during the data collection. However, rec-tal diclofenac probably may have a limited impact in low PEP rate units. In our recent article, with unselected ERCP patients, PEP rate was similar, 2.8%, in 1000 historic con-trols without diclofenac prophylaxis and in 1000 patients with the prophylaxis. The rate in native papilla cases was 3.9% and 3.6%, accordingly [21]. Also, protective pancre-atic stenting was rare, and it was mainly used with papillec-tomy cases. Preventive pancreatic stents have been used to prevent PEP. In meta-analyses, PEP rate was 13.6–18.9% without protective pancreatic stents, but with the stent the PEP rate was 3.2–7% [22, 23]. Majority of the patients, however, had sphincter of Oddi dyskinesia (SOD) or other high PEP risk status as an ERCP indication. In our unit, SOD is an extremely rare indication for ERCP. In recent meta-analysis of 12 RCT and 1369 patients, prophylactic pancreatic stents significantly decreased the odds of PEP (odds ratio 0.28; 95% confidence interval: 0.18–0.42) [24]. In a Californian study of 1873 patients, overall biliary can-nulation success rate was 97% and advanced cannulation techniques (DGW, TPBS and NKS) were needed in 12%. Protective PD stents were placed with repeated PD cannu-lation and a policy of giving indomethacin suppositories with advanced cannulation techniques was started. Overall, PEP rate was only 0.4% [25]. Our main rescue method was TPBS and we seldom used other methods. In the future, these advanced methods should be compared in a prospec-tive randomized study.
Conclusion
The ERCP-endoscopist should monitor the difficult cannulation criteria in clinical practice. Risk of PEP increases when at least one criterion is present. Counting
Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
www.eurojgh.com 1205Criteria for difficult biliary cannulation Ismail et al.
5-5-2-criteria will help in decision making when to change the cannulation method. TPBS seems to be an efficient res-cue method.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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21 Rainio M, Lindström O, Udd M, Louhimo J, Kylänpää L. Diclofenac does not reduce the risk of post-endoscopic retrograde cholangio-pancreatography pancreatitis in low-risk units. J Gastrointest Surg 2017; 21:1270–1277.
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IV
https://doi.org/10.1177/1457496918822616
Scandinavian Journal of Surgery 1 –6 © The Finnish Surgical Society 2019Article reuse guidelines: sagepub.com/journals-permissionsDOI: 10.1177/1457496918822616journals.sagepub.com/home/sjs
SCANDINAVIANJOURNAL OF SURGERY
SJSEffEct And PrEdictivE vAluE Of rOutinE PrEOPErAtivE lAbOrAtOry tEsting fOr EndOscOPic rEtrOgrAdE chOlAngiOPAncrEAtOgrAPhy
J. Jokelainen1,2, s. ismail1,3, l. Kylänpää1,3, M. udd1,3, h. Mustonen1,3, O. lindström1,3, r. Pöyhiä1,4
1University of Helsinki, Helsinki, Finland2 Department of Anesthesia and Intensive Care Medicine, South Karelia Central Hospital, Lappeenranta, Finland
3 Department of Gastroenterological and General Surgery, Helsinki University Hospital, Helsinki, Finland 4Kauniala Hospital, Kauniainen, Finland
AbstrAct
Background and Aims: several studies and guidelines are questioning routine preoperative laboratory tests in surgical and endoscopic procedures. their effect in endoscopic retrograde cholangiopancreatography is not currently known. this study was carried out to evaluate the risk of adverse effects in endoscopic retrograde cholangiopancreatography and their association with preoperative lab tests.Materials and Methods: A single-center, prospective observational study on all 956 patients undergoing 1196 endoscopic retrograde cholangiopancreatographies in the Endoscopy unit of helsinki university central hospital from 1 March 2012 to 28 february 2013. routine preoperative laboratory test results (basic blood count, creatinine, potassium, sodium, international normalized ratio/thromboplastin time, and amylase), health status, medication, and demographic information of all patients were analyzed in relation to adverse effects related to endoscopic retrograde cholangiopancreatography and procedural sedation.Results: Multivariate analysis showed post–endoscopic retrograde cholangiopancreatography pancreatitis (43 cases, 3.6%) to have no association with abnormal routine preoperative laboratory tests. respiratory depression caused by sedation (128 cases, 11%) was not associated with abnormal routine preoperative laboratory tests, and anemia was found to be a slightly protecting factor. cardiovascular depression caused by sedation was associated
Correspondence:Jarno Jokelainen Department of Anesthesia and Intensive Care Medicine South Karelia Central Hospital Valto Käkelän katu 1 53130 Lappeenranta Finland Email: [email protected]
Original Research Article
J. Jokelainen, et al.2
with thrombocytopenia (odds ratio = 1.87, p = 0.025) and, in male patients, hyponatremia (odds ratio = 3.66, p < 0.001). incidence of other adverse effects was too low for statistical analysis.Conclusion: routine universal preoperative lab testing was not found to be successful in predicting adverse effects in endoscopic retrograde cholangiopancreatography procedures. laboratory testing should be done focusing on each patient’s individual needs.
Key words: Cholangiopancreatography; endoscopic retrograde; pancreatitis; endoscopy; hematologic tests; adverse effects; anesthesia
InTRODUCTIOn
Routine preoperative laboratory testing (RPLT) is a practice of ordering a given set of laboratory tests to every patient before a procedure regardless of the health status of individual patients. Traditionally, rou-tine laboratory tests have been part of the protocol for endoscopic retrograde cholangiopancreatography (ERCP) in our institution. Several studies and guide-lines are questioning such policy for surgery and endoscopy (1–3). ERCP is one of the most technically demanding endoscopic procedures with a risk for seri-ous adverse effects (4). To our knowledge, no studies have been made to assess the effect of RPLT on patient outcomes and adverse effects for ERCP. Because of the policy of RPLT in our institution, we had a large data-base of preoperative laboratory results we could com-pare with adverse effects associated with ERCP.
This study was carried out in order to assess the association of RPLT before ERCP with adverse effects and mortality in the Endoscopic Unit of Meilahti Hospital, a tertiary university clinic where over 1200 ERCP procedures are performed annually.
MATERIAL AnD METHODS
This study was approved by the Institutional Ethics Committee of Helsinki University Central Hospital (Ethics Committee, Department of Surgery, Biomedicum Helsinki 2C, Tukholmankatu 8C, PL 705, 00029 Helsinki, Finland).
A total number of 1228 ERCPs were attempted at the hospital during the 12-month period from 1 March 2012 to 28 February 2013. All the adult patients who were treated in the Endoscopy Unit were included in the study.
The following data were registered on each patient: age, weight, height, American Society of Anesthesiology (ASA) physical status classification, RPLT results (basic blood count (BBC), electrolytes (P-na and P-K), throm-boplastin time (P-TT) and international normalized ratio (P-InR), amylase levels before the procedure and 4 and 24 h after the procedure), indications of ERCP, cannulation method, performed procedures, duration of the procedure, ERCP adverse events (pancreatitis, bleeding, perforation, etc.), sedation-related adverse effects (cardiovascular depression—defined as systolic blood pressure <90 mm Hg, respiratory depression—defined as oxygen saturation SpO2 < 90%, need for mask ventilation, need for intubation), comorbidities (diabetes treated with insulin, diabetes treated with
oral medication, electrocardiogram (ECG) analysis, hypertension, cardiovascular disease, cerebrovascular disease, atherosclerosis, chronic obstructive pulmo-nary disease, other pulmonary disease, kidney failure, hypothyreosis/other endocrinological disease, malig-nancy, bleeding disorders, other), regular medication (opioids, diuretics, beta blockers, other cardiological medication, corticosteroids, anticoagulants, benzodi-azepines, other psychopharmacological drugs, and chemotherapy within the last 30 days), smoking and alcohol consumption, and 1-day and 30-day mortality were recorded.
Primary end points were adverse effects related to ERCP, sedation, or both.
The results are reported as medians and interquar-tile ranges (median (IQR)) or number of patients and percentages. Logistic regression analysis was used to assess the risk of adverse effects. Forward stepping was used with p < 0.05 inclusion and p < 0.1 removal criteria (preselection from univariate with p < 0.1); however, age and gender were included in all the models. Statistical calculations were generated using IBM SPSS Statistics 21 (International Business Machines Corporation, Endicott, nY, USA).
RESULTS
We excluded 15 ERCPs performed in the operation theater and 17 ERCPs performed on patients under 18 years of age. In total, 956 patients with 1196 ERCPs were left in our analysis. Two gastroenterologists per-formed 253 ERCPs for cases with suspected or diag-nosed primary sclerosing cholangitis (PSC) and 4 gastrointestinal surgeons performed 943 ERCP proce-dures with other indications. All patients were in prone position during the procedure.
DEMOGRAPHICS
Median age of the 956 patients was 59.0 [25] years (range 18–100 years) and median body mass index (BMI) 24.8 [6.2] kg/m2, 529 (55%) were male and 427 (45%) female. The median length of the procedure was 23 [19] min. There were 299 (25%) procedures regarded as emergency ERCPs.
COMORBIDITIES
ASA classification of the patients was as follows (num-ber of patients (percentage)): ASA 1: 35 (2.9%), ASA 2:
Routine preoperative laboratory testing for ERCP 3
417 (34.8%), ASA 3: 585 (48.7%), ASA 4: 160 (13.4%), and ASA 5: 2 (0.2%). Major comorbidities were as fol-lows: diabetes: 256 (21.4%), chronic hypertension 404 (33.8%), cardiovascular disease 204 (17.1%), and liver disease 331 (27.7%). Prevalence of other diseases was less than 10%. 191 (16.0%) of the patients were smok-ers.
ERCP DETAILS
ERCP was considered successful if the level of papilla or anastomosis was reached and the intended duct was successfully cannulated. Attempted ERCP was unsuccessful in 33 out of 1196 procedures. In 20 proce-dures, papilla was not reached or found (postopera-tive state (gastric resection, pancreaticoduodenectomy) (n = 5), obstruction proximal to papillary region (n = 6), edema of the descending duodenum (n = 8)) and one ERCP could not be performed due to patient’s allergy to sedatives. In 13 cases, papilla was reached, but the desired duct could not be cannulated. The endoscopic procedures included 1844 biliary tract interventions (biliary cytology, biliary sphincterotomy, biliary dila-tation, or stent application) and 503 pancreatic proce-dures (pancreatic cytology, pancreatic dilatation, or stent application). Majority of the patients (787, 82%) had only one ERCP, but 116 (12%) had two, 42 (4%) had three, and 11 (2%) had four or more ERCPs per-formed on them during the study period.
LABORATORY TEST RESULTS
Laboratory test results, listed here as median (IQR), followed by reference values were given as follows: hemoglobin (g/L): female 122 (20), 117–155, male 135 (29.5), 134–167. Platelet count (10E9/L): 243 (126), 150–360; potassium (P-K, mmol/L), 3.9 (0.53), 3.3–4.9; sodium (P-na): 139 (4), 137–145; thromboplastin time (P-TT, %): 95 (41), 70–130; and international normal-ized ratio (P-InR): 1.1 (0.2), 2–3 (patients on anticoag-ulants). Hypokalemia was found on 62 patients, most of which was mild and required no intervention. Hypokalemia was treated with intravenous potas-sium chloride before the procedure on 20 patients. P-InR or P-TT levels needed to be normalized with prothrombin complex concentrate on 44 patients before the procedure.
ADVERSE EFFECTS—ERCP
There were altogether 315 adverse events in 956 patients. Post-ERCP pancreatitis was defined as pain in the stomach, rise in the plasma amylase by three times the upper range limit, and the patient had to be hospitalized for 2 days because of pancreatitis. Pain in the stomach was experienced by 118 (9.9%) of patients. This was associated with already hospitalized patients (p = 0.012). Post-ERCP pancreatitis developed after 43 out of 1196 ERCPs, (3.6%). 24 of them were catego-rized as mild, 14 moderate, and 5 severe (5). Multivariate analysis (Table 1) showed that abnormal-ities in none of the RPLTs were associated with increased risk of post-ERCP pancreatitis.
Post-sphincterotomy bleeding (17 cases, 1.4%) and periampullary perforations (6 cases, 0.5%) were treated conservatively. no luminal perforation occurred. In addition, 12 patients (1%) with guide-wire-induced perforations received antibiotics. 17 (1.2%) patients had post-ERCP cholangitis, of which 2 patients (0.2%) were treated with antibiotics. In addi-tion, 19 miscellaneous adverse events (1.6%; pseudo-cyst infection, stent migration, stent rupture, peptic ulcer bleeding, air embolism, etc.) and 5 cardiopulmo-nary adverse events (0.4%; myocardial infarction and pulmonary embolism) occurred.
Two patients died the same day ERCP was per-formed (one due to air embolism caused by gas insuf-flation during endoscopy on a patient with a transplanted liver and one elderly patient because of acute myocardial infarction). In total, 10 patients (1%)
TABLE 1Univariate and multivariate analysis of risk factors of post-ERCP
pancreatitis.
p Odds ratio
95% CI
lower upper
UnivariateDiabetes, insulin treatment 0.053 0.140 0.019 1.024Diabetes, oral medication 0.132 0.216 0.030 1.587Hypertension 0.034 0.431 0.198 0.937Cardiovascular disease 0.329 0.625 0.243 1.607Opioid use 0.376 1.494 0.615 3.632Anticoagulant use 0.416 0.695 0.290 1.669Smoker 0.171 0.481 0.169 1.372Hospitalized patient 0.497 0.770 0.362 1.636Outpatient case 0.451 1.336 0.629 2.839P-Tromb < 150 0.065 0.154 0.021 1.125P-TT < 70% 0.030 0.206 0.049 0.860Abnormal ECG 0.158 0.596 0.291 1.222Hyponatremia 0.127 0.506 0.211 1.212Hypernatremia 0.647 0.626 0.084 4.657Hypokalemia 0.325 1.837 0.547 6.162Hyperkalemia 0.208 3.895 0.468 3.400Leukocytes/10 units 0.265 0.570 0.220 1.520Amylase (preoperative)a 0.357 1.43 0.67 3.05ALT/100 units 0.167 0.82 0.61 1.09ALP/100 units 0.177 0.91 0.78 1.05Bilirubine/100 units 0.857 0.97 0.74 1.29Bilirubine, conjugated/100 units 0.330 1.18 0.84 1.67ASA 1–2 versus 3–5 0.033 0.51 0.28 0.95Age 0.004 0.97 0.96 0.99Age > 60 years old 0.016 0.44 0.23 0.86Sex: female versus male 0.264 0.70 0.37 1.32Anemia 0.231 0.67 0.34 1.29Multivariate analysisAge > 60 years old 0.070 0.525 0.261 1.054Sex: female versus male 0.313 0.714 0.370 1.375Diabetes, insulin treatment 0.052 0.138 0.019 1.020P-TT < 70% 0.056 0.244 0.057 1.037
CI: confidence interval; ECG: electrocardiogram; ASA: American Society of Anesthesiology.aLog-transformed, pancreas-specific amylase.
J. Jokelainen, et al.4
died within a week after the procedure, 8 patients with end stage cancer, 1 patient suffering from compli-cations of cholecystectomy died of pulmonary embo-lism 5 days after ERCP, and 1 elderly patient died of myocardial infarction on the third day after ERCP. The 30-day mortality was 44 (4.6%).
ADVERSE EFFECTS—SEDATIOn
Respiratory depression occurred with 11% of patients (128 of 1196). The multivariate analysis of respiratory depression (Table 2) showed no association with pre-operative laboratory tests. There was an interaction between anemia and cardiovascular disease in the sta-tistical model, and upon further analysis, anemia was found to be a stronger protective factor (p < 0.001, odds ratio (OR) = 0.26), if the patient had no cardiovas-cular disease.
Cardiovascular depression occurred in 7.2% of patients (86 of 1196). The multivariate analysis of car-diovascular depression (Table 3) showed that the risk of cardiovascular depression was increased if the patient had hyponatremia, thrombocytopenia, or was over 60 years old. There was an interaction between gender and hyponatremia in this statistical model, according to which hyponatremia was associated slightly more with cardiovascular depression on men than women.
In total, 20 (1.7%) patients had both cardiovascular and respiratory depression as defined in the study. The procedure had to be paused due to mask ventila-tion 20 times (1.7% of patients). 3 patients were intu-bated (one case of air embolism leading to resuscitation, one case of laryngobronchospasm, and one ICU patient with septic cholecystitis, already intubated upon arrival to endoscopy room). Other sedation-related adverse events were not observed. Statistical analysis of the risk of mask ventilation or intubation was not feasible due to the small number of cases.
DISCUSSIOn
It has been estimated that ERCP is needed in about 50–100 per 100,000 persons per year. As more thera-peutic options become available, the need will most likely rise (6, 7). As the need for ERCP rises, the eco-nomic burden of preoperative testing will also rise. In our institution, the RPLT package costs about US$49 (€41) on one elective patient. In case of emergency patients, the costs of same package are significantly higher, about US$79 (€66). If we had refrained from taking RPLTs from patients not considered to be at risk for adverse effects or abnormal laboratory test results based on clinical judgment, based on the data gath-ered for this study, we would not have taken RPLTs from 805 patients, which translates to savings of at least US$40,000 (€33,000), assuming they were elective procedures. Systematic preoperative laboratory screening will most likely lead to excessive testing without any true impact on clinical decisions as has been shown by numerous studies and guidelines (1–3, 8). While most such studies are focused on surgery, comparable results are also found on studies on endos-
TABLE 2Univariate and multivariate analysis of risk factors of respiratory
depression.
p Odds ratio 95% CI
Lower Upper
UnivariateDiabetes, insulin treatment 0.110 1.477 0.916 2.380Diabetes oral medication 0.830 1.069 0.581 1.965Hypertension 0.502 1.139 0.778 1.668Cardiovascular disease 0.014 1.721 1.117 2.651Cerebrovascular disease 0.669 1.308 0.382 4.484Atherosclerosis 0.800 1.147 0.397 3.316COPD 0.216 0.405 0.097 1.695Kidney failure 0.502 0.609 0.143 2.590Endocrinological disease 0.188 1.753 0.760 4.044Opioid use 0.277 0.688 0.351 1.350Anticoagulant use 0.409 1.210 0.769 1.904Benzodiazepine use 0.656 0.629 0.082 4.846Smoker 0.564 0.843 0.472 1.505Hospitalized patient 0.223 0.760 0.488 1.183Outpatient case 0.076 1.518 0.957 2.407Thrombocytopenia 0.855 0.950 0.546 1.651P-TT < 70% 0.300 1.264 0.812 1.967P-InR > 2 0.432 0.648 0.219 1.914Abnormal ECG 0.287 1.229 0.841 1.797Hyponatremia 0.747 0.931 0.601 1.441Hypernatremia 0.853 1.094 0.423 2.832Hypokalemia 0.691 1.194 0.498 2.867Hyperkalemia 0.870 1.192 0.145 9.772Leukocytes/10units 0.340 1.24 0.80 1.92Amylase (preoperative)a 0.030 0.59 0.36 0.95ALT/100 units 0.068 0.87 0.74 1.01ALP/100 units 0.276 0.96 0.90 1.03Bilirubine/100 units 0.240 0.89 0.74 1.08Bilirubine, conjugated/100 units
0.240 0.86 0.67 1.11
ASA 1–2 versus 3–5 0.169 1.32 0.89 1.95Age > 60 years old 0.506 1.13 0.78 1.63Sex: female versus male 0.205 1.27 0.88 1.83Anemia <0.001 0.44 0.29 0.68Multivariate, all patientsAge > 60 years old 0.686 1.09 0.72 1.64Sex: female versus male 0.840 1.04 0.71 1.53Cardiovascular disease 0.003 2.07 1.29 3.34Anemia 0.000 0.39 0.25 0.61Patients without cardiovascular diseaseAge > 60 years old 0.732 1.08 0.69 1.69Sex: female versus male 0.976 0.99 0.64 1.54Anemia 0.000 0.26 0.14 0.48Patients with cardiovascular diseaseAge > 60 years old 0.517 1.45 0.47 4.51Sex: female versus male
0.483 1.34 0.59 3.02
Anemia 0.706 0.86 0.38 1.92
CI: confidence interval; COPD: chronic obstructive pulmonary disease; ECG: electrocardiogram; ASA: American Society of Anesthesiology.A significant interaction was found in between cardiovascular disease and anemia; therefore, a split analysis was performed according to cardiovascular disease.aLog-transformed, pancreas-specific amylase.
Routine preoperative laboratory testing for ERCP 5
copy, even though they are fewer in number. Also, one could assume that an endoscopic procedure such as ERCP would cause less stress on the patient and there-fore require even less preoperative routine testing than patients undergoing surgery. Some RPLT results did indeed have an impact on the treatment of these patients, such as correcting hypokalemia or coagula-tion levels with prothrombin complex concentrate. However, the vast majority with only a few excep-tions, these patients had a health condition or medica-tion that would have warranted laboratory testing regardless of RPLT.
The rate of adverse effects of ERCP (9, 10) and seda-tion (11, 12) in this study was similar to other studies on the subject. This would lend credence to the notion that the results of this study should be applicable out-side the Endoscopy Unit, in which this study was con-ducted.
There are some limitations to our study. First, being a single-center study, its applicability to other institu-tions with less experience with treating these patients may be limited. Also, the relatively small number of adverse effects prevents making solid conclusions on the matter, but does provide a foundation for possible further studies. There were 15 ERCPs performed in the operating theater instead of the Endoscopy Unit. The reason for this was because the patients were con-sidered too unstable for sedation and required gen-eral anesthesia and more stringent monitoring than was available in the endoscopy unit. naturally, this will create a possibility for bias, but the total number of these procedures is low, and the effect should be minimal.
We did not differentiate between acute and elective setting of ERCP. The rationale behind this was that RPLT is more relevant in the elective setting since patients having acute ERCP are already having labo-ratory testing done on them because of the underlying medical condition. When considering this—and the fact that patients receiving acute ERCP are more prone to adverse effects and abnormal laboratory test results—we should not expect the results to be biased against RPLT when considering all the patients as a single group, since RPLT is the focus of this study.
This study found that none of the RPLTs that were used were directly associated with any adverse effects for ERCP. There was an association with RPLT and adverse effects related to sedation with thrombocyto-penia and hyponatremia and cardiovascular depres-sion. However, the causal link between these findings is unclear and does warrant further studies. Both hyponatremia and thrombocytopenia are usually caused by some other health-related issues, and it is these root causes which are most likely responsible for hypotension during sedation. Simply correcting the values would most likely not alleviate the problem. Also, a clinical assessment of the patient before the procedure would probably inform the anesthesiolo-gist of the risk of cardiovascular depression even without the preoperative laboratory testing. Therefore, it would seem that the policy of RPLT is not positively affecting the patients’ treatment and care and is not economically sound. That is not to say preoperative testing should be abandoned completely, but should
TABLE 3Univariate and multivariate analysis of risk factors of cardiovascular
depression.
p Odds ratio
95% CI
Lower Upper
UnivariateDiabetes, insulin treatment 0.355 1.316 0.735 2.357Diabetes, oral medication 0.291 1.431 0.736 2.781Hypertension 0.175 1.363 0.871 2.134Cardiovascular disease 0.000 2.854 1.780 4.576Cerebrovascular disease 0.218 2.183 0.630 7.566Atherosclerosis 0.003 3.664 1.542 8.704COPD 0.004 3.219 1.441 7.190Kidney failure 0.037 2.874 1.065 7.760Endocrinological disease 0.217 1.835 0.700 4.816Opioid use 0.500 1.56 0.648 2.434Anticoagulant use 0.002 2.162 1.335 3.502Benzodiazepine use Chemotherapy < 30 days ago Smoker 0.130 1.585 0.874 2.874Hospitalized patient 0.080 1.516 0.952 2.414Outpatient case 0.146 0.706 0.441 1.129P-Tromb < 150 0.004 2.194 1.289 3.734P-TT < 70% 0.002 2.151 1.325 3.492P-InR > 2.0 0.072 0.367 0.123 1.096Abnormal ECG 0.001 2.121 1.365 3.297Hyponatremia 0.000 2.641 1.684 4.142Hypernatremia Hypokalemia 0.388 1.522 0.587 3.947Hyperkalemia Leukocytes/10 units 0.085 1.52 0.94 2.44Amylase (preoperative)a 0.443 0.81 0.48 1.38ALT/100 units 0.084 1.09 0.99 1.21ALP/100 units 0.435 1.03 0.96 1.09Bilirubine/100 units 0.000 1.49 1.30 1.71Bilirubine, conjugated/100 units
0.000 1.52 1.28 1.82
ASA 1–2 versus 3–5 0.000 3.70 2.02 6.75Age > 60 years old 0.000 4.06 2.41 6.85Sex: female versus male 0.805 0.95 0.61 1.47Anemia 0.005 1.89 1.22 2.94Multivariate analysis, all patientsAge > 60 years old 0.000 3.34 1.95 5.72Sex: female versus male 0.468 0.84 0.53 1.34Atherosclerosis 0.053 2.41 0.99 5.89P-Tromb < 150 0.025 1.87 1.08 3.25Hyponatremia 0.001 2.22 1.40 3.52Male patientsAge > 60 years old 0.000 4.79 2.23 10.30Atherosclerosis 0.088 2.58 0.87 7.70P-Tromb < 150 0.164 1.69 0.81 3.53Hyponatremia 0.000 3.66 1.98 6.75Female patientsAge > 60 years old 0.050 2.14 1.00 4.60Atherosclerosis 0.263 2.53 0.50 12.89P-Tromb < 150 0.078 2.14 0.92 4.99Hyponatremia 0.823 1.09 0.51 2.32
CI: confidence interval; COPD: chronic obstructive pulmonary disease; ECG: electrocardiogram; ASA: American Society of Anesthesiology.A significant interaction was found in between gender and hyponatremia; therefore, a split analysis was performed according to gender.aLog-transformed, pancreas-specific amylase.
J. Jokelainen, et al.6
be focused on those patients that would benefit from them. Interestingly, anemia was found to be a protect-ing factor for respiratory depression caused by seda-tion, especially on patients without cardiovascular disease. It could be that anemia causes sensitization to hypoxemia and thus leads to pronounced reactivity and increased respiratory drive when the patient is sedated, and respiratory center is affected by the seda-tive agents. However, clinical utilization of this find-ing, should it prove to be factual in possible further studies, is somewhat difficult, since anemia is some-thing to be avoided when possible in clinical practice.
In conclusion, while it is not possible to give precise recommendations on RPLTs based on our study, we would venture to suggest the following general rules based on clinical experience and generally accepted med-ical practices as shown in Table 4. Other laboratory tests should be prescribed by the treating physician’s delibera-tion based on the patient’s individual health status.
ACKnOWLEDGEMEnTS
J.J. and S.I. contributed equally to this paper. This work was carried out in the Endoscopy Unit, Helsinki University Hospital, Helsinki, Finland.
DECLARATIOn OF COnFLICTInG InTERESTS
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
FUnDInG
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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Received: February 21, 2018Accepted: December 4, 2018
TABLE 4.Suggested laboratory tests before ERCP.
Medical condition Suggested laboratory test
ASA 4–5 BBC, ECG, creatinine, P-na, P-KCoronary artery disease, atherosclerosis, kidney failure, use of diuretics BBC, ECG, creatinine, P-na, P-Koral anticoagulant use (warfarin), liver disorder P-InR
ASA: American Society of Anesthesiologists physical status classification, BBC: basic blood count, ECG: electrocardiogram, P-na: plasma sodium, P-K: plasma potassium; P-InR: international normalized ratio.