pharmacological prophylaxis of acute pancreatitis ... · pancreatitis at 6 hours, and of those...
TRANSCRIPT
PHARMACOLOGICAL PROPHYLAXIS
OF ACUTE PANCREATITIS
ENDOSCOPIC RETROGRADE
CHOLANGIOPANCREATOGRAPHY
– ABSTRACT OF THE PhD THESIS –
PhD SUPERVISOR:
Prof. Univ. Dr. Gheorghe BĂLAN
PhD STUDENT:
Laura PAVEL
2020
2
Keywords:
Endoscopic retrograde cholangiopancreatography, prophylaxis, acute pancreatitis,
non-steroidal anti-inflammatory drugs, acetylcysteine
The doctoral thesis includes:
123 pages - of which 40 pages General part;
80 Figures - of which 66 in the Personal Part;
33 Tables - of which 31 in the Personal Part;
184 bibliographical references.
In this summary, the table of contents, the numbering of the selected figures
and tables and the list of abbreviations are kept in the same form as in the
doctoral thesis. The selective bibliography presented in the abstract includes 23
of the total of the 184 bibliographical references of the doctoral thesis.
2
TABLE OF CONTENTS
Abbreviations ............................................................................................................... IV
INTRODUCTION .................................................................................................. 1
GENERAL PART
Chapter 1 THE CURRENT STAGE OF KNOWLEDGE ............................................................. 2
Chapter 2 GENERAL DATA ON BILIARY PATHOLOGY ....................................................... 4
2.1. Classification and frequency of biliary pathology ................................................. 4
2.1.1. Benign biliary pathology ............................................................................ 4
2.1.2. Malignant biliary pathology ....................................................................... 5
2.2. Risk factors and etiopathogenesis of gallstones .................................................... 5
2.2.1. Family history and genetics ........................................................................ 6
2.2.2. Age ............................................................................................................. 6
2.2.3. Female sex .................................................................................................. 6
2.3. Diagnostic methods of biliary pathology ............................................................... 6
2.3.1. Abdominal ultrasonography ....................................................................... 6
2.3.2. Nuclear magnetic resonance imaging (MRI) .............................................. 7
2.3.3. ERCP as a diagnostic method ..................................................................... 7
2.4. Advances in interventional endoscopy ................................................................... 7
2.5. Surgical costs ......................................................................................................... 8
2.6. Incidence of complications .................................................................................... 9
2.6.1. Mortality and morbidity attributed to ERCP .............................................. 9
2.6.2. ERCP complications ................................................................................... 9
2.6.2.1. Acute pancreatitis ......................................................................... 9
2.6.2.2. Digestive hemorrhage................................................................... 10
2.6.2.3. Digestive perforation .................................................................... 10
2.6.2.4. Infectious complications............................................................... 11
2.6.2.5. Cardiopulmonary complications .................................................. 11
2.6.2.6. Other complications ..................................................................... 11
Chapter 3 THE PLACE OF INTERVENTIONAL ENDOSCOPY
IN THE PATHOLOGY OF THE BILIARY TRACT .................................................. 12
3.1. ERCP – general aspects ......................................................................................... 12
3.2. ERCP indications ................................................................................................... 15
3
3.2.1. Choledocholithiasis and acute angiocolitis ................................................. 15
3.2.2. Benign biliary strictures .............................................................................. 16
3.2.3. Biliary obstruction of a neoplastic nature ................................................... 16
3.2.4. Acute pancreatitis ....................................................................................... 17
3.2.5. Chronic pancreatitis .................................................................................... 17
3.2.6. Pancreatic tumors ....................................................................................... 17
3.3. Post-ERCP complications ...................................................................................... 18
3.3.1. Acute pancreatitis ....................................................................................... 18
3.3.2. Digestive hemorrhage ................................................................................. 18
3.3.3. Digestive perforation .................................................................................. 19
3.3.4. Acute angiocolitis ....................................................................................... 19
3.3.5. Cardiopulmonary complications ................................................................. 20
3.3.6. Long - term complications .......................................................................... 20
Chapter 4 SPHINCTEROTOMY .................................................................................................. 21
4.1. Biliary sphincterotomy ........................................................................................... 21
4.1.1. Indications for biliary sphincterotomy ........................................................ 24
4.1.2. Contraindications to biliary sphincterotomy ............................................... 24
4.1.3. Complications of biliary sphincterotomy ................................................... 24
4.1.4. Needle-knife sphincterotomy ...................................................................... 25
4.1.5. Precinct sphincterotomy ............................................................................. 25
4.1.6. Biliary sphincterotomy in patients with difficult anatomy ......................... 26
4.2. Pancreatic sphincterotomy ..................................................................................... 26
4.2.1. Indications for pancreatic sphincterotomy .................................................. 27
4.2.1.1. Primary therapy - indications ....................................................... 27
4.2.1.1.1. Pancreas divisum and
Oddi sphincter dysfunction (DSO) ............................... 27
4.2.1.1.2. Chronic pancreatitis ..................................................... 27
4.2.1.2. Secondary therapy - indications ................................................... 28
4.2.2. Complications of pancreatic sphincterotomy ............................................. 28
4.2.3. Pull sphincterotomy .................................................................................... 29
4.2.4. Needle-knife pancreatic sphincterotomy ..................................................... 29
4.2.5. Precinct sphincterotomy ............................................................................. 29
4.3. Peculiarities of sphincterotomy .............................................................................. 31
4.3.1. Difficult cannulation and sphincterotomy .................................................. 31
4.3.2. Catheter versus sphincterotome for cannulation ......................................... 31
4.3.3. Endoscopic sphincterotomy of the minor papilla ....................................... 32
Chapter 5 MOUNTING STENTS IN ERCP ................................................................................. 33
5.1 Hilarious biliary obstruction ................................................................................... 33
5.2. Stent mounting technique ....................................................................................... 34
5.3. Insertion of intrapancreatic stents .......................................................................... 34
4
5.4. Indications for the use of stents .............................................................................. 35
5.4.1. Biliary indications ...................................................................................... 35
5.4.2. Pancreatic indications ................................................................................. 35
5.5. Complications ........................................................................................................ 36
Chapter 6 POST-ERCP ACUTE PANCREATITIS ...................................................................... 37
6.1. Risk factors ............................................................................................................ 37
6.2. Prophylaxis of acute post-ERCP pancreatitis ......................................................... 38
6.2.1. Pharmacological prophylaxis ..................................................................... 38
6.2.1.1. Non-steroidal anti-inflammatory drugs (NSAIDs) ....................... 38
6.2.1.2. Corticosteroids ............................................................................. 38
6.2.1.3. Oddi sphincter relaxants ............................................................... 38
6.2.1.4. Hormone therapy .......................................................................... 39
6.2.1.5. Intravenous fluid administration................................................... 39
6.2.2. Interventional endoscopy ............................................................................ 40
THE PERSONAL PART
Chapter 7 MOTIVATION AND OBJECTIVES OF THE RESEARCH ...................................... 41
7.1. Rationale for choosing the theme ........................................................................... 41
7.2. Purpose and objectives of the research .................................................................. 42
Chapter 8 MATERIAL AND METHOD ...................................................................................... 44
8.1. Descriptive retrospective study .............................................................................. 44
8.2. Prospective analytical study ................................................................................... 45
8.3. Study on the efficacy of pharmacological prophylaxis
of acute post-ERCP pancreatitis ............................................................................ 47
Chapter 9
RESULTS ..................................................................................................................... 48
9.1. Results of the retrospective descriptive study ........................................................ 48
9.2. Results of the prospective analytical study ............................................................ 49
9.2.1. Results of the comparative study of clinical and biological data
in the three lots ........................................................................................... 50
9.2.2. The results of the comparative study of the evolution of clinical
and biological factors at 6 hours and at 24 hours in the 3 groups
with different medication ............................................................................ 63
9.2.3. The results of the comparative study of the evolution of clinical
and biological factors at 6 hours and at 24 hours in the 3 groups
correlated with the presence of risk factors ................................................ 71
9.2.3.1. Witness group ............................................................................... 71
5
9.2.3.2. Group 1 - patients treated
with Indomethacin 50 mg suppositories + ACC 600 mg .............. 81
9.2.3.3. Group 2 - patients treated
with Indomethacin 50 mg suppositories ........................................ 91
9.3. Results of the assessment of the incidence of post-ERCP PA in function
the presence of risk factors and medication administered ...................................... 101
Chapter 10
DISCUSSIONS ............................................................................................................. 104
Chapter 11
FUTURE RESEARCH CONTRIBUTIONS AND DIRECTIONS .............................. 121
11.1. Originality of the study ........................................................................................ 121
11.2. Research perspectives .......................................................................................... 122
Chapter 12
GENERAL CONCLUSIONS ....................................................................................... 123
Bibliography ................................................................................................................. 127
Annex
6
ABBREVIATIONS
ACC - acetylcysteine
NSAIDs - non-steroidal anti-inflammatory drugs
APP - personal pathological history
BRC - chronic kidney disease
CBIH - intrahepatic bile ducts
CBP - the main bile duct
CRP - C-reactive protein
CSP - primitive sclerosing cholangitis
CT - computer tomography
DSO - Oddi sphincter dysfunction
DZ - diabetes mellitus
EKG – electrocardiogram
ERCP - Endoscopic retrograde cholangiopancreatography
FiA - atrial fibrillation
FR - risk factor
GGT - gamma-glutamyltransferase
Hb - hemoglobin
HD - straight hypochondrium
HLG - blood count
High blood pressure - essential hypertension
CHF - chronic heart failure
IGH - Institute of Gastroenterology and Hepatology
IL - interleukin
MRI - nuclear magnetic resonance imaging
LBV - gallstones
LC - choledochal lithiasis
MAPK - protein kinases activated by mitogens
N - normal
NF-κB - nuclear factor kappa B
NTG - nitroglycerin
OR - odds ratio
PA - acute pancreatitis
PCR - C-reactive protein
RCUH - ulcerative hemorrhage
MRI - nuclear magnetic resonance
SIRS - systemic inflammatory response syndrome
MS - Mirizzi syndrome
BP - blood pressure
PET - pulmonary thromboembolism
TGO - glutamate-oxalate transaminase
TGP - glutamate-pyruvate transaminase
TNF - tumor necrosis factor
1
GENERAL CONSIDERATIONS
Endoscopic retrograde cholangiopancreatography (ERCP) appeared in 1968 and was
used as a diagnostic method in the pathology of the bile ducts. The diagnosis and
therapeutic usefulness of ERCP have been well demonstrated for a variety of conditions,
including the management of choledocolithiasis, the diagnosis and management of
cholangiocarcinomas and pancreatic neoplasms, as well as the postoperative management
of perioperative bile complications. (Baron et al., 2003, Maple et al., 2010, ASGE, 2012,
Costamagna et al., 2003).
As is well known, without a well-defined statistical basis, in the early 1980s the first
interventions of the Endoscopic retrograde cholangiopancreatography (ERCP) were
performed at the ”St. Spiridon” Hospital in Iaşi. In the years that followed, but especially
in the last 30 years, activity in this area has gradually intensified in line with a similar
trend internationally.
Bibliographical sources estimate that in 2006 the number of ERCP interventions was
about 2,600, considered too small for a country with a population the size of Romania. It
was estimated at the time that 20,000 PPRE would give patients due access to interven-
tional endoscopy treatment. (Bataga et al., 2006) In parallel with the intensification of
practical activity, there was also a significant increase in scientific research on various
aspects of the SPRE. For example, the NCBI (The National Center for Biotechnology In-
formation) database has an inventory of about 70 articles related to this issue in Romania.
In line with the national trend, currently in the Institute of Gastroenterology and
Hepatology of the Hospital ”St. Spiridon” in Iaşi, there is an intense practical activity
coupled with scientific research in the field, concreted in doctoral thesis and scientific
articles published in prestigious national and international specialized journals. In this
context, the research theme proposed by this thesis, which concerns the pharmacological
prophylaxis of acute post-ERCP pancreatitis, is a topical one, with the aim of deepening
the topic of prevention of the abovementioned complication.
Acute pancreatitis (PA) is by far the most common and serious complication of this
procedure. For this reason, over time, researchers have studied various methods, both
pharmacological and non-pharmacological, to prevent the occurrence of post-ERCP PA.
The main pharmacological methods mentioned in the literature are: administration of non-
steroidal anti-inflammatory drugs (NSAIDs), octreotide, physiological infusion serum,
antioxidant products, etc. Regarding non-pharmacological methods, it is mentioned the
installation of stents in the pancreatic duct.
Regarding the pharmacological prophylaxis with NSAID-type suppositories, a study
conducted and published by Leerhøy B. at the Institute of Gastroenterology of Hvidovre
Hospital, Copenhagen (Denmark), reveals the following: out of 400 patients undergoing
research, 218 were part of the control group that was not given diclofenac, and 182 were
included in the group that received prophylaxis with a suppository with diclofenac in a
single dose of 100 mg, given immediately post-ERCP. The results showed that NSAIDs
administered intrarectally in a single dose, immediately post-ERCP, decreased the inci-
dence of acute post-ERCP pancreatitis. This result is also confirmed by a second study
2
conducted in the Department of Gastroenterology at Castle Hill Hospital (UK). (Wong
et al., 2014) This study, conducted in the form of a meta-analysis, reveals that 100 mg
indomethacin administered intrarectally, immediately pre- or post-ERCP, decreases the
incidence of acute pancreatitis, a result confirmed by other research. (Leerhøy, Nordholm-
Carstensen, 2014)
Studies confirming the beneficial role of NSAIDs administered intrarectally pre- and
/ or post-ERCP are supported by both the European Guide to the Society of Gastro-
intestinal Endoscopy and the American Guide to Gastroenterology. Both guidelines
recommend the administration of intrarectal NSAIDs before or after the procedure to
prevent acute pancreatitis. (Dai et al., 2009, Ding et al., 2012)
Recent results attest to an essential role of oxidative stress in the etiopathogenesis of
acute pancreatitis. Its involvement is highlighted by the decrease in serum glutathione and
lipid peroxidation in the pancreas. Oxygen free radicals produce an increase in the
immune response by increasing the serum level of IL-6, which is the earliest mediator of
inflammation in acute pancreatitis. All this mechanism mediates apoptosis in pancreatic
acinar cells type AR42J. However, oxygen free radicals are considered mediators of the
inflammatory process and cell destruction and not factors in the occurrence of acute
pancreatitis.
There is currently controversy over the involvement of oxidative stress and pro-
inflammatory cytokines, especially TNF-α, which amplifies the cascade of the inflam-
matory process through various mechanisms, such as activation of MAPK (mitogen-
activated protein kinases), NF-κB (kappa B nuclear factor) and / or protein phosphatase
inactivation. (Braganza et al., 1995, López, Carrillo Alcaraz, 2011).
A not very recent study, published in 2006 by Milewski J. in the World Journal of
Gastroenterology, demonstrates that acetylcysteine has not been beneficial in preventing
acute post-ERCP pancreatitis, conclusions drawn from the analysis of patients' post-ERCP
serum and urinary amylase. This aspect is not conclusive, however, as serum and urinary
amylase are not specific to acute pancreatitis, therefore the study is not very relevant.
(Milewski et al., 2006)
In this context, there is an obvious need to continue researching the role of medica-
tion administered in the prophylaxis of acute post-ERCP pancreatitis and especially the
role of antioxidants, in order to obtain convincing results in order to implement prophy-
lactic treatment with a high degree of certainty.
PERSONAL PART
MOTIVATION AND OBJECTIVES OF THE RESEARCH
Motivation for choosing the theme
The doctoral thesis aims to evaluate the epidemiological data, risk factors and their
influence on the occurrence of post-ERCP AP. At the same time, based on a simple blind,
randomized randomized trial, the efficiency of pharmacological prophylaxis applied to
patients undergoing this type of investigation was followed, both clinically and biologi-
cally.
3
Why acute post-ERCP pancreatitis?
Acute pancreatitis is the most common and serious complication that can occur
following Endoscopic retrograde cholangiopancreatography. Its mechanisms, although
known, cannot always be counteracted. The development of acute pancreatitis can be a
serious problem that can endanger the patient's life. Therefore, the identification of
effective prophylactic methods is a plus in medicine.
Why pharmacological prophylaxis?
Over time, researchers have tried to find an effective method to reduce the incidence
of post-ERCP acute pancreatitis: from the study of antioxidants, nitrates, somatostatin,
NSAIDs to invasive methods such as mounting pancreatic stents. Of those mentioned,
only two seem to outline a beneficial role, demonstrating its usefulness during studies,
namely: intrarectal administration of NSAIDs (diclofenac, indometacin) and placement of
stents. We chose to study NSAIDs, as this, of the two, is the cheapest and easiest method
to apply in our research center.
Current level of knowledge
As we mentioned at the end of the general part, the current state of knowledge
related to this topic is one that requires further research. The fact that the administration of
NSAIDs has led to good results has led to the introduction of this prophylactic method in
International Guidelines as a standard method in the prophylaxis of post-ERCP PA.
However, there are some studies that contradict initial results. It is the context in which I
appreciated the opportunity of a research proposed within the topic for the elaboration of
the doctoral thesis.
Why within the Institute of Gastroenterology and Hepatology in Iasi?
Obstructive pathology of the bile ducts is a relatively common occurrence in the
adult population. Gallstones are one of the common causes, especially in women, fol-
lowed by obstruction of a benign nature (tumors, strictures, etc.) or malignant (primary,
secondary tumors). Patients who go to the hospital for the typical symptoms of obstructive
jaundice are always referred to the Institute of Gastroenterology and Hepatology (IGH) in
Iasi for additional investigations and specialized treatment, being the only center in the
region of Moldova that has specialized equipment and doctors trained in this sense.
Purpose and objectives of the research
Based on these observations, a protocol was imagined to assess the clinical-biologi-
cal status of pre- and post-interventional patients, with the aim of identifying the influence
of demographic aspects and risk factors on clinical-biological evolution, using various
pharmacological methods of IP prophylaxis.
Our research has been carried out in several directions, each with its own objectives:
1. Descriptive retrospective study on the incidence of acute post-ERCP pancreatitis
in a tertiary Gastroenterology center with specific objectives;
2. Prospective analytical study of risk factors in the etiopathogenesis of acute
post-ERCP pancreatitis;
4
3. Prospective analytical study of risk factors in the etiopathogenesis of acute
post-ERCP pancreatitis;
4. Analysis of the performances and limits of the study;
5. Establishing future research directions.
MATERIAL AND METHOD
Descriptive retrospective study
In order to lay the foundations of our prospective study, it was first necessary that, through a retrospective study, we obtain an overview of patients previously hospitalized in the Institute of Gastroenterology and Hepatology in Iasi, patients who, of course, had as ERCP indication. In this sense, the information was collected from hospitalized patients between January 2015 and January 2016, who had a complete biological and imaging profile and to whom this intervention was applied.
The retrospective descriptive study, which took place during the above-mentioned period, targeted a group of 135 patients admitted to the Gastroenetrology and Surgery Clinics of the Hospital “St. Spiridon” from Iași, with the diagnosis of obstructive jaundice and the absence of PA without pancreatic involvement as a diagnosis at hospitalization (exclusion criterion) to which ERCP was applied. The following parameters of the patients were evaluated: age, sex, pre-ERCP imaging – abdominal ultrasound, pre-ERCP biological samples (markers of cholestasis, hepatic cytolysis, inflammatory syndrome, amylase, lipase, hemoleucleogram) before and at 24 hours post-ERCP (hemoleucleogram, amylase, lipase, CRP), description of duodenal anatomical features, description of ERCP protocol (sphincterotomy, mild or difficult cannulation, volume of contrast agent in excess). The assessment of the occurrence of BP in relation to known risk factors (related to the patient and related to the procedure itself) was performed using multivariate analysis methods. It should be noted that in this retrospective descriptive study, patients did not receive any prophylactic measures for BP.
The exploration was performed after topical (pharyngeal) administration of lidocaine 2%, and after analgesic i.v. with midazolam and fentanyl. The equipment and materials needed for the intervention were: videododoscope model TJFQ180V (Olympus), sphinct-erotomes, guidewire, balloon catheter and / or Dormia basket probes for stone extraction, iodinated water-soluble contrast agent 300 mg I / ml (Optiray). No stents were used for prophylactic purposes.
All patients were continuously monitored during the intervention, being assisted by the anesthesiologist, and the parameters related to the procedure (number of cannulations, amount of contrast agent, duration of the procedure) were recorded in the database.
Also, all 135 patients in the group were initially diagnosed ultrasound with biliary obstruction (ultrasound criteria for diagnosing biliary obstruction: dilated CBP> 6mm, dilated CBIH, +/- direct signs of calculation).
Prospective analytical study
Patients The study took place in the Institute of Gatroenterology and Hepatology within the
Emergency Clinical Hospital "St. Spiridon ”from Iași, between March 2017 - December
5
2018. The design of the study was one of prospective amalithic type, simple blind trial,
randomized random and evaluated comparatively and dynamically the efficacy of three
pharmacological regimens (indomethacin in different doses associated or not with
acetylcysteine) administered for prophylactic purposes in patients with obstructive
jaundice with indication for ERCP.
Out of a total of 500 ERCPs performed during the research, 211 patients over 18
years of age were initially evaluated for inclusion in the study. The exclusion criteria were
the presence of acute pancreatitis or other acute inflammatory conditions at hospitaliza-
tion, pregnancy, contraindications for NSAIDs, recent episode of upper gastrointestinal
bleeding (less than 1 month), hypersensitivity to antioxidants or patient refusal.
After the initial assessment, 186 patients remained in the study who met the inclu-
sion criteria and signed the informed consent. They were divided into 3 groups, being ran-
domized: 98 patients (52.7%) were the control group, who received prophylaxis according
to the European guideline with 100 mg Indomethacin suppositories immediately post-
ERCP, 32 patients ( 17.2%) constituted group 1 - which received ACC 600 mg iv 30 min-
utes before performing ERCP and suppository Indomethacin 50 mg before 30 minutes and
50 mg immediately after performing ERCP; and group 2 consisted of 56 patients (30.1%)
who received Indomethacin suppositories 50 mg 30 minutes before and 50 mg immedi-
ately after ERCP.
Working protocol After signing the informed consent (see Annex 2 - we mention here that 25 patients
refused to sign the consent), each patient included in the study was evaluated to identify
risk factors by history, clinical examination, laboratory tests (complete blood count, serum
and urinary pancreatic enzymes, inflammatory syndrome, cholestasis and hepatic cytolysis
syndrome, renal tests) and imaging (ultrasound and possibly CT scan of the abdomen /
cholangioRM) according to the protocols in force. ERCP was performed according to the
standard protocol, after consulting the anesthesiologist. The hemoleukogram was mainly
aimed at identifying leukocytosis, but also anemic and thrombocytopenic syndrome. The
increase of C-reactive protein was considered slight at a value of up to 3 mg / dl, moderate
at values between 3-10 mg / dl and a significant increase was seen at values above
10 mg / dl. Also, amylase values were quantified at values up to 200 U / l as values
<2xN, between 200 and 300 U / l values over 2xN and over 300 U / l as values over 3xN.
The value of serum lipase was also quantified in the same terms, for the first category
being, however, a range up to 120 U / l, the second between 120-180 U / l and the third
with values over 180 U / l it.
The imaging used before the intervention aimed to identify the etiology of biliary
obstructive syndrome. For some patients, two diagnostic methods were used, abdominal
ultrasound and abdominal MRI.
The exploration was performed after topical (pharyngeal) administration of lidocaine
2%, and after analgesic i.v. with midazolam and fentanyl. The equipment and materials
needed for the intervention were: videododoscope model TJFQ180V (Olympus), sphinc-
terotomes, guidewire, balloon catheter and / or Dormia basket probes for stone extraction,
iodinated water-soluble contrast agent 300 mg I / ml (Optiray). No stents were used for
prophylactic purposes.
6
All patients included in the study were continuously monitored during the interven-
tion, being assisted by the anesthesiologist, and the parameters related to the procedure
(number of cannulations, amount of contrast agent, duration of the procedure) were re-
corded in the database.
All adverse effects related to the procedure or medication administered, as well as
the length of hospitalization, were also recorded. The study medication was administered
as previously mentioned.
Post-ERCP at 6 hours and 24 hours post-ERCP, respectively, as well as if necessary,
in case of post-procedure pain symptoms, the clinical parameters (presence of abdominal
pain, vomiting, fever, transit disorders) and a part of the biological parameters (HLG,
PCR, pancreatic enzymes).
The diagnosis of post-ERCP BP was considered if the patient reported the occur-
rence of post-procedure specific abdominal pain or the intensification of pre-existing pain
and the increase of pancreatic enzymes by at least three times the normal value. The in-
crease in pancreatic enzymes in the absence of symptoms was classified as asymptomatic
hyperamylasemia and hyperlipasemia.
Patients were removed from the monitoring protocol 24 hours after performing
ERCP if no special events were reported or after resolving the event in the first 24 hours
post-ERCP, being re-evaluated 30 days after discharge, in the case of a complicated
evolution.
Data obtained after evaluating patients at all stages of monitoring (pre- and post-
procedural) were entered into a database.
Data were presented as absolute values, percentages and standard deviations. To
compare the data were used: the t-Student test for continuous variables and Chi square-χ2
or Fisher tests, which were used for qualitative variables when appropriate. The results
were considered significant when p <0.05.
Statistical analysis was performed using Excel® 2007 (Microsoft Office®,
Redmond, WA, USA) and SPSS® version 20.0 for Windows (SPSS Inc., Chicago, IL).
The study protocol and the informed consent model were previously approved by the
ethics commissions of the “Grigore T. Popa” University of Medicine and Pharmacy of Iași
and of the “Sf. Spiridon” from Iași.
RESULTS
Results of the descriptive retrospective study
Out of the total of 135 selected patients, 52% of the patients were women, which
means a number of 70 and 65 (48%) were men. Of these cases, only 97 (71.8%) were
confirmed by ERCP. The average age was 65 years.
From the point of view of symptoms, the patients showed the following signs and
symptoms at admission: clero-tegumentary jaundice in proportion of 85%, pain in the
right hypochondrium in 70% and nausea and vomiting in 53%.
Biologically, hepatic cholestasis was present in 89% of patients, followed by hepatic
cytolysis with 73% and inflammatory syndrome in 45% of patients. The rest of the
biological changes are insignificant in percentage.
7
For biliary lithiasis, 78 patients were diagnosed by ultrasound (57.7%), subsequently
by ERCP, and 71 cases (52%) were confirmed. In 94% of cases, lithiasis was located in
the choledochus, in 2% of cases in the intrahepatic bile ducts, and the rest were with both
locations (Fig. 9.1).
In 83% of cases, sphincterotomy was performed with the extraction of stones. 26%
of patients also presented gallstones, 45 patients were cholecystectomized, of which 32
underwent surgery less than 2 years ago.
There were 4 cases with the diagnosis of bile duct abnormalities, all confirmed by
ERCP. The abnormalities detected were choledococcus, Caroli's disease and megacoledocus.
Ultrasound, 28 patients with malignant stenoses were detected, only 22
(16.3%) being confirmed by ERCP, 90% being cholangiocarcinomas and 9.7% Vaterian
ampullomas. 7 cases showed benign stenoses.
The diagnosis of post-ERCP BP was considered if the patient reported the occur-
rence of post-procedure specific abdominal pain or the intensification of pre-existing pain
and the increase of pancreatic enzymes by at least three times the normal value. The in-
crease in pancreatic enzymes in the absence of symptoms was classified as asymptomatic
hyperamylasemia and hyperlipasemia.
In the present study, 45 (33.3%) of patients undergoing ERCP developed a biological
pancreatic reaction, and of these, 22 (16.6%) had clinical criteria for BP. Of the 22
patients, 15 were women (68%) and 10 also had juxtapapillary diverticulum (42%). There
is a significant correlation between the potential risk factors studied and the occurrence of
BP. The analysis of the partial correlation coefficients indicates that a significant influence
on the occurrence of BP has the risk factor represented by sexulfeminin (partial = 0.56,
p <0.01), sphincterotomy (partial = 0.45, p <0.01) and the juxtapapillary duodenal
diverticulum (rpartial = 0.34, p <0.000556). According to statistical results, women have a
higher risk of developing post-ERCP BP, and thermal injury through sphincterotomy and
the presence of juxtapapillary diverticulum are also risk factors in post-ERCP BP.
Results of the prospective analytical study
The batches were statistically analyzed and compared according to various parameters.
The study group consisted of 186 patients, 102 women (54.8%) and 84 men (45.2%),
separate into 3 different batches depending on the medication received, respectively:
LOT 1 - 32 patients (17.2%) who received Indomethacin 50 mg pre- and post-
ERCP suppositories + ACC 600 mg i.v. pre-ERCP;
LOT 2 - 56 patients (30.1%) who received only Indomethacin 50 mg
suppositories pre and post ERCP;
LOT WITNESS - 98 patients (52.7%) without pre-ERCP medication but with
100 mg Indomethacin post-ERCP suppositories.
The mean age of the patients was 64.32 ± 14,911 years, with no statistically
significant differences between the sexes or between the 3 groups in which the study was
conducted. It can be seen, however, that women are about 3 years older than men, but in
the 3 groups in which the study is conducted, patients are homogeneous ages.
The most common symptom is pain in the right hypochondrium (HD), identified in
80.6% of cases; jaundice was present in 38.7% of patients, nausea in 23.7%, and low-
8
grade fever, abdominal bloating, physical asthenia and constipation were identified in 4
patients, which means 2.2%.
Regarding the biological data of the patients, 18 patients were registered (9.7%) with
all normal biological parameters monitored; 6 of the patients belong to group 1 (18.8%),
and the other 12 belong to the control group (12.2%); In group 2 no patients with normal
biological parameters were identified, but the differences observed between the 3 groups
did not have statistical significance. Otherwise, cholestasis is the most common, identified
in 84.9% of the total group, followed by cytolysis (78.5% of total cases); the other
biological factors have a much lower and even sporadic incidence (4 patients with
thrombocytopenia and anicteric cholestasis, respectively 8 patients with leukopenia).
Several personal pathologies in patients included in the study were also observed.
132 patients out of the 186, ie 71%, had such a history, spread relatively homogeneously
in the three study groups and without statistically significant differences; the most
frequent were the cases of cholecystetomy (39.8%), followed by those of hypertension
(23.7%) – which can be explained by the relatively advanced age of the patients; there
were also 12.9% cases of LBV, the others (ICC, BRC, FiA, PET, type 2 diabetes) being
diagnostic (4 - 2.2%, respectively 8 - 4.3% patients).
Known risk factors for the literature for acute post-ERCP pancreatitis are female
gender, young age (under 60 years), normal bilirubin, excess contrast, and a history of
acute post-ERCP pancreatitis; 142 of the patients included in the study had at least one of
these risk factors, which corresponds to an overall percentage of 76.3%, ie quite high; the
patients in question are homogeneously divided into the 3 groups, so that no statistically
significant correlation is identified between the pre-ERCP medication and the presence of
the analyzed risk factors. The risk factor with the highest incidence is represented by
females (71.4%), followed, at a distance, by young age (30.1%) and normal bilirubin
(26.9%); there were 16 patients with excessive contrast and 4 patients with a history of
acute post-ERCP pancreatitis.
Regarding abdominal ultrasounds, 82.6% were identified with choledochal lithiasis,
13.0% with choledochal and gallbladder stones, and there were 4 patients (4.3%) with
cholangiocarcinomas. MRI investigations identified choledochal lithiasis observed in
77.4% of cases, choledochal and gallbladder lithiasis in 11.3% of cases and 12 patients
(also 11.3%) with cholangiocarcinoma.
The sphincterotomy + cannulation procedure was applied to the vast majority of
patients, with the exception of only 4 patients (2.2%). The comparative study in the three
groups did not reveal statistically significant differences (Chi-square = 1,358, p = 0.399),
which attests to the absence of any correlation between pre-ERCP medication and applied
procedures. It can be seen, however, that all patients for whom no sphincterotomy and
cannulation were performed come from the control group. In 24 patients, the diagnosis of
difficult cannulation was reported - which represents a percentage of 12.9% of the global
group; these patients came from all three groups, with the lowest share in group 1 (2.5%)
and the highest share in group 2 (14.3%) - close in incidence to the control group (12.2
%). However, the differences recorded are not statistically significant (Chi-square = 0.069,
p = 0.966).
9
The results of the comparative study of the evolution of clinical and biological factors
at 6 hours and 24 hours in the 3 groups with different medication
Thus, in the control group amylase at 6 hours was identified as normal in 69.4% of
patients, the rest having amylase twice higher than normal (12.2%) or even 3 times higher
than this value ( 18.4%). At 24 hours, as a result of the treatment, the number of patients
with normal amylase increases significantly (85.7%), decreasing accordingly the percent-
ages of patients with elevated amylase. In group 1, no cases with amylase 3 times higher
than the normal value were registered from the start; at 6 hours there are 25% of patients
with amylase 2 times higher than normal, and at 24 hours their percentage decreases to
12.5%. In group 2, the situation is not as favorable; thus, at 6 and 24 hours the percentage
of patients with normal amylase is constant (71.4%), but a significant aggravation is ob-
served, in the sense that for all patients who at 6 hours had amylase 2 times higher than
the value normal, at 24 hours this value increases, reaching 3 times higher than the normal
value. The evolution of lipase values in turn follows the same trends, with statistically
significant improvements in group 1 and control group.
The CRP values, on the other hand, register also important fluctuations, statistically
significant, at the level of all the 3 groups, and not necessarily in the sense of their
improvement. Thus, in the control group the percentage of patients with normal CRP was
69.4% initially, decreasing after the intervention to 49%, a value that remains constant at
both 6 and 24 hours. The percentage of patients with strongly increased CRP increases
from 4.1% at 6 hours to 8.2% at 24 hours, which shows some aggravation; In contrast, the
percentage of patients with moderately elevated CRP decreases slightly from 6 hours
(26.5%) to 24 hours (22.4%), and the percentage of patients with minimally elevated CRP
is steady. This means a relatively positive development, given that, in fact, for only 4
patients the CRP values worsened from 6 to 24 hours.
Leukocytosis, in turn, registers an obviously favorable evolution, statistically signifi-
cant, at the level of all the three groups studied. Thus, in all three groups the percentage of
patients with normal leukocytosis values is constantly improving from the initial time to 6
hours and 24 hours after the intervention, respectively. Apart from this predominant trend,
it can only be observed that in the control group there was initially a percentage of 24.5%
of patients with slightly increased leukocytosis, which at 24 hours after the intervention
reaches only 8.2%, and In group 2 there were initially 7.1% of patients (4) with slightly
increased leukocytosis, but who normalize their values after the intervention, both at 6 and
24 hours. In group 1, on the other hand, although the percentage of patients with increased
leukocytosis decreases, from 31.3% initially to 25% 6 hours after the intervention, we can
also speak of a slight aggravation – because initially no reports were reported. patients
with moderately increased leukocytosis, but at 6 hours after the intervention a percentage
of 12.5% of patients with this characteristic appears – a percentage that remains constant
even at 24 hours after the intervention.
The assessment of the clinical status of the patients was also performed at 6 and 24
hours, being expressed by the number of acute pancreatitis triggered after the intervention.
In the case of the control group, 8 patients developed acute pancreatitis 6 hours after the
intervention, which corresponds to a percentage of 8.2% – a situation that remained sta-
tionary at 24 hours, in the sense that no new cases of BP appeared. The same is observed
10
in the case of group 1, where, although it is about 4 patients, from a percentage point of
view they correspond to a slightly higher value (12.5%) - but still stationary at 24 hours.
In group 2, however, the situation worsens significantly from 6 to 24 hours because, if at 6
hours there are 4 patients with acute pancreatitis (7.1%), in the time interval up to 24
hours there are still 8 diseases, which corresponds to an overall percentage of 21.4%, ie
more than one fifth of all patients in group 2.
The results of the comparative study of the evolution of clinical and biological factors
at 6 hours and 24 hours in the 3 groups correlated with the presence of risk factors
In each of the three groups we performed a comparative study of the evolution of
clinical and biological factors at 6 and 24 hours in the presence and, respectively, the
absence of monitored risk factors. 5 distinct risk factors were followed, marked from FR 1
to FR 5 and having the following meaning:
RF 1: female;
RF 2: young age (<60 years);
RF 3: normal serum bilirubin;
RF 4: excess contrast agent;
RF 5: history of acute post-ERCP pancreatitis.
In the control group, amylase values at 6 hours are statistically significantly influ-
enced only by the presence of risk factors RF2 and RF4, although discrepancies were
identified for all 5 risk factors analyzed, which are not necessarily statistically significant.
The same phenomenon of increasing the share of patients with normal amylase values is
observed when at least one of the investigated risk factors is present (from 54.5% to
73.7%). In the presence of RF1, the percentage of normal values decreases and that of
amylase values increases twice as much as the normal value (from 7.4% to 18.2%). All
patients with present RF2 have normal amylase values, which is also identified as statisti-
cally significant. The presence of RF4 is also statistically significant, which shows a sig-
nificant decrease in the share of normal values (from 74.4% to 33.3%); In addition, all
patients with pathological values (66.7%) have amylase 3 times higher than normal. The
presence of RF5 attracts atypical behavior, respectively all patients have normal amylase
values.
Lipase values at 6 hours are statistically significantly influenced only by the presence
of risk factors RF2 and RF4. In general, the presence of at least one of the risk factors is
associated with an increase in the share of normal lipase values from 54.5% to 73.7% and
a decrease in the share of values three times higher than normal. (from 45.5% to 26.3%);
however, this variation has no statistical significance. The presence of the RF2 factor
seems to lead to a significant improvement in lipase values: the share of patients with
normal values increases from 58.1% to 88.9%, and, in turn, the share of values three times
higher decreases accordingly. than normal. The presence of the RF4 factor entails, on the
other hand, a significant aggravation: the share of normal values decreases from 74.4% to
33.3%, with the corresponding aggravation of the values three times higher than normal.
The only risk factor that statistically significantly influences CRP values is RF2; however,
the differences appear to correspond to an improvement in the patients' situation, and not
11
to an aggravation. Leukocytosis values at 6 hours are statistically significantly influenced
only by risk factors RF2 and RF3.
Altered clinical status at 6 hours was expressed by the onset of acute pancreatitis; a
number of 8 patients in the control group developed BP at 6 hours, and all 8 had at least
one of the risk factors analyzed, which corresponds to a percentage of 8.2% – although,
importantly, this percentage is still too low for to report a statistically significant cor-
relation between the general presence of a risk factor and the occurrence of acute
pancreatitis at 6 hours. However, the particularized study for each separate risk factor
nuances to some extent this general observation. So:
All 8 cases of acute pancreatitis were women – so the female sex as a risk factor
determines a percentage of 18.2% acute pancreatitis, whose value is statistically
significant compared to the zero percentage of acute pancreatitis in men in the
group;
Young age is associated with a zero percentage of acute pancreatitis installed at 6
hours, which shows that this element plays a positive role, but not in a statisti-
cally significant way;
Of the 8 patients who had acute pancreatitis, 4 patients had normal bilirubin and
the other 4 did not; therefore this element (RF3) is not statistically significantly
correlated with the occurrence of acute pancreatitis;
However, the excess contrast substance is significant and most dramatically
correlated with the onset of acute pancreatitis at 6 hours; thus, of the 12 patients
with excessive contrast, 8 had acute pancreatitis – which corresponds to 66.7%,
while none of the patients without excessive contrast had this diagnosis;
A history of acute pancreatitis does not correlate statistically significantly with
recurrence; none of the patients with a history of acute pancreatitis had acute
pancreatitis at 6 hours, and of those without a history of acute pancreatitis there
was a low percentage (8.5%) of patients who had acute pancreatitis at 6 hour.
In group 1, the presence of risk factors is associated with a degradation of amylase
values at 6 hours Thus, if none of the patients without risk factors has increased amylase,
of those with at least one risk factor were identified 36.4 % with amylase twice as high as
normal – which is a significant impairment. The most significant influence, statistically
significant, has RF3, associated with an increase in amylase values in 50% of patients,
while none of the patients with absent RF3 has increased amylase.
The risk factor RF3 has a worsening effect on lipase levels, but less pronounced.
Thus, in its presence the share of patients with normal lipase decreases slightly (from
62.5% to 50%), but instead there is a percentage of patients (25%) who have lipase only
twice higher than normal, and not three times (in the other group of patients with absent
RF3, all those with high lipase (37.5%) had it three times higher than normal. The risk
calculation also shows RF3 as having the potential to worsen, although not very None of
the risk factors monitored statistically significantly influence CRP values at either 6 or 24
hours, however, the risk calculation shows a supra-unitary risk of impaired CRP values
within 24 hours of the general presence of one of the 5 risk factors, and in particular RF2,
respectively of affecting the CRP values at 6 hours in the presence of risk factors RF2 and
RF3.
12
There were 4 patients who had acute pancreatitis 6 hours after surgery; they belong
to the sublot with at least one of the risk factors present, which means that at least one of
the risk factors influences the onset of the diagnosis of acute pancreatitis, although in a
statistically insignificant manner. Neither women nor younger patients had this complica-
tion. In contrast, all patients had normal bilirubin (present RF3), which means that the
only risk factor among those investigated for the complication of acute post-ERCP pan-
creatitis is this.
In group 2, the influence of RF1 factor (female) is statistically significant; none of
the men have elevated amylase, and instead 40% of women have three times higher than
normal amylase. An also statistically significant aggravating role is played by the RF4
factor; all patients with present RF4 have three times the amylase of normal, compared
with only 23.1% of patients with absent RF4.
Lipase values at 24 hours have a very similar evolution to those at 6 hours under the
action of the investigated risk factors. Thus, the percentage of patients with lipase three
times higher than normal and at least one of the present risk factors is also 36.4%, as in
the case of the determination at 6 hours – without also being patients with high lipase
among those without any risk factor. Similarly, females have the same statistically
significant action on lipase values as at 6 hours, respectively 40% of women have lipase
and at 24 hours three times higher than normal, compared to men who have normal lipase.
All patients with RF4 present were recorded at 24 hours with lipase three times higher
than normal, compared with 23.1% of patients with high lipase without those with RF4.
Therefore, the presence of the risk factor RF4 (excess contrast agent) entails a statistically
significant increase in lipase values.
The risk factor with the highest effect among those analyzed, in terms of associated
risks, is RF1, respectively female, which affects CRP values at both 6 and 24 hours; the
degree of impairment is also transmitted at the level of the cumulated action of the
analyzed risk factors, which also seems to entail the systematic increase of the CRP
values.
Subsequent analysis reveals that all 12 patients who developed BP are female, which
is the only risk factor with potential for worsening clinical status, although statistically
insignificant. The other risk factors monitored (RF2 - young age, RF3 - normal bilirubin
and RF4 - excess contrast agent) do not in any way influence the onset of the diagnosis of
acute pancreatitis, as none of the patients with acute pancreatitis were registered with any
of the other risk factors.
DISCUSSIONS
The foundation and the beginning of the research of this doctoral thesis take place at
the beginning of 2017. After choosing the topic, the courses conducted within the doctoral
program were designed to teach and guide doctoral students to conduct a valid doctoral
research both in terms of methodological, as well as of the acquired information necessary
for the elaboration of the doctoral study.
13
Following the elaboration of the study protocol and the collection of the necessary
data, multiple results were obtained, depending on the criteria selected for their analysis.
The study protocol included, among others, data collection and computerization, according
to pre-existing international protocols.
Starting from the protocols already implemented, the study sought to observe, in
other research conducted internationally, similar ideas, directions, in order to support and
supplement with new solutions, which would bring an element of novelty in this field.
Thus, the current State of Knowledge Chapter was created. On account of the studied
articles, the results obtained in this doctoral thesis can be compared with those in the
literature.
Post-ERCP pancreatitis is the result of mechanical, thermal, chemical, enzymatic or
hydrostatic lesions that occur during the procedure. Based on this pathophysiological
aspect, various types of treatments for its prophylaxis have been sought and tried, includ-
ing: installation of pancreatic stents, inhibition of intraacinar trypsinogen by inhibiting
pancreatic protease, amelioration of Oddi sphincter spasm by administration of glucagon
or nitroglicerin and facilitation of secretin injection at the time of cannulation. However,
the most promising results were obtained by anti-inflammatory drugs, which target
chemical lesions in the inflammatory process once activated in this context.
Nonsteroidal anti-inflammatory drugs are inexpensive, easy to administer and effec-
tive inhibitors of phospholipase A2 and cyclooxygenase, which modulate inflammatory
activity in the pathophysiology of acute pancreatitis, which is why we were able to use
them in the study, without the need for financial capital. important. (Muhammad et al.,
2020)
In our research we performed a statistical analysis of the demographic data of
patients undergoing Endoscopic retrograde cholangiopancreatography, the reasons for
hospitalization, the main diagnosis at hospitalization, which was the indication for
performing ERCP. The diagnosis was mainly mechanical jaundice due to obstruction of
the choledochus by stones, but also malignant obstruction, such as cholangiocarcinoma.
The increase in the number of ERCPs performed, both globally and nationally, also
entails the predisposition to increase the number of cases in which post-ERCP complica-
tions occur. Although ERCP techniques have evolved, the procedure is performed by
qualified staff who have gained more and more experience, although many prophylactic
methods have been studied in order to implement protocols to reduce the incidence of AP,
however this complication tends to keep a percentage constant incidence in recent years,
an issue that must remain in the attention of researchers and doctors, as severe forms of
BP have an increased risk of mortality. This fact offers a certain opportunity for further
research, in an attempt to identify an optimal treatment option that reduces the number of
post-ERCP PAs as much as possible.
GENERAL CONCLUSIONS
The conclusions of this study are presented in a structured manner, in correspon-
dence with the proposed research directions and the objectives corresponding to each
direction respectively.
14
The results of the clinical research carried out in the Institute of Gastroenterology
and Hepatology Iași, research aimed at analyzing the evolutionary profile of acute
pancreatitis developed subsequent to the practice of endoscopic retrograde cholangio-
pancreatography and therapeutic techniques derived by reporting the significance of
risk factors and potential profile value. Therapeutic sheets under evaluation allow the
formulation of the following conclusions:
1. During the research, 186 patients were enrolled in the study out of a total of
approximately 500 ERCPs performed at the Institute of Gastroenterology and
Hepatology Iasi.
2. The profile of the patients was characterized by the presence of obstructive
jaundice, abdominal pain syndrome, emitting syndrome and / or imaging detec-
tion of biliary obstruction.
3. Risk factors known and mentioned in the literature for the development of acute
post-ERCP pancreatitis were present in over 70% of cases, with females in the
first place, excess injection of the contrast agent and normal serum bilirubin
values at admission, which were in much lower percentages.
4. A percentage of 13% of the patients enrolled in the study presented the diagnos-
tic criteria for acute pancreatitis, a percentage similar to those mentioned in the
literature.
5. Of the total number of patients who developed acute pancreatitis, 4 had moderate
and 20 mild.
6. In the control group (treated with Indomethacin 100 mg postprocedurally) and in
group 1 (treated with Indomethacin suppositories 50 mg pre- and postproce-
durally and 600 mg ACC iv preprocedural), the PA incidence values were close,
stating that in the control group they were present 2 moderate forms of BP, and
in group 1 none.
7. In study group 2, treated with Indomethacin suppositories 50 mg pre- and
postprocedurally, it was the highest incidence rate of acute pancreatitis, relative
to both percentage and absolute value, suggesting that this prophylactic method
was the least efficient.
8. The batch additionally treated with acetylcysteine had a better evolution of post-
ERCP patients compared to the batch treated sequentially with Indomethacin
suppositories only.
9. Compared to the retrospective study, in which patients did not receive any
prophylactic medication, there was an improvement in the results represented by
a decrease in the incidence of BP from 16.6% (in patients without prophylaxis) to
13% (in patients with pharmacological prophylaxis).
10. In the groups studied, some risk factors well known in the literature appeared not
to negatively influence the biological markers studied (amylase, lipase, CRP,
leukocytosis), which may be a surprising issue of further research and analysis.
15
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