Download in combination with a hemoglobin drop of 1.3 mmol/L

1
Early biliary decompression versus conservative treatment in
2
acute biliary pancreatitis (APEC trial): design and rationale of a
3
randomised multicenter trial [ISRCTN97372133]
4
5
Nicolien J Schepers1,2, Olaf J Bakker3, Marc GH Besselink4, Thomas L Bollen5, Marcel GW
6
Dijkgraaf6, Casper HJ van Eijck7, Paul Fockens8, Erwin JM van Geenen9, Janneke van
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Grinsven4,8, Nora DL Hallensleben1,10, Bettina E Hansen1, Hjalmar C van Santvoort10, Robin
8
Timmer1, Marie-Paule GF Anten11, Clemens JM Bolwerk12, Foke van Delft13, Hendrik M van
9
Dullemen14, G Willemien Erkelens15, Jeanin van Hooft8, Robert Laheij16, René WM van der
10
Hulst17, Jeroen M Jansen18, Frank JGM Kubben19, Sjoerd D Kuiken20, Lars E Perk21, Rogier
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JJ de Ridder22, Marno CM Rijk23, Tessa EH Römkens24, Erik J Schoon25, Matthijs P
12
Schwartz26, BW Marcel Spanier27, Adriaan CITL Tan28, Willem J Thijs29, Niels G Venneman30,
13
Frank P Vleggaar31, Wim van de Vrie32, Ben J Witteman33, Hein G Gooszen34 and Marco J
14
Bruno1
15
for the Dutch Pancreatitis Study Group
16
17
Corresponding author
18
Nicolien J Schepers, MD
19
Dutch Pancreatitis Study Group
20
St. Antonius Hospital
21
Koekoekslaan 1
22
3430 EM Nieuwegein
23
The Netherlands
24
Tel: +31 614411960
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Fax: +31 306098316
26
E-mail: [email protected]
27
1
28
Author details
29
1. Dept. of Gastroenterology and Hepatology, Erasmus Medical Center, PO 2040, 3000 CA
30
Rotterdam; the Netherlands
31
2. Dept. of Gastroenterology and Hepatology, St Antonius Hospital, PO 2500, 3430 EM
32
Nieuwegein; the Netherlands
33
3. Dept. of Surgery, University Medical Center Utrecht, PO 85500, 3508 GA Utrecht; the
34
Netherlands
35
4. Dept. of Surgery, Academic Medical Center University of Amsterdam, PO 22660, 1100 DD
36
Amsterdam; the Netherlands
37
5. Dept. of Radiology, St Antonius Hospital, PO 2500, 3430 EM Nieuwegein; The
38
Netherlands
39
6. Clinical Research Unit, Academic Medical Center University of Amsterdam, PO 22660,
40
1100 DD Amsterdam; the Netherlands
41
7. Dept. of Surgery, Erasmus Medical Center, PO 2040, 3000 CA Rotterdam; the
42
Netherlands
43
8. Dept. of Gastroenterology and Hepatology, Academic Medical Center University of
44
Amsterdam, PO 22660, 1100 DD Amsterdam; the Netherlands
45
9. Dept. of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre,
46
HP 690, PO 9101, 6500 HB Nijmegen; the Netherlands
47
10. Dept. of Surgery, St Antonius Hospital, PO 2500, 3430 EM Nieuwegein; the Netherlands
48
11. Dept. of Gastroenterology and Hepatology, Sint Franciscus Gasthuis, PO 10900, 3004
49
BA, Rotterdam; the Netherlands
50
12. Dept. of Gastroenterology and Hepatology, Reinier de Graaf Hospital, Reinier de
51
Graafweg 3-11, 2625 AD Delft; the Netherlands
52
13. Dept. of Gastroenterology and Hepatology, VU University Medical Center Amsterdam,
53
PO Box 7057, 1007 MB Amsterdam; the Netherlands
54
14. Dept. of Gastroenterology and Hepatology, University Medical Center Groningen, PO
55
30001, 9700 RB Groningen; the Netherlands
2
56
15. Dept. of Gastroenterology and Hepatology, Gelre Hospital, PO 9014, 7300 DS
57
Apeldoorn; the Netherlands
58
16. Dept. of Gastroenterology and Hepatology, St. Elisabeth Hospital, PO 90151, 5000 LC
59
Tilburg; the Netherlands
60
17. Dept. of Gastroenterology and Hepatology, Kennemer Gasthuis, PO 417, 2000 AK
61
Haarlem; the Netherlands
62
18. Dept. of Gastroenterology and Hepatology, Onze Lieve Vrouwe Gasthuis; Postbus
63
95500, 1090 HM Amsterdam; the Netherlands
64
19. Dept. of Gastroenterology and Hepatology, Maasstad Hospital, Maasstadweg 21, 3079
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DZ Rotterdam; the Netherlands
66
20. Dept. of Gastroenterology and Hepatology, Sint Lucas Andreas Hospital, PO 9243
67
1006 AE Amsterdam; the Netherlands
68
21. Dept. of Gastroenterology and Hepatology, Medical Center Haaglanden, PO 432
69
2501 CK Den Haag; the Netherlands
70
22. Dept. of Gastroenterology and Hepatology, Maastricht University Medical Center, PO
71
5800, 6202 AZ Maastricht; the Netherlands
72
23. Dept. of Gastroenterology and Hepatology, Amphia Hospital, PO 90158, 4800 RK Breda;
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the Netherlands
74
24. Dept. of Gastroenterology and Hepatology, Jeroen Bosch Hospital, PO 90153, 5200 ME
75
‘s-Hertogenbosch; the Netherlands
76
25. Dept. of Gastroenterology and Hepatology, Catharina Hospital, PO 1350, 5602 ZA
77
Eindhoven; the Netherlands
78
26. Dept. of Gastroenterology and Hepatology, Meander Medical Center, PO 1502, 3800
79
BM, Amersfoort; the Netherlands.
80
27. Dept. of Gastroenterology and Hepatology, Rijnstate Hospital, PO 9555, 6800 TA
81
Arnhem; the Netherlands
82
28. Dept. of Gastroenterology and Hepatology, Canisius-Wilhelmina Hospital, PO 9015, 6500
83
GS Nijmegen; the Netherlands.
3
84
29.
85
9700 RM Groningen; the Netherlands
86
30. Dept. of Gastroenterology and Hepatology, Medisch Spectrum Twente, PO 50000, 7500
87
KA Enschede; the Netherlands.
88
31. Dept. of Gastroenterology and Hepatology, University Medical Center Utrecht, PO 85500,
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3508 GA Utrecht; the Netherlands
90
32. Dept. of Gastroenterology and Hepatology, Albert Schweitzer Hospital, PO 444
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3300 AK Dordrecht; the Netherlands
92
33. Dept. of Gastroenterology and Hepatology, Hospital Gelderse Vallei Ede, PO 9025, 6710
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HN Ede; the Netherlands
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34. Dept. of Operating Rooms - Evidence Based Surgery, Radboud University Nijmegen
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Medical Centre, HP 690, PO 9101, 6500 HB Nijmegen; the Netherlands.
Dept.
of
Gastroenterology
and
Hepatology,
Martini
Hospital,
PO
30033
96
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Abstract (max 350 words, now 262)
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Background: Acute pancreatitis is mostly caused by gallstones or sludge. Early
100
decompression of the biliary tree by endoscopic retrograde cholangiography (ERC) with
101
sphincterotomy may improve outcome in these patients. Whereas current guidelines
102
recommend early ERC in patients with concomitant cholangitis, early ERC is not
103
recommended in patients with mild biliary pancreatitis. Evidence on the role of routine early
104
ERC with endoscopic sphincterotomy in patients without cholangitis but with biliary
105
pancreatitis at high risk for complications is lacking. We hypothesize that early ERC with
106
sphincterotomy improves outcome in these patients.
107
Methods/Design: The APEC trial is a randomised controlled, parallel-group, superiority
108
multicenter trial. Within 24 hours after presentation to the emergency department, patients
109
with biliary pancreatitis without cholangitis and at high risk for complications, based on Acute
110
Physiology And Chronic Health Evaluation (APACHE-II) score of 8 or more, Modified
111
Glasgow score of 3 or more, or serum C-reactive protein above 150 mg/L, will be
112
randomised. In 27 hospitals of the Dutch Pancreatitis Study Group, 232 patients will be
113
allocated to early ERC with sphincterotomy or to conservative treatment. The primary end
114
point is a composite of major complications (i.e. organ failure, pancreatic necrosis,
115
pneumonia, bacteremia, cholangitis, pancreatic endocrine or exocrine insufficiency) or death
116
within 180 days after randomization. Secondary end points include ERC related
117
complications, infected necrotising pancreatitis, length of hospital stay and an economical
118
evaluation.
119
Discussion: The APEC trial investigates whether an early ERC with sphincterotomy reduces
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the composite end point of major complications or death compared with conservative
121
treatment in patients with biliary pancreatitis at high risk of complications.
122
Trial registration: Current Controlled Trials ISRCTN97372133
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Keywords (max 10): Acute pancreatitis, Treatment, Endoscopy, Pancreas, ERCP, ERC
5
125
Background
126
127
Acute pancreatitis is a leading cause for acute hospitalization [1]. In most cases pancreatitis
128
results from gallstones causing obstruction of Vater’s ampulla [2, 3]. As biliary stones or
129
sludge are thought to initiate and aggravate pancreatitis, early biliary decompression –
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achieved by endoscopic retrograde cholangiography (ERC) with sphincterotomy – may
131
ameliorate the disease course [4, 5]. In return, ERC with sphincterotomy itself may also be
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associated with complications in up to 10% of patients [6, 7].
133
Several studies have investigated the effect of routine ERC in biliary pancreatitis [8].
134
Guidelines state an undisputed indication for ERC in patients with concurrent cholangitis and
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pancreatitis [2, 9]. In patients with mild disease, early ERC is not indicated because in these
136
patients the risk for complications does not outweigh the potential benefit [2, 9].
137
Recent guidelines advise to perform ERC with sphincterotomy in case of pancreatitis
138
with cholestasis, but acknowledge the moderate quality of evidence for this recommendation
139
[2, 9]. In patients with pancreatitis at high risk for developing complications (i.e. predicted
140
severe) without cholangitis, data are conflicting. A meta-analysis found no beneficial effect of
141
routine early ERC compared with conservative treatment [8]. However, the studies have
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notable shortcomings that preclude reliable recommendations on the use of ERC in patients
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with predicted severe biliary pancreatitis without cholangitis [10]. First, patients included were
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those with a low pre-likelihood of a biliary etiology, those at low risk for developing
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complications (i.e. predicted mild), and those with cholangitis at presentation. Second,
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patient selection criteria and study end points (complications) varied considerably between
147
studies and also included clinically less relevant complications such as pleural effusion or
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ascites. Third, the trials did not present data separately regarding liver biochemical tests,
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which precludes performing a subgroup analysis for patients with cholestasis. Fourth, routine
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‘early’ ERC was performed during a wide time frame (48 to 72 hours after admission) which
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may be too late to prevent complications from severe disease or increase the risk for ERC
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related complications. Fifth, the trial protocols did not specify precisely when sphincterotomy
6
153
should be performed. This resulted in many patients who underwent ERC without
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sphincterotomy. We believe sphincterotomy should routinely be performed during ERC to
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decompress the biliary duct, even in the absence of gallstones or visible sludge in the
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common bile duct [11-13]. Sixth, no criteria were set to guarantee that ERCs were performed
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by experienced endoscopists, although ERC is an intervention that requires considerable
158
training and expertise [14, 15]. Finally, even if the data of all available randomised trials are
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pooled, such analysis will still not have sufficient power to detect clinically relevant and
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statistically significant effects of early ERC with sphincterotomy on major complications or
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death in patients with predicted severe biliary pancreatitis without cholangitis [16, 8].
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The APEC trial is designed to investigate whether early ERC with sphincterotomy
163
compared with conservative treatment improves outcome in patients with biliary pancreatitis
164
without cholangitis who are at high risk for complications.
165
7
166
Methods/Design
167
168
The APEC trial is a randomised controlled, parallel-group, superiority, multicenter trial.
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Patients with acute pancreatitis will be assessed for study eligibility within 24 hours after
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presentation to the emergency department. Patients with biliary pancreatitis without
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cholangitis and at high risk of developing severe disease are eligible for randomisation.
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Patients are randomised to early ERC with sphincterotomy or to conservative treatment. The
173
trial will be conducted in 27 hospitals of the Dutch Pancreatitis Study Group. The APEC trial
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protocol is in accordance with the Spirit Guidelines [17].
175
176
Primary end point (see Table 1 for definitions)
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The primary end point is a composite of major complications or death occurring within 180
178
days after randomisation (i.e. the composite end point can only occur once per patient).
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Major complications are defined as persistent organ failure, pancreatic necrosis, bacteremia,
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cholangitis, pneumonia and pancreatic endocrine or exocrine insufficiency.
181
182
Secondary end points
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 “Per protocol” analysis of the primary endpoint
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 “As treated” analysis of the primary endpoint
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 Individual components of the primary end point
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 Infected necrotising pancreatitis
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 Need for new intensive care unit admission
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 Length of stay at intensive care unit
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 ERC related complications (see Table 2 for definitions)
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 Cholangitis during admission
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 Number of endoscopic, radiological and operative (re-)interventions
8
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 Readmission for biliary events (recurrent acute biliary pancreatitis, cholecystitis, biliary
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colics, cholangitis)
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 Difficulty of cholecystectomy (as scored by Visual Analogue Scale 1-10)
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 Quality of life (Short Form-36 and EQ5D-5L) including quality adjusted life year’s (QALY)
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 Direct medical costs, direct and indirect non-medical costs
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Inclusion criteria
199

Acute pancreatitis; defined as the presence of at least 2 out of the following 3 criteria: 1)
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pain in the upper abdomen, 2) serum amylase or lipase concentration > 3 times the
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upper limit of normal or 3) imaging features of acute pancreatitis on Computed
202
Tomography (CT) or Magnetic Resonance Imaging (MRI) [18]
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
High risk of developing severe disease (i.e. predicted severe) based on either one of the
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following criteria: Acute Physiology and Chronic Health Evaluation (APACHE II score) ≥ 8
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[19] (see Table 4) 2) Modified Glasgow score ≥ 3 [20] (see Table 3), or 3) C-reactive
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protein >150 mg/L [21, 22].
207

High probability of a biliary aetiology based on at least one of the following criteria: 1)
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gallstones or biliary sludge on imaging (any type), 2) dilated common bile duct on
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imaging defined as >8mm in patients ≤75 years or >10mm in patients >75 years, 3)
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alanine aminotransferase (ALAT) > two times upper limit of normal (no absolute
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numerical value is chosen because of multicentric design with varying upper limits
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between hospitals and gender-based differences in upper limit of normal values [23-25])
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
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215
Ability to perform ERC within 24 hours after presentation to the emergency department
and no more than 72 hours after symptom onset

216
In case of a previous episode of necrotising pancreatitis, patient should be fully recovered
(confirmed on imaging)
217

Age ≥18 years
218

Written informed consent
9
219
220
Exclusion criteria
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
Cholangitis (see Table 1 for definition)
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
Pancreatitis due to other causes such as alcohol abuse (more than 4 units per day),
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metabolic causes (hypertriglyceridemia, hypercalcemia), medication, trauma, etc.
224

Previous pancreatic sphincterotomy or needle knife precut
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
Chronic pancreatitis (see Table 5 for definition)
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
International Normalized Ratio that cannot be corrected to less than 1.5 with clotting
227
228
factors or fresh frozen plasma

Pregnancy
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Randomisation
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Patients are randomised to early ERC with sphincterotomy or to conservative treatment (1:1
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ratio) with a web-based randomization module (ALEA, Academic Medical Center,
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Amsterdam) in random blocks of size two, four or six. At randomisation, patients are stratified
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according to the presence of cholestasis and for region of the hospital. Cholestasis is defined
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as a serum bilirubin >40 μmol/L at randomization or a dilated common bile duct (defined as
236
>8mm in patients ≤75 years or >10mm in patients >75 years).
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Treatment protocol
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
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Early ERC with sphincterotomy is performed within 72 hours after symptom onset and within
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24 hours of hospital admission. A sphincterotomy is always performed irrespective of the
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presence of common bile duct stones. ERC is performed by or under the direct supervision
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of an experienced endoscopist defined as a person who has done more than 400 ERCs in
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his or her lifetime and has performed more than 50 ERCs yearly on average in the previous
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three years. When unable to cannulate the common bile duct, even after precut
Early ERC with sphincterotomy
10
246
sphincterotomy, the ERC procedure will be ended and the patient is treated conservatively.
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After the patient has recovered from the acute pancreatitis attack, a repeat ERC is scheduled
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to perform a full sphincterotomy. According to the intention-to-treat principle, these patients
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will be analyzed according to their original treatment allocation: i.e. early ERC with
250
sphincterotomy. In case of incomplete stone-extraction a plastic endoprosthesis is inserted
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and an elective ERC is scheduled. Antibiotics are only administered in case of contrast
252
injection without adequate biliary drainage.
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254

255
Patients in the conservative group are managed according to the conservative supportive
256
treatment regimen for patients with acute biliary pancreatitis as described in the paragraph
257
below. A rescue ERC is performed when a patient develops cholangitis (see Table 1 for
258
definition). Whenever the attending physician is in doubt whether or not an ERC should be
259
performed, the study coordinator presents the case to an expert panel. This expert panel,
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consisting of an independent gastroenterologist and a gastrointestinal surgeon, provides a
261
treatment advice within 24 hours. Retained bile duct stones are removed during an elective
262
ERC when the patient is recovered from the initial pancreatitis episode.
Conservative treatment
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General treatment regimen
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Both groups are treated with intravenous infusion of fluids to ensure adequate hydration and
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diuresis, appropriate analgesic treatment, enteral nutrition if necessary, treatment of
267
endocrine and exocrine pancreatic insufficiency, and a gastric tube in case of vomiting. No
268
antibiotic prophylaxis is given. The treating physician assesses whether the patient requires
269
intensive care monitoring or further supportive measures (e.g. mechanical ventilation). All
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patients will undergo a contrast-enhanced CT (CECT) 5 to 7 days after hospital admission for
271
assessment of pancreatic necrosis. In case patients quickly recover and are discharged
272
within 5 days, CECT will not be routinely performed and the disease will be considered mild.
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Readmission within 10 days after initial discharge for complications related to pancreatitis is
11
274
regarded as primary admission. The timing of cholecystectomy is determined by the treating
275
physician depending on the patient’s condition and outcome of pancreatitis.
276
277
Data collection
278
Clinical data are collected using case record forms. At all sites an independent monitor will
279
assess the study forms including informed consent documents and compare these with
280
source-documents. The in-hospital utilization of healthcare will be registered as part of the
281
data collection. Out-of-hospital use of healthcare will be documented by self-administered
282
questionnaires.
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284
Follow-up
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After hospital discharge patients are seen at the outpatients clinic and further monitored at
286
the discretion of the physician. After 1, 3, and 6 months patients receive a questionnaire (SF-
287
36, SF-HLQ and EQ5D-5L) [26, 27]. A visit is scheduled at 3 months after randomization to
288
identify persistent common bile duct stones or detect endocrine or exocrine pancreatic
289
insufficiency (serum liver- and glucose measurements and fecal elastase).
290
291
Safety
292
An independent Data Safety Monitoring Committee (DSMC) is appointed to assess protocol
293
adherence, patient recruitment, and patient safety. All physicians who are involved in the trial
294
are asked to report all adverse events to the coordinating investigator. Adverse events are
295
reported using the online module (https://www.toetsingonline.nl) of the Dutch Central
296
Committee on Research involving human subjects. All adverse events are collected and
297
reported unblinded to the DSMC every time 60 patients are randomised, after randomization
298
of the final patient, and at the end of follow-up of the final patient. In addition, a continuous
299
sequential safety analysis on mortality is performed to ensure patient’s safety throughout the
300
trial. The DSMC discusses all adverse events and the progress of the trial, and reports to the
12
301
trial steering committee. A copy is sent to the ethical committee and all physicians who are
302
involved with the study.
303
304
Ethics
305
The APEC trial is performed in accordance to the declaration of Helsinki and the Dutch law
306
regarding research involving human subjects (Wet Medisch wetenschappelijk Onderzoek
307
met Mensen). The ethical committee of the Erasmus Medical Center in Rotterdam, the
308
Netherlands, approved the study protocol on the 12th of December 2012. Subsequently, the
309
boards of the 27 participating hospitals gave permission for conducting the trial. The APEC
310
trial is registered with identification number ISRCTN97372133.
311
312
Statistical considerations
313

314
The sample size calculation is based on a recent Dutch multicenter, observational study in
315
patients with biliary pancreatitis at high risk for complications [11]. The primary end point
316
occurred in 32% of patients in which ERC was performed compared with 46% of patients
317
who were treated conservatively. Taken into account that ERC was not always performed
318
within 24 hours and that sphincterotomy was not routinely performed, a correction factor of
319
2% for both percentages is added to both incidence rates. The APEC trial is a superiority trial
320
in which the sample size calculation is based on the assumption that early ERC with
321
sphincterotomy reduces the incidence of the primary end point by 18% (48% to 30%). With a
322
power of 80%, a two sided significance level of 5% and a 1% drop-out rate, a total of 232
323
patients are required to be included in the study.
Sample size calculation
324
325

326
The following patient characteristics before randomization will be described: age, sex, body
327
mass index, co-morbidity, American Society of Anaesthesiologists (ASA) score, duration of
328
symptoms before randomization, duration of symptoms before ERC, serum bilirubin levels,
Descriptive statistics
13
329
dilated common bile duct on ultrasound or computed tomography, presence of (multi) organ
330
failure or systemic inflammatory response syndrome (SIRS), Sequential Organ Failure
331
Assessment (SOFA) scale [28], Multiple Organ Dysfunction Score (MODS) [29], predicted
332
disease severity according to APACHE-II, modified Glasgow, blood urea nitrogen and C-
333
reactive protein. Data will be presented in percentages for categorical variables. Continuous
334
data with normal distribution will be presented as mean with standard deviation, and as
335
median with interquartile range in case of skewed distribution.
336
337

338
After 232 patients in total have completed their 6 months follow-up, raw data regarding
339
potential end points will be presented to an adjudication committee blinded for treatment
340
allocation to determine whether end points meet the protocol-specified criteria. In case of
341
dissenting opinions, a consensus meeting will follow. Primary analysis, using the Pearson’s
342
Chi-squared test, is based on the intention-to-treat principle with patients being analyzed
343
according to original treatment allocation, irrespective whether cannulation or sphincterotomy
344
was successful. For exploratory reasons a per-protocol analysis will be performed to
345
compare treatment groups. A tabular listing of all patients excluded from the intention-to-treat
346
populations will be provided together with the reasons for exclusion. Data will be presented
347
as relative risks with 95% confidence intervals. A two-tailed P<0.05 is considered statistically
348
significant.
Analyses
349
350

351
Predefined subgroup analysis will be done according to the presence of cholestasis. Logistic
352
regression models will be used to test whether treatment effects differ significantly between
353
these subgroups. Secondary end points will be compared using the Pearson’s chi-squared
354
test or Mann-Whitney U test. Additionally, secondary end points will be analyzed separately
355
using Cox regression analysis censoring patients no longer at risk and categorising missing
356
data as no event. For all other analyses, data will be considered missing at random. To
Additional analyses
14
357
evaluate differences in systemic inflammatory response after randomisation, the APACHE-II,
358
C-reactive protein levels and presence of SIRS from randomization to day 7 will be
359
calculated and compared between treatment groups. To gain further insight into factors that
360
are predictive of major complications or death after ERC, exploratory analysis of the effects
361
of (essential) baseline covariates (and potential interactions) will be performed using logistic
362
regression analysis.
363
Direct medical and non-medical costs, and indirect costs will be compared to assess
364
costs per patient with poor outcome (death or severe complications). Validated
365
questionnaires will be analyzed to assess differences in quality of life and provide input to
366
compare costs per quality adjusted life year (QALY). Health utility scoring algorithms for the
367
EQ5D-5L health status profiles available from the literature, based on preferences in the
368
general population using time trade-off elicitation techniques, will be used to derive a QALY
369
estimate for each patient. This QALY will be calculated as the product sum of health utilities
370
and the lengths of the periods in-between successive measurements [30, 31].
371
372

373
An interim-analysis will be performed when 116 patients (50%) are randomised and
374
discharged after their initial hospital admission. Raw data pertaining to potential end points
375
will be presented to an adjudication committee blinded for treatment allocation to determine
376
whether end points meet the protocol-specified criteria. In case of dissenting opinions, a
377
consensus meeting will follow. The interim-analysis will be performed by an independent
378
statistician who reports to the DSMC. The DSMC will have unblinded access to all data when
379
discussing the results of the interim-analysis and reports to the steering committee. The
380
steering committee will decide upon continuation of the APEC trial. The Haybittle-Peto
381
approach is used for beneficial effect, meaning that the trial will be ended using symmetric
382
stopping boundaries at P<0.001 [32, 33]. The trial will not be stopped for futility.
Premature termination of the study
15
383
Discussion
384
385
The APEC trial is designed to provide an answer to a persisting clinical dilemma; whether or
386
not to routinely perform early ERC with sphincterotomy in patients with biliary pancreatitis at
387
high risk for complications, but without concurrent cholangitis. Guidelines clearly advise
388
urgent ERC with sphincterotomy in patients with concomitant cholangitis and discard this
389
intervention in patients with a predicted mild disease course. A recent Cochrane meta-
390
analysis comparing routine ERC versus conservative treatment found no difference in
391
complications and death in patients with pancreatitis at high risk for complications [8].
392
However, besides some notable limitations in the design of the studies included, the pooled
393
sample size of patients with biliary pancreatitis who were at high risk for complications
394
without concurrent cholangitis was too small to detect a difference in effect. As long as the
395
precise role of early ERC in biliary pancreatitis in patients at high risk for complications
396
without concurrent cholangitis remains unclear, patients are either withheld a potentially
397
beneficial intervention or exposed to a treatment from which they cannot benefit and may
398
only suffer its potential complications. The APEC trial is the first randomised controlled trial in
399
this particular subset of patients that is adequately powered to detect statistically significant
400
differences in clinically relevant outcomes of early ERC and sphincterotomy. The APEC trial
401
will also provide insights into the cost-effectiveness of routine early ERC and sphincterotomy
402
and the amount of cost savings that can be achieved.
403
404
To date, the optimal timing of early ERC in biliary pancreatitis is unclear. Previous studies
405
suggest that the severity of the pancreatitis is related to the duration of biliopancreatic ductal
406
obstruction [34, 35]. These observations provide the rationale to perform an ERC and
407
sphincterotomy early after the onset of symptoms. For this reason, albeit logistically
408
challenging, in the APEC trial ERC with sphincterotomy is performed within 72 hours after
409
symptom onset and within 24 hours after hospital admission to achieve the optimal effect of
410
the intervention.
16
411
Recent guidelines state that early ERC is probably beneficial in patients with cholestasis
412
[2], albeit with the acknowledgement that the level of evidence is low to moderate. To
413
investigate whether the potential beneficial effects of ERC with sphincterotomy depend on
414
the presence of cholestasis, patients in the APEC trial will be stratified according to this
415
baseline variable.
416
The primary end point of the APEC trial is a composite of major complications and death.
417
One of the major complications that may occur in the course of biliary pancreatitis is
418
pancreatic necrosis. Opposed to the definition of necrotising pancreatitis according to the
419
recently updated Atlanta classification, we excluded extrapancreatic necrosis alone as a
420
major complication [18] the rationale being that extrapancreatic necrosis alone is suggested
421
to be a separate entity in necrotising pancreatitis associated with less complications
422
compared with pancreatic necrosis [36].
423
Commonly used biochemical and radiologic predictors of biliary obstruction are unreliable
424
in the early phase of acute pancreatitis [37]. Advanced imaging modalities such as magnetic
425
resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) have
426
improved accuracy in detecting common bile duct stones and could therefore be applied to
427
select patients for therapeutic ERC [38]. However, EUS is not available in all centres.
428
Moreover, performing either MRCP or EUS within 24 hours after presentation can be
429
challenging and proof to be unfeasible because of limited local resources and expertise,
430
particularly during on call hours. The use of MRCP and EUS before ERC is also not
431
incorporated in the APEC-trial because it is hypothesised that the beneficial effect of an early
432
sphincterotomy might also be present irrespective of a stone or visible sludge in the CBD
433
[11]. Hence, even if CBD stones are detected by EUS or MRCP, the question remains
434
whether sphincterotomy in the early phase of the disease improves outcome in these
435
patients.
436
The APEC trial will be performed in 27 centers that participate in the Dutch Pancreatitis
437
Study Group. The fact that ERCs will not be performed exclusively in high volume expert
438
centers, but in hospitals nationwide by endoscopists with a predefined skill level ensures that
17
439
the results of the APEC trial can be extrapolated to comparable clinical practice settings
440
worldwide.
441
442
Conclusion
443
The APEC trial is a multicenter randomised trial that investigates whether routine early ERC
444
with sphincterotomy reduces the composite end point of major complications or death in
445
patients with biliary pancreatitis at high risk for complications, but without cholangitis, as
446
compared with conservative treatment.
447
448
449
Trial Status
450
The trial was registered on the 7th of December 2012 in the ISRCTN register. The first
451
patient was randomised on the 1st of March 2013. To date, 144 patients have been
452
randomised and inclusion is on schedule.
453
454
455
Abbreviations
456
ALAT: alanine aminotransferase;
457
APACHE: Acute Physiology and Chronic Health Evaluation;
458
CBD: Common Bile Duct;
459
CECT: Contrast-Enhanced Computed Tomography;
460
CT: Computed Tomography;
461
DSMC: Data Safety Monitoring Committee;
462
EUS: Endoscopic UltraSound;
463
ISRCTN: International Standard Randomised Controlled Trial Number;
464
MRCP: Magnetic Resonance Cholangio Pancreatography;
465
MRI: Magnetic Resonance Imaging
466
QALY: Quality Adjusted Life Year.
18
467
468
Competing interests
469
The authors declare that they have no competing interests.
470
471
Authors’ contributions
472
NJS drafted the manuscript. OJB, MGHB, HvS, MJB co-authored the writing of the
473
manuscript. NJS, OJB, MGHB, HCvS, EJvG, BEH, RT, PF, HGG, MGWD and MJB
474
participated in the design of the study during several meetings of the Dutch Pancreatitis
475
Study Group. NJS and MGWD performed the sample size calculation.
476
All authors critically assessed the study design, edited the manuscript and read and
477
approved the final manuscript.
478
479
Acknowledgements
480
Funding
481
Fonds NutsOhra (grant number 1203-052), The Netherlands Organization for Health
482
Research and Development, Health Care Efficiency Research program (ZonMw, grant
483
number 837002008) and the patient organization for pancreatic diseases financially
484
supported the APEC trial. The APEC trial is an investigator initiated trial. The sponsors had
485
no influence on the design of the study, data collection, results or publications.
486
487
Steering committee
488
M.J. Bruno, MD PhD, department of Gastroenterology and Hepatology, Erasmus MC
489
University Medical Center (chair)
490
B.E. Hansen, MD PhD, department of Gastroenterology and Hepatology, Erasmus MC
491
University Medical Center, Rotterdam
492
C.H.J. van Eijck, MD PhD, department of Surgery, Erasmus MC University Medical Center,
493
Rotterdam
494
E.J. van Geenen, MD PhD, department of Gastroenterology and Hepatology, Radboud
19
495
University Medical Center, Nijmegen
496
T.L. Bollen, MD, department of Radiology, St. Antonius Hospital Nieuwegein
497
M.G.H. Besselink, MD PhD, department of Surgery, AMC Amsterdam
498
O.J. Bakker, MD, department of Surgery, UMC Utrecht
499
H.C. van Santvoort, MD PhD, department of Surgery, UMC Utrecht
500
P. Fockens, MD PhD, department of Gastroenterology and Hepatology, AMC Amsterdam
501
H.G. Gooszen, MD PhD, department of Operation Rooms/Evidence Based Surgery, UMC St
502
Radboud Nijmegen
503
R. Timmer, MD PhD, department of Gastroenterology, St Antonius Hospital
504
N.J. Schepers, MD, department of Gastroenterology and Hepatology, Erasmus MC
505
University Medical Center, Rotterdam
506
507
Data Safety Monitoring Committee
508
U.H.W. Beuers, MD PhD, department of Gastroenterology and Hepatology, AMC Amsterdam
509
L.P.S. Stassen, MD PhD, department of Surgery, MUMC Maastricht
510
A.H. Zwinderman, MD PhD, department of Epidemiology, AMC Amsterdam
511
R. van Hillegersberg, MD PhD, department of Surgery, UMC Utrecht
512
J.W.F.M. Bartelsman, MD PhD, Gastroenterologist
513
H.R. van Buuren, MD PhD, department of Gastroenterology and Hepatology, Erasmus MC
514
University Medical Center
515
516
Independent physician
517
V.M.C.W. Spaander, MD PhD, department of Gastroenterology and Hepatology, Erasmus
518
MC University Medical Center,
519
520
Clinical centers and principal investigators (all in the Netherlands):
521
1. Academic Medical Center University of Amsterdam, PO 22660, 1100 DD Amsterdam; JE
522
van Hooft, MD PhD, dept. of Gastroenterology;
20
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
2. Albert Schweitzer Hospital, PO 444, 3300 AK Dordrecht; W van de Vrie, MD PhD, dept.
of Gastroenterology
3. Amphia Hospital Breda, PO 90158, 4800 RK Breda; M Rijk, MD PhD, dept. of
Gastroenterology;
4. Canisius-Wilhelmina Hospital, PO 9015, 6500 GS Nijmegen; ACITL Tan, MD PhD, dept.
of Gastroenterology;
5. Catharina Hospital, PO 1350, 5623 EJ Eindhoven; E Schoon, MD PhD, dept. of
Gastroenterology;
6. Erasmus Medical Center, PO 2040, 3000 CA Rotterdam; MJ Bruno, MD PhD, professor,
dept. of Gastroenterology;
7. Gelre Hospital, PO 9014, 7300 DS Apeldoorn; W Erkelens, MD PhD, dept. of
Gastroenterology;
8. Hospital Gelderse Vallei, PO 9025, 6710 HN Ede; B Witteman, MD PhD, professor, dept.
of Gastroenterology;
9. Jeroen Bosch Hospital, PO 90153, 5200 ME Den Bosch; TEH Römkens, MD PhD, dept.
of Gastroenterology;
10. Kennemer Gasthuis, PO 417, 2000 AK Haarlem; RWM van der Hulst, MD PhD, dept of
Gastroenterology;
11. Maasstad Hospital Rotterdam, PO 9100, 3007 AC Rotterdam; FJGM Kubben, MD, dept.
of Gastroenterology;
12. Maastricht University Medical Center, PO 5800, 6202 AZ Maastricht; R de Ridder, MD
PhD, dept. Of Gastroenterology;
13. Martini Hospital, PO 30033, 9700 RM Groningen; WJ Thijs, MD PhD, dept of
Gastroenterology
14. Meander Medical Center, PO 1502, 3800 BM, Amersfoort; MP Schwartz, MD PhD, dept.
of Gastroenterology;
15. Medical Center Haaglanden, PO 432, 2501 CK Den Haag; LE Perk, MD PhD, dept of
Gastroenterology
21
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
16. Medisch Spectrum Twente, PO 50000, 7500 KA Enschede; NG Venneman, MD PhD,
dept. of Gastroenterology;
17. OLVG Amsterdam, PO 95500, 1090 HM Amsterdam; JM Jansen, MD PhD, dept. of
Gastroenterology;
18. Radboud University Nijmegen Medical Center, PO 9101, 6500 HB Nijmegen; EJM van
Geenen, MD PhD, dept. of Gastroenterology;
19. Reinier de Graaf Groep Delft, PO 5011, 2600 GA Delft; CJM Bolwerk, MD PhD, dept. of
Gastroenterology;
20. Rijnstate Hospital, PO 9555, 6800 TA Arnhem; BMW Spanier, MD PhD, dept. of
Gastroenterology;
21. Sint Franciscus Gasthuis, PO 10900, 3004 BA Rotterdam; MGPF Anten, MD, dept. Of
Gastroenterology
22. Sint Lucas Andreas Hospital, PO 9243, 1006 AE Amsterdam; SD Kuiken, MD, dept. Of
Gastroenterology
23. St Antonius Hospital, PO 2500, 3430 EM Nieuwegein; R Timmer, MD PhD, dept. of
Gastroenterology;
24. St. Elisabeth Hospital, PO 90151, 5000 LC Tilburg; R Laheij, MD PhD, dept. of
Gastroenterology
25. University Medical Center Groningen, PO 30001, 9700 RB Groningen; HM van Dullemen,
MD PhD, dept. of Gastroenterology;
26. University Medical Center Utrecht, PO 85500, 3508 GA Utrecht; FP Vleggaar, MD PhD,
dept. of Gastroenterology;
27. VU University Medical Center Amsterdam, PO 7057, 1007 MB Amsterdam; F van Delft,
MD, dept. of Gastroenterology.
575
576
Key staff at coordinating centers
577
AMC Amsterdam: MGH Besselink, HC van Santvoort
578
Erasmus MC University Medical Center: MJ Bruno (principal investigator), NDL Hallensleben
22
579
(coordinator), NJ Schepers (coordinator)
580
St. Antonius Hospital, Nieuwegein: S Jans (research nurse), NDL Hallensleben (coordinator),
581
NJ Schepers (coordinator)
582
UMC Utrecht, Utrecht: OJ Bakker
583
23
584
Table 1. Definitions primary end point
Event
Definition
New-onset
New-onset (i.e. not present at randomisation) and persistent (i.e. >48 hours)
organ failure
failure of organ(s) according to the modified Marshall score [18, 29].
Pancreatic
Presence of diffuse or focal areas of pancreatic non-enhancement on contrast
necrosis
enhanced CT performed at 5-7 days after admission.
Bacteremia
Demonstrated with positive blood cultures. Blood samples will be drawn when
temperature
>38.5°C.
For
non-pathogens
(e.g.
Coagulase
negative
staphylococci) at least 2 samples have to be positive.
Cholangitis
Highest in-hospital body temperature in previous 24 hours: ≥ 38.5ºC with chills,
without an obvious other cause (e.g., cystitis, pneumonia, thrombophlebitis, etc),
or 39ºC without chills, without an obvious cause for fever, and either:
1) Choledocholithiasis on abdominal US, CT, EUS or MRI, or
2) A dilated common bile duct on imaging defined as >8mm in patients ≤75 years
or >10mm in patients >75 years or
3) Progressive cholestasis for at least two consecutive days and a bilirubin >2.3
mg/dL (40 μmol/L).
Pneumonia
Coughing, dyspnoea, chest film showing infiltrative abnormalities, lowered
arterial blood gas with positive sputum culture. If in intensive care, a positive
endotracheal culture is mandatory.
Exocrine
Fecal elastase <200µg/g and the need for pancreatic enzyme supplementation
pancreatic
at 3 months after discharge; this requirement was not present before onset of
insufficiency
pancreatitis.
Endocrine
The need for insulin or oral antidiabetic drugs at 3 months after discharge; this
pancreatic
requirement was not present before onset of pancreatitis.
insufficiency
585
24
586
Table 2. ERC related complications
Event
Definition
Clinically relevant bleed
The presence of melena, hematochezia of hematemesis,
in combination with a hemoglobin drop of 1.3 mmol/L or the
need for blood transfusion (defined according to the American
Society for Gastrointestinal Endoscopy ASGE [39])
Perforation
New development of free gas on imaging with progressive
complaints of abdominal discomfort and pain after ERC, or
perforation detected at surgery
Respiratory insufficiency
pO2<60mmHg despite FiO2 of 30% or requiring
mechanical ventilation
Cardiovascular
complications
o
Acute
myocardial (1) Typical rise and gradual fall (troponin) or
infarction
more rapid rise and fall (CK-MB) of biochemical markers of
myocardial necrosis with at least one of the following: (a)
ischemic symptoms; (b) development of pathologic Q-waves
on the ECG; (c) ECG changes indicative of ischemia (ST
segment elevation or depression); or (d) coronary artery
intervention (e.g., coronary angioplasty) [40, 41].
o
o
Cerebrovascular
Defined by the clinical event and subsequent findings on cross-
accident
sectional imaging investigations
Shock
Systolic blood pressure below 90 mmHg despite adequate fluid
resuscitation or need for inotropic catecholamine support
587
25
588
Table 3. Modified Glasgow score [20]
Each parameter scores 1 point.
Age
>55 years
PO2 arterial
<60 mmHg
Albumine
<32 g/L
Total calcium
<2 mmol/L
Leukocytes
>15 x 10 9/L
LDH
>600 U/L
Glucose (non diabetics)
>10 mmol/L
Ureum after rehydration
>16 mmol/L
589
26
590
Table 4. Acute Physiology and Chronic Health Evaluation (APACHE II score) [19]
High abnormal
Low abnormal
+4
+3
Temperature (°C)
≥ 41
39.0-40.9
Mean Arterial Pressure
(mmHg)
≥ 160
130-159
110-129
70-109
50-69
Heart rate
≥ 180
140-179
110-139
70-109
55-69
Respiratory rate
≥ 50
35-49
Oxygenation
FiO2 ≥ 0.5, record A-aDO2
FiO2 < 0.5, record PaO2
≥ 500
-
350-49
-
Arterial pH
≥ 7.7
7.6-7.69
Serum sodium (mmol/l)
≥ 180
160-179
Serum potassium (mmol/l)
≥7
6.0-6.9
Serum creatinine (μmol/l)
Double score for AKI
≥ 302
169-301
Haematocrit (%)
≥ 60
50-59.9
White blood cell count
(total/mm3)
≥ 40
20-39.9
Physiological variable
+2
200-349
-
155-159
+1
0
+1
+2
+3
+4
38.5-38.9
36-38.4
24-35.9
32-33.9
30-31.9
≤ 29.9
≤ 49
40-54
≤ 39
≤5
25-34
12-24
10-11
6-9
-
< 200
> 70
61-70
-
55-60
≤ 55
7.5-7.59
7.33-7.49
7.25-7.32
7.15-7.24
≤ 7.14
150-154
130-149
120-129
111-119
≤ 110
5.5-5.9
3.5-5.4
3-3.4
2.5-2.9
≤ 2.4
53-124
≤ 52
46-49.9
30-45.9
20-29.9
≤ 19
15-19.9
3-14.9
1-2.9
≤ 0.9
125-168
15 - Glasgow coma scale
Total Acute Physiology score (APS)
< 44
0
45-54
2
Age points
55-64
3
65-74
5
≥ 75
6
APACHE-II score
(sum of APS + age points + chronic health points)
Chronic Health points: If the patient has a history of severe organ system insufficiency or is
immunocompromised, assign points as follows:
For non-operative or emergency postoperative patients, 5 points
For elective postoperative patients, 2 point
A-aDO2, alveolar-arterial oxygen tension difference; AKI, acute kidney injury; FiO2, fractional inspired
oxygen; PaO2, arterial oxygen tension
27
591
Table 5. Definition of Chronic Pancreatitis
592
593
Chronic pancreatitis is confirmed according to the following criteria (adapted from the
594
M-ANNHEIM diagnostic criteria) [42]:
595
596
 Typical clinical history of chronic pancreatitis (i.e. recurrent pancreatitis or abdominal
pain), and:
597
598
One or more of the following additional criteria for the diagnosis of chronic pancreatitis:
599
 Pancreatic calcifications
600
 Moderate or marked ductal lesions (according to the Cambridge classification) on
601
602
MRCP, CT, or EUS
 Marked and persistent exocrine insufficiency defined as:
603
a) Pancreatic steatorrhea clearly relieved by enzyme supplementation, and/or
604
b) Fecal elastase levels of ≤200µg/g
605
28
606
Figure 1. Flowchart APEC trial according to CONSORT [43]
All patients with acute pancreatitis
Ineligible
Did not meet inclusion criteria
Had no biliary etiology
Not at high risk for complications
Had other reasons
Met exclusion criteria
Were admitted to the hospital >24 hours
Had concomitant cholangitis
Had previous sphincterotomy or precut
Had symptoms for > 72 hours
Had other reasons
Eligible but excluded
Had logistic issues
Were unable to give informed consent
(e.g. metal capacity, severe organ
failure)
Declined to participate
Were transferred from other hospital >24 hours after
primary admission
Had other reasons
232 Patients to be randomized
116 Assigned to early ERC with sphincterotomy
Received allocated treatment
116 Assigned to conservative treatment
Received allocated treatment
Excluded
Excluded
1 Lost to follow-up
1 Lost to follow-up
115 Analyzed
115 Analyzed
607
29
608
Figure 2. Flowchart study protocol APEC trial
Acute biliary pancreatitis and at high risk for
severe disease, without cholangitis
Randomization
Early ERC with sphincterotomy
Conservative treatment
<24 hours after hospital admission
<72 hours after symptom onset
In case of cholangitis
ERC with sphincterotomy
609
610
30
611
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646
647
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658
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