Early (<4 Weeks) Versus Standard (≥ 4 Weeks) Endoscopically Centered Step-Up Interventions for Necrotizing Pancreatitis

Abstract

Objectives:
Current guidelines for necrotizing pancreatitis (NP) recommend delay in drainage ± necrosectomy until 4 or more weeks after initial presentation to allow collections to wall off. However, evidence of infection with clinical deterioration despite maximum support may mandate earlier (<4 weeks) intervention. There are concerns, but scant data regarding risk of complications and outcomes with early endoscopic intervention. Our aim was to compare the results of an endoscopic centered step-up approach to NP when initiated before versus 4 or more weeks.

Methods:
All patients undergoing intervention for NP were managed using an endoscopically centered step-up approach, with transluminal drainage whenever feasible, ±necrosectomy, and/or percutaneous catheter drainage as needed, with surgery only for failures. Interventions were categorized as early or standard based on timing of intervention (<4 weeks or ≥ 4 weeks from onset of pancreatitis). Demographic data, indications and timing for interventions, number and type of intervention, mortality and morbidity (length of stay in hospital and ICU) and complications were compared.

Results:
Of 305 patients with collections associated with NP, 193 (63%) (median age-52 years) required intervention, performed by a step-up approach. Of the 193 patients, 76 patients underwent early and 117 patients standard intervention. 144 (75%) interventions included endoscopic drainage ± necrosectomy. As compared with standard intervention, early intervention was more often performed for infection (91% vs. 39%, p < 0.05), more associated with acute kidney injury (43% vs. 32%, p = 0.09), respiratory failure (41% vs. 22%, p = 0.005), and shock (13% vs. 4%, p < 0.05). Organ failure improved significantly after intervention in both groups. There was a significant difference in mortality (13% vs. 4%, p = 0.02) and need for rescue open necrosectomy (7% vs. 1%, p = 0.03) between groups. Patients undergoing early intervention had increased median hospital (37 days vs. 26 days, p = 0.01) and ICU stay (median 2.5 days vs. 0 days, p = 0.001). There was no difference in complications.

Conclusions:
When using an endoscopically centered step-up strategy in necrotizing pancreatitis, early (<4 weeks) interventions were more often performed for infection and organ failure, with no increase in complications, similar improvement in organ failure, slightly increased need for surgery, and relatively low mortality. Early endoscopic drainage ± necrosectomy should be considered when there is a strong indication for intervention.

Full text

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© 2018 The American College of Gastroenterology The American Journal of GastroenteroloGy
ARTICLE
INTRODUCTION
Acute pancreatitis (AP) can vary markedly in severity. Although
the majority of patients have a mild and uneventful course,
~5–10% develop necrotizing pancreatitis [1]. Mortality ranges
from ~15% in patients with sterile necrosis to as much as 39 % in
patients with infected necrosis, which occurs in ~40–70 % of cases
with necrotizing pancreatitis [1–5]. Infected necrosis is generally
regarded as a late event in the natural course of acute pancreatitis.
However, in a quarter of patients, infection can occur as early as
the rst week of the disease [6].
Early (<4 Weeks) Versus Standard (≥ 4 Weeks)
Endoscopically Centered Step-Up Interventions
for Necrotizing Pancreatitis
Guru Trikudanathan, MD1, Pierre Tawfik, MD2, Stuart K. Amateau, MD, PhD1, Satish Munigala MBBS, MPH3, Mustafa Arain, MD1,
Rajeev Attam, MD1, Gregory Beilman, MD4, Siobhan Flanagan, MD5, Martin L. Freeman, MD1 and Shawn Mallery, MD1
OBJECTIVES: Current guidelines for necrotizing pancreatitis (NP) recommend delay in drainage ± necrosectomy
until 4 or more weeks after initial presentation to allow collections to wall off. However, evidence
of infection with clinical deterioration despite maximum support may mandate earlier (<4 weeks)
intervention. There are concerns, but scant data regarding risk of complications and outcomes with
early endoscopic intervention. Our aim was to compare the results of an endoscopic centered step-up
approach to NP when initiated before versus 4 or more weeks.
METHODS: All patients undergoing intervention for NP were managed using an endoscopically centered step-
up approach, with transluminal drainage whenever feasible, ±necrosectomy, and/or percutaneous
catheter drainage as needed, with surgery only for failures. Interventions were categorized as early
or standard based on timing of intervention (<4 weeks or ≥ 4 weeks from onset of pancreatitis).
Demographic data, indications and timing for interventions, number and type of intervention,
mortality and morbidity (length of stay in hospital and ICU) and complications were compared.
RESULTS: Of 305 patients with collections associated with NP, 193 (63%) (median age-52 years) required
intervention, performed by a step-up approach. Of the 193 patients, 76 patients underwent
early and 117 patients standard intervention. 144 (75%) interventions included endoscopic
drainage ± necrosectomy. As compared with standard intervention, early intervention was more often
performed for infection (91% vs. 39%, p < 0.05), more associated with acute kidney injury (43% vs.
32%, p = 0.09), respiratory failure (41% vs. 22%, p = 0.005), and shock (13% vs. 4%, p < 0.05).
Organ failure improved signicantly after intervention in both groups. There was a signicant
difference in mortality (13% vs. 4%, p = 0.02) and need for rescue open necrosectomy (7% vs. 1%,
p = 0.03) between groups. Patients undergoing early intervention had increased median hospital (37
days vs. 26 days, p = 0.01) and ICU stay (median 2.5 days vs. 0 days, p = 0.001). There was no
difference in complications.
CONCLUSIONS: When using an endoscopically centered step-up strategy in necrotizing pancreatitis, early (<4
weeks) interventions were more often performed for infection and organ failure, with no increase
in complications, similar improvement in organ failure, slightly increased need for surgery, and
relatively low mortality. Early endoscopic drainage ± necrosectomy should be considered when there
is a strong indication for intervention.
Am J Gastroenterol https://doi.org/10.1038/s41395-018-0232-3
1Division of Gastroenterology, University of Minnesota, Minneapolis, MN, USA. 2Department of Internal Medicine, University of Minnesota, Minneapolis, MN, USA.
3Saint Louis University Center for Outcomes Research, St Louis, MO, USA. 4Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
5Department of Radiology, University of Minnesota, Minneapolis, MN, USA. This study was presented as an oral presentation at American Pancreas
Association 2017, San Diego. Correspondence: S.M. (email: malle004@umn.edu)
Received 26 July 2017; accepted 19 July 2018

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Current criteria categorize collections occurring 4 weeks or less
aer presentation as “acute necrotic collections”, and those at more
than 4 weeks as “walled o necrosis” [1]. Published guidelines for
the management of necrotizing pancreatitis recommend delay
in invasive interventions where feasible for at least 4 weeks aer
initial presentation to allow the collection to become “walled-o”
[2–4]. It has been suggested that this delay enables easier drain-
age and debridement and mitigates the risk of complications or
death, but these concerns are primarily based on literature involv-
ing surgical intervention [7, 8]. However, necrotizing pancreatitis
with clear evidence of infection, and clinical deterioration despite
maximum medical support, may sometimes warrant earlier (<4
weeks) intervention for drainage and/or debridement. A “step-up”
approach involves initial minimally invasive drainage followed by
on-demand necrosectomy and is the most accepted and studied
approach to intervention for walled-o necrosis [4, 9–12]. Initial
drainage is increasingly performed endoscopically [5, 9, 13–15].
However, endoscopic intervention is oen deferred to percuta-
neous or even surgical drainage in the early stages of necrotizing
pancreatitis particularly when collections are not in contact with
the GI tract or extend into inaccessible regions for endoscopic
debridement [2]. Although the use of a step-up approach has
become standard of care for walled-o necrosis, the safety and e-
cacy of an endoscopically centered approach earlier than 4 weeks
has not been well studied.
e purpose of this study was to compare the clinical outcomes
of a step-up approach to necrotizing pancreatitis when initiated
before versus aer 4 weeks.
METHODS
Patients
Consecutive patients with collections resulting from necrotizing
pancreatitis and undergoing any form of drainage/necrosectomy
at University of Minnesota Medical Center over a 6-year period
from 2010 to 2016 were identied from a prospectively main-
tained database. Based on timing of intervention, patients were
categorized into two groups: “early” or “standard” based on timing
of intervention (<4 weeks or ≥ 4 weeks from onset of pancreati-
tis). Demographic data, indication for and timing of intervention,
number and type of intervention, clinical outcomes, and com-
plications (procedure-related adverse events, organ dysfunction,
length of stay, ICU stay, and mortality) were compared between
the groups.
Imaging
All available computed tomography (CT) imaging prior to initial
intervention were independently reviewed by SM and were cat-
egorized using a classication system similar to the one adopted
by the Dutch pancreatitis group [16]. Morphological criteria on
CT such as size of the collection (maximal length of collection),
location of the collection (pancreatic vs. peripancreatic), degree
of encapsulation of the collection, contents of the collection, pres-
ence of gas bubble within collection, and presence of ascites was
compared between both the groups.
Interventions
All management decisions regarding interventions were made in a
multi-disciplinary manner involving pancreatologists/therapeutic
endoscopists, interventional radiologists, intensivists, and surgeons
using our previously described algorithm [5]. Patients needing
interventions were managed using an endoscopically centered
“step-up approach” based on endoscopic and/or percutaneous cath-
eter drainage as felt optimal for rst line treatment, with subsequent
endoscopic necrosectomy as required and with video-assisted
retroperitoneal debridement (VARD) or open surgery reserved
for treatment failures or severe complications such as peritonitis,
ischemic bowel/perforation, or clinical failure of step-up approach.
Endoscopic transluminal drainage (ETD) was the preferred initial
approach for management of necrotic collections adjacent to the
stomach and duodenum. Primary percutaneous drainage was typi-
cally reserved for collections not amenable to endoscopic therapy
due to a lack of contact with the gastric or duodenal wall. Adjunc-
tive percutaneous drainage was performed in addition to endo-
scopic drainage in the setting of large necrotic collections with deep
retroperitoneal extension, peritoneal involvement, and for scat-
tered multifocal collections. An entirely retroperitoneal approach
was strongly preferred in order to allow for subsequent endoscopic
debridement via sinus tract endoscopy (STE). Transperitoneal
drain placement was reserved for collections not amenable to a
retroperitoneal approach due to intervening bowel or a collection
location completely within the peritoneal cavity [2, 9, 17–19].
e initial choice for transluminal stent evolved over the course
of the study and ranged from multiple plastic double-pigtail stents,
to single fully covered metallic biliary or esophageal stents, and
eventually to lumen-apposing metal stents (LAMS). Endoscopic
transluminal necrosectomy (ETN) was performed as needed aer
initial drainage, based on clinical and radiographic response, typi-
cally within 3 to 5 days aer ETD for patients with infected necro-
sis and organ failure, or later for patients with less acute illness and/
or primarily liquied collections. Necrosectomy was repeated as
needed based on the clinical course and until there was complete
resolution of solid necrosis. Following completion of debridement,
all stents were removed unless there was evidence of disconnected
pancreatic duct by imaging, in which case 7 or 10 Fr plastic dou-
ble-pigtail stents were le in cystenterostomy tracts indenitely.
Patients with adjuvant percutaneous drainage catheters in com-
munication with transluminal stents and thus stomach or duo-
denum were treated with vigorous ushing and lavage (typically
100–150 cc of saline every 6–8 h). In cases with deep, endoscopi-
cally inaccessible cavities, and refractory solid necrosis, the percu-
taneous drains were gradually upsized to 24 F or greater. Sinus tract
endoscopy was then performed by the advanced endoscopy service
using exible forward viewing video endoscopes through the ret-
roperitoneal percutaneous drain tracts [20]. Alternatively, a small
number of selected cases underwent VARD through this percuta-
neous catheter tract by the surgical service using both rigid and
exible instruments. Open surgical necrosectomy was reserved for
patients with progressive clinical deterioration despite maximal
minimally invasive approaches or in cases with evidence of bowel
infarction or perforation mandating initial surgical intervention.

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Follow-up
Post-intervention follow-up included scheduled procedural or pan-
creas clinic visits with interval cross-sectional imaging as needed to
evaluate residual necrosis, stent position, and stulae patency.
Outcomes
e primary study outcome was mortality and need for res-
cue open necrosectomy in both groups. Secondary outcome
measures included improvement in new-onset multi-organ
failure aer intervention, length of hospital stay (LOS), length
of ICU stay (ICU-LOS), and complications. Organ failure was
dened as per the modied Marshall scoring system used in the
revised Atlanta classication [1, 21]. Acute respiratory failure
was dened as PaO2 of 60 mm of Hg despite fraction of inspired
oxygen (FIO2) of 25% or need for mechanical ventilation. Acute
kidney injury was dened as serum creatinine level more than
1.9 mg/dL aer rehydration, or new need for hemoltration or
hemodialysis. Circulatory failure was dened as systolic blood
pressure below 90 mm Hg unresponsive to uid resuscitation
or need for inotropic pressor support [21]. Multi-organ failure
was dened as failure of two or more organ systems for 48 h
or longer.
Complications
Complications were dened according to the American Society
of Gastrointestinal Endoscopy criteria that include infection,
bleeding, perforation, stulae, and new-onset diabetes [22, 23].
Bleeding was dened as hemorrhage needing blood transfusion
or requiring subsequent endoscopic or radiologic intervention for
hemostasis. New-onset diabetes was dened as either HbA1C > 7
and/or need for anti-hyperglycemic agents or insulin during
follow-up.
Statistical analysis
Descriptive statistics included continuous data presented as
median and interquartile range (IQR), and categorical data were
presented as frequencies and proportions. Univariate analysis was
performed to check for signicance between the two groups by
using the two-tailed Student t-test or Mann–Whitney U test (for
continuous variables) and χ2 test or Fisher exact test (for categori-
cal variables) where appropriate. p values ≤ 0.05 were considered
signicant. Statistical analyses were performed using Statistical
Analysis Soware 9.3 (SAS Institute, Cary, NC).
RESULTS
Baseline characteristics
A total of 305 patients with necrotizing pancreatitis were man-
aged at our center during the study period. 193 (63%) of these
patients underwent intervention for drainage and/or debridement
of necrotic collections. In total, 171 (89%) of 193 patients were
referred from other facilities aer failing conservative manage-
ment or initial intervention. Baseline and clinical characteristics
of the 193 patients included in the study are outlined in Table1
with no signicant dierences between patients undergoing
interventions at less than 4 weeks (early), versus 4 or more weeks
aer AP (standard). Patients undergoing early interventions
tended to be older (median age 55 years vs. 50 years) however this
was not statistically signicant (p = 0.14). e proportion of males
and females were comparable between groups. e most common
etiology for pancreatitis was biliary (45% in both the groups)
followed by alcohol (25% vs. 26%).
Imaging
e maximum diameter of collections was signicantly larger in
the early group (175 mm vs. 140 mm, p < 0.005) as outlined in
Table2. Both a pancreatic and peripancreatic component with
mixed solid and liquid contents were present in the majority of
patients. Completely encapsulated collections were present in
only in 5 (7%) of the early group as compared to 48 (43%) of the
standard group (p < 0.005). Ascites was noted to be signicantly
more common in the early intervention group (68% vs.33%,
p < 0.001).
Interventions
New-onset organ failure was more frequent in patients undergo-
ing early interventions, with 43% vs. 32% (p = 0.09) developing
acute kidney injury and 41% vs. 22% (p = 0.005) acute respira-
tory failure needing mechanical ventilation. Hypotension needing
vasopressor support was also more frequent in early intervention
group (13% vs 4%), p = 0.03. Interventions performed before 4
weeks were primarily (91%) performed for infected necrosis.
Infection (39%), persistent unwellness (39%), and gastric outlet
Table 1 Baseline demographic data of all necrotizing pancreatitis
who underwent intervention (<4 weeks) vs. standard ( ≥ 4 weeks)
NP < 4 weeks
(n = 76) NP ≥ 4 weeks
(n = 117) p value
Median age (years),
IQR
55 (39–68) 50 (37–63) 0.143
Sex 0.189
Male 51 (67.1%) 89 (76.1%)
Female 25 (32.9%) 28 (23.9%)
Race
White 66 (86.8%) 107 (91.5%) 0.059
African American 5 (6.6%) 1 (0.9%) Reference
Other 4 (6.6%) 9 (7.7%) 0.074
Etiology for
pancreatitis
Biliary 34 (44.7%) 53 (45.3%) Reference
Alcohol 19 (25.0%) 30 (25.6%) 0.972
Other etiologya9 (11.8) 10 (8.5) 0.813
Idiopathic 14 (18.4%) 24 (20.5%) 0.506
IQR interquartile range, NP necrotizing pancreatitis
aOther etiologies (ANC—drug-induced 2, hypertriglyceridemia 4, post ERCP 2,
other 1; WON—hypertriglyceridemia 4, post ERCP 1, other 5)

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obstruction (13%) were the most common primary indications
for interventions performed at 4 or more weeks (as shown in
Table3).
Endoscopic transluminal drainage was the initial intervention
in the majority of patients in both the early and standard groups
(62% vs. 77%) respectively. Percutaneous catheter drainage was the
initial intervention in 29% of patients undergoing early cases ver-
sus 14% of patients undergoing standard intervention (as shown
in Fig. 1) (p = 0.47). Five (7%) patients in the early group and
six (5%) patients in the standard group were treated by immedi-
ate open necrosectomy due to acute severe decompensation with
either peritonitis or abdominal compartment syndrome. Signi-
cantly larger number of patients in the standard group (27% vs 9%,
p = 0.002) were managed only by endoscopic transluminal drain-
age. Ten (13%) patients in the early group and six (8%) patients
in the standard group were managed only by percutaneous drain-
age. Majority of patients in both early and standard group needed
necrosectomy (71% vs 62%, p = 0.2).
Outcomes
Signicantly increased mortality (13% vs. 4%, p = 0.02) and need
for open necrosectomy (7% vs. 1%, p = 0.04) occurred in patients
undergoing early interventions. In addition, LOS (median (IQR)
37 days (27–61 days) vs. 26 days, (0–207 days), p < 0.05) and length
of ICU stay (median (IQR) 2.5 days (0–22 days) vs. 0 days (0–3
days), p < 0.05) were signicantly longer in patients undergoing
early interventions, as was need for adjuvant percutaneous drain-
age (32 (42%) vs. 25 (21%), p < 0.005). In early as well as standard
intervention groups organ failure improved substantially within
1 week aer step-up intervention (as shown in Fig.2). Among
12 patients on dialysis who underwent early step-up interven-
tion, 7 (58%) became dialysis independent aer 1 week. Similarly,
16 (75%) of the 30 patients needing mechanical ventilation were
weaned o respiratory support within 1 week following interven-
tion. 7 (70%) of 10 patients needing inotropic pressor support for
circulatory failure, came o pressors within 1 week.
Adverse events
Clinically signicant hemorrhage related to either cystenteros-
tomy or pseudoaneurysm was comparable between groups (11%
vs. 10%, p > 0.05), including bleeding that required blood transfu-
sion and/or subsequent endoscopic or percutaneous intervention.
Transluminal stent occlusion and infection needing repeat inter-
vention was frequent in both the groups (40% vs. 33%, p > 0.05).
ere was no dierence in the rate of stulae (cyst-enteric,
enterocutaneous, and pancreaticocutaneous) between the two
groups (33% vs. 21%, p > 0.05). However, perforation occurred
only in the patients who underwent intervention beyond 4 weeks
(n = 7). Four (57%) of these 7 patients with perforation needed
exploratory laparotomy, while three were managed conserva-
tively. e incidence of new-onset diabetes was similar in both
the two groups (20% vs. 21%, p > 0.05).
DISCUSSION
e revised Atlanta criteria have standardized morphological char-
acterization of collections based on the time elapsed aer onset of
pancreatitis, the contents of the cavities, and encapsulation of the
wall [1, 24]. Accordingly, acute necrotic collections are generally
thought to occur within the rst 4 weeks and walled-o necrosis
aer that interval [1]. While infected necrosis is tradionally regarded
as a late event in the natural course of AP, it may occur early within
the rst 4 weeks in almost a quarter of patients (Fig.3) [6]. Cur-
rent international guidelines advocate postponement of all forms
of invasive interventions in patients for infected necrosis preferably
until the stage of walled-o necrosis (WON), which usually occurs
about 4 weeks aer disease onset [2, 3]. Conservative manage-
ment with medical support is recommended to bridge the period
between acute necrotic collection and the formation of walled-o
necrosis [25]. However, despite maximal medical therapy, clinical
decompensation occurs in a subset of patients wherein interven-
tions become inevitable to temporize sepsis and improve clinical
status. A recent international survey of a group of expert pan-
creatologists suggested a lack of consensus regarding the optimal
Table 2 Imaging characteristics of the necrotic collections < 4
weeks vs. ≥ 4 weeks
Nature of necrotic
collections NP < 4 weeks,
n = 76, n (%) NP ≥ 4 weeks,
n = 117, n (%) p value
Median size of collec-
tion in mm (IQR)
175 (134–
234)
140 (92–186) 0.001
Location of necrosis
Pancreatic 2 (2.7) 15 (13.3) Reference
Peripancreatic 16 (21.6) 16 (14.1) 0.015
Both 56 (75.8) 82 (72.6) 0.035
Degree of encapsula-
tion
No wall 6 (8.1) 2 (1.8) 0.08
Some wall formation 36 (48.6) 23 (20.3) 0.021
Extensive wall
formation
27 (36.5) 40 (35.4) Reference
Complete wall
formation
5 (6.8) 48 (42.5) 0.0004
Contents 0.0002
Only solid 0 1
Only liquid 4 30
Both solid and liquid 70 (94.6) 82 (72.6)
Number of collections 0.335
Single 53 (72.6) 89 (78.8)
Multiple 20 (27.4) 24 (21.2)
Presence of gas
bubbles
19 (26.0) 19 (16.8) 0.128
Presence of ascites 50 (67.6) 37 (32.7) <0.0001
p value calculated using χ2 test or Fisher exact test for categorical variable and
Kruskal–Wallis test for continuous variables where appropriate.
IQR interquartile range
Bold values represent p-values which were signicant and hence important

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Early (<4 Weeks) Versus Standard (≥ 4 Weeks) Endoscopically Centered Step-Up Interventions...
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timing of interventions under these circumstances [26]. Percuta-
neous drainage has historically been favored for early drainage due
to an expected lower risk of cavity rupture and peritoneal contami-
nation [25]. e paucity of data on the safety of endoscopic drain-
age with or without necrosectomy in the early stages of necrotizing
pancreatitis set up the context for the current study.
In our cohort of NP patients, infected necrosis was the pri-
mary indication for early intervention in most patients (91%).
A substantial number of these patients had new-onset of organ
failure or shock that was refractory to medical management. All
patients had clinical deterioration prompting a multi-disciplinary
decision that further delay in intervention could not be justied.
Initial intervention involved endoscopic transluminal drainage as
the rst step in the majority (62% in early vs. 77% in the standard
group).
Organ failure in AP is related to the presence of infection and
the extent of necrosis [27, 28]. A recent large retrospective study
showed that mortality due to primary organ failure from AP
per se was relatively higher than secondary organ failure due to
infected necrosis (49.5% vs. 36%, p = 0.06). Drainage of infected
uid or necrotic collections (with or without necrosectomy) pro-
vides a window of opportunity to temporize sepsis and resultant
secondary organ failure [29]. In our study, utilizing an endoscopi-
cally based step-up approach when feasible, there was substantial
improvement in organ dysfunction aer early as well as conven-
tionally timed interventions. A majority of patients were suc-
cessfully weaned o pressor support, mechanical ventilation, and
dialysis. ese ndings are consistent with the PENGUIN trial and
retrospective studies showing that endoscopic intervention is asso-
ciated with a reduction in inammatory response and new-onset
organ failure [13, 30]. A meta-analysis of 14 observational stud-
ies showed that organ failure was associated with mortality in 30%
of patients with infected necrosis, and with worse outcomes when
associated with organ failure [31]. e mortality in the early inter-
vention group in the current study was 13%, which is relatively low
by comparison [14, 29]. e reduction of organ failure following
Table 3 Indications and interventions between the two groups
All NP patients (2010–2016) NP patients with interventions < 4
weeks) (n = 76) NP patients with interventions ≥ 4
weeks (n = 117) p value
New-onset organ failure prior to intervention
Acute kidney injury (AKI) 33 (43.4%) 37 (31.6%) 0.095
AKI requiring dialysis 13 (17.1%) 10 (8.6%) 0.073
Acute respiratory failure needing mechanical ventilation 31 (40.8%) 26 (22.2%) 0.005
Hypotension needing vasopressors 10(13.2%) 5(4.2%) 0.03
Primary indications for intervention
Infection 69 (90.8%) 46 (39.3%) 0.045
Gastric outlet obstruction 4 (5.3%) 15 (12.8%) 0.70
Biliary tract obstruction 2 (2.6%) 5 (4.3%) 0.522
Abdominal pain 0 45 (38.5%) -
Other indicationsa1 (1.3) 6 (5.1%) Reference
Median days from AP presentation to intervention (IQR) 20 (13–24) 78 (42–178) <0.0001
Initial intervention at outside center vs. our center 12 (15.8%) vs. 64 (84.2%) 10 (8.6%) vs.107 (91.4%) 0.122
Initial intervention
Endoscopic transluminal drainage 47 (61.8%) 90 (76.9%) 0.459
Percutaneous drainage 22 (28.9%) 16 (13.7%) 0.467
Endo and perc drainage 2 (2.6%) 5 (4.3%) 0.477
Surgical necrosectomy 5 (6.6%) 6 (5.1%) Reference
Subsequent/adjuvant intervention
Endoscopic transluminal necrosectomy (median/range) 1 (0–5) 1 (0–7) 0.118
Adjuvant percutaneous drain 32 (42.1%) 25 (21.4%) 0.002
Sinus tract endoscopy 4 (5.3%) 4 (3.4%) 0.714
VARD 6 (7.9%) 2 (1.7%) 0.059
Open necrosectomy 5 (6.9%) 1 (0.9%) 0.036
IQR interquartile range, AP acute pancreatitis, AKI acute kidney injury, VARD video-assisted retroperitoneal debridement
aOther indications—Abdominal compartment syndrome 1 for ANC and Disconnected duct 1, Failure to thrive 4, other 1 for WON
Bold values represent p-values which were signicant and hence important

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endoscopic step-up approach is thus clinically relevant since organ
dysfunction is one of the determinants of long-term morbidity and
death following pancreatitis [32].
In this study, an early endoscopic centered step-up approach to
the management of necrotizing pancreatitis was found to be asso-
ciated with similar outcomes to cases treated aer the traditionally-
recommended 4-week delay. In all cases, intervention was clearly
indicated, with infection the leading indication. Although there an
increase in mortality (13% vs. 4%) and need for rescue open sur-
gery (7% vs. 1%) in those undergoing early versus standard inter-
vention, there was no increased risk of complications. Our ndings
suggest that the traditional 4-week waiting period is somewhat
arbitrary, and that early endoscopic based step-intervention is fea-
sible if strongly indicated in the setting of clinical decompensation.
e outcomes are likely to be optimal when performed in a multi-
disciplinary tertiary care setting with prompt back-up available as
needed in the event of a complication, or failure to respond,
e all-cause mortality in our cohort of patients undergoing
interventions for necrotizing pancreatitis was 7.8 % (15/193),
which is substantially lower than the 15–39% mortality sug-
gested in the overall literature, and somewhat lower than mortal-
ity reported in recent prospective randomized trials of minimally
invasive or endoscopic interventions [2, 9, 13, 14]. It is possible
that the endoscopically based step-up approach, by blunting the
inammatory response, improves organ function which in turn
improves the overall mortality. Although, there was a somewhat
45%
40%
35%
30%
25%
20%
15%
10%
5%
0% Renal failure requiring dialysis
17%
7%
9%
1%
41%
11%
22%
3%
13%
5% 4%
0%
NP (<4 weeks) pre-intervention NP (<4 weeks) post-intervention NP (>4 weeks) pre-intervention NP (>4 weeks) post-intervention
Respiratory failure requiring mechanical ventilation Shock requiring vasopressors
Fig. 2 Effect of interventions on organ failure, comparing early (<4 weeks) versus standard (4 or more weeks)
Fig. 1 Algorithm used for multi-disciplinary interventions for necrotizing pancreatitis [5]

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Early (<4 Weeks) Versus Standard (≥ 4 Weeks) Endoscopically Centered Step-Up Interventions...
© 2018 The American College of Gastroenterology The American Journal of GastroenteroloGy
increased mortality in necrotizing pancreatitis aer interventions
before versus at or more than 4 weeks (13% vs. 4%), as well as
increased lengths of ICU and hospital stay, the dierence in out-
comes likely reects severity of illness rather than complications
of interventions. To evaluate whether a 3-week cuto would be
more signicant than the traditional 4-week cuto, a sensitivity
analysis was further performed. 43 patients underwent interven-
tions before 3 weeks and 146 patients underwent interventions at
or aer 3 weeks. Not surprisingly, there was an increased mortality
in the group who underwent interventions before 3 weeks (19%
vs. 5%, p = 0.003), and increased length of hospital stay (median
40, IQR (24–70) days) vs. (median 30, IQR (16–44) days). It was
still comparable to the recent prospective trials of interventions at
all intervals, and a pooled international analysis of 1980 cases of
minimally invasive and endoscopic versus open necrosectomy for
necrotizing pancreatitis [9, 13–15].
Procedure-related complications did not dier aer early com-
pared with standard timing of intervention (Table 4). is was
surprising, as early endoscopic intervention, particularly when the
necrotic cavity is not adherent to the stomach or duodenum, would
be anticipated to cause more perforation, cavity leakage, and perito-
neal contamination. e majority of initial endoscopic transluminal
drainages utilized lumen-apposing metallic stents once they became
available, which could be postulated to reduce risk, but the type of
stent aected neither complications nor ultimate outcome (Table5).
is nding is in keeping with data from other centers with per-
haps only a trend towards less need for transluminal necrosectomy
[33–36]. Somewhat surprisingly, early intervention did not result
in an increased risk of cavity leakage and peritoneal contamination,
with the only cases of perforation occurring aer the traditional
4-week maturation period. In contrast to most other studies, the
majority of our patients failed to respond adequately to minimally
invasive drainage alone (early vs. standard: 78% versus 68%) and
required endoscopic transluminal and /or sinus tract necrosectomy
to achieve clinical response and resolve necrotic collections.
e current study provides data comparing the outcomes of an
endoscopically step-up approach initiated before versus 4 or more
weeks for collections associated with necrotizing pancreatitis. Our
ndings suggest that interventions need not necessarily be delayed
until the arbitrary cut-o period of 4 weeks, especially in the set-
ting of clinical deterioration and multi-organ failure suggesting
infection. Likewise, our ndings suggest that an urgent need for
intervention earlier than 4 weeks does not preclude successful
endoscopically based management and does not mandate percu-
taneous or surgical intervention. Recommendations for delayed
intervention stem primarily from studies in the era of open necro-
sectomy involving surgical debridement of unorganized collec-
tions, which was not just technically challenging, but associated
Fig. 3 Images representing serial interventions on a 69-year-old male with severe acute pancreatitis due to gallstones, resulting in acute respiratory failure
requiring mechanical ventilation and acute renal failure requiring CRRT. Three weeks after presentation, CT showed poorly demarcated acute necrotic
collection with ascites (a); the patient decompensated further with hemodynamic instability, and underwent endoscopic transluminal drainage with lumen-
apposing metallic stent (b), followed by left retroperitoneal percutaneous catheter drainage (c), with resolution of hemodynamic instability and decrease to
intermittent hemodialysis; after endoscopic transluminal necrosectomy and placement of second transgastric lumen-apposing metallic stent (d), repeat CT
showed signicant decrease in size and extent of acute necrotic collection (e)

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Trikudanathan et al.
8
The American Journal of GastroenteroloGy www.nature.com/ajg
with complications and immense physiologic stress resulting in
worsened organ failure [37–40]. It is unclear if these recommenda-
tions are relevant in the era of advanced expertise and experience
in endoscopic transluminal drainage and necrosectomy. Since
there is no clear evidence to suggest superiority for postponed
percutaneous drainage, the Dutch Pancreatitis Study Group has
embarked on a randomized controlled trial (the POINTER trial—
ISRCTN33682933) comparing immediate and delayed primary
percutaneous drainage until there is walled-o necrosis [25, 26].
e results of this landmark study are expected to shed further
insight regarding the ideal timing of primary percutaneous drain-
age. Similar prospective multi-center studies regarding timing of
endoscopic transluminal drainage are needed to further validate
our conclusions regarding endoscopically centered approaches.
ere are some potential strengths and a number of limitations
to the current study. A potential strength is that it is based on a
prospectively maintained database of all patients admitted to the
hospital with necrotizing pancreatitis of any extent—and as such it
may be the rst study of endoscopic interventions to represent the
entire spectrum of patients rather than a case series pre-selected
for suitability and perhaps high feasibility of successful endoscopic
management. However, it was a single center study, and the out-
comes were analyzed retrospectively. e results may not be gen-
eralizable, as all patients were managed at a single tertiary center,
mostly aer referral from a wide range of outside hospitals, and by
a highly-specialized multi-disciplinary team with extensive expe-
rience and expertise in the entire spectrum of interventions for
necrotizing pancreatitis.
In conclusion, an endoscopically centered step-up approach in
necrotizing pancreatitis may be utilized earlier than 4 weeks in
the setting of severe necrotizing pancreatitis with infection refrac-
tory to medical management. e outcomes of earlier intervention
appear to be similar the outcomes obtained aer the typically-rec-
ommended 4-week delay. Further multi-center prospective studies
are needed to validate the conclusions of our study.
CONFLICT OF INTEREST
Guarantor of the article: Shawn Mallery, MD.
Potential competing interests: M.L.F. is a consultant for Boston
Scientic and Cook Medical. M.A. is a consultant for Boston
Scientic. S.K.A is a consultant for Boston Scientic, US Endoscopy,
Neometrics, Merit Endoscopy, and a research collaborator with
Cook Medical. S.M. is a consultant for Boston Scientic. e
remaining authors declare that they have no conict of interest.
Specic author contributions: G.T. and S.Ma. played a role
Table 5 Outcomes by type of transluminal stents used for initial drainage
Outcome Early intervention (<4 weeks) Type of stent Standard intervention (≥ 4 weeks) Type of stent p value
Plastic N = 41 Lumen apposing
N = 27 Other metal
N = 8 Plastic N = 57 Lumen apposing
N = 38 Other metal
N = 20
Mortality 6 (14.6%) 2 (7.4%) 2 (25.0%) 2 (3.5%) 0 2 (10.0%) >0.05
Hospital LOS (median, IQR) 37 (29–62) 35 (25–60) 34 (22–58) 22 (11–41) 26 (13–55) 29 (17–38) >0.05
ICU LOS (median, IQR) 6 (0–26) 0 (0–15) 10 (0–22) 0 (0–1) 0 (0–5) 0 (0–5) >0.05
Complications
Perforation 0 0 0 4(7%) 2(5%) 1(5%) <0.05
Stent occlusion and infection 16 (39.0%) 14 (51.9%) 4 (40.0%) 17 (29.8%) 15 (39.5%) 6 (30.0%) >0.05
Fistulae (including pancreatic-,
cyst-, or entero-cutaneous)
16 (39.0%) 7 (25.9%) 2 (25.0%) 14 (24.6%) 7 (18.4%) 3 (15.0%) >0.05
Bold values represent p-values which were signicant and hence important
Table 4 Outcomes and complications of interventions
Outcomes NP patients
with interven-
tions < 4 weeks
(usually ANC
collections)
(n = 76)
NP patients
with interven-
tions ≥ 4 weeks
(usually WON
collections)
(n = 117)
p value
Mortality (%) 10 (13.2%) 5 (4.3%) 0.024
Morbidity (%)
aMedian length of stay
in days (IQR)
37 (27–61) 26 (0–207) <0.001
bMedian length of ICU
stay in days (IQR)
2.5 (0–22) 0 (0–3) <0.001
Complications
(procedure and
disease related)
Stent occlusion and
infection
30(40%) 39(33%) 0.36
Bleeding 8 (10.5%) 12 (10.3%) 0.95
Perforation 0 7 (6.0%) 0.044
Fistulae (including
pancreatic-, cyst-,
or entero-cutaneous
25 (32.9%) 24 (20.5%) 0.054
New-onset diabetes 15 (19.7%) 25 (21.4%) 0.785
arange (ANC—min 6, max 319; WON—min 0, max 207)
b(ANC—min 0, max 319; WON—min 0, max 186)
Bold values represent p-values which were signicant and hence important

Pancreas
9
Early (<4 Weeks) Versus Standard (≥ 4 Weeks) Endoscopically Centered Step-Up Interventions...
© 2018 The American College of Gastroenterology The American Journal of GastroenteroloGy
in planning and/or conducting the study, collecting and/or
interpreting data, and/or draing the manuscript. P. T. played
a role in planning and/or conducting the study, collecting and/
or interpreting data. S.A., M.A., R.A., G.B., and S.F. played a role
in planning and/or conducting the study. S.Mu. was involved in
collecting and/or interpreting data. M.F. played a role in planning
and/or conducting the study and draing the manuscript.
Financial support: None.
REFERENCES
1. Banks PA, Bollen TL, Dervenis C, et al. Classication of acute pancreati-
tis–2012: revision of the Atlanta classication and denitions by interna-
tional consensus. Gut. 2013;62:102–11.
2. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA
evidence-based guidelines for the management of acute pancreatitis.
Pancreatology. 2013;13:e1–15.
3. Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterol-
ogy guideline: management of acute pancreatitis. Am J Gastroenterol.
2013;108:1400–15. 1416
4. Freeman ML, Werner J, Santvoort HCvan, et al. Interventions for ne-
crotizing pancreatitis: summary of a multidisciplinary consensus confer-
ence. Pancreas. 2012;41:1176–94.
5. Trikudanathan G, Attam R, Arain MA, et al. Endoscopic interventions for
necrotizing pancreatitis. Am J Gastroenterol. 2014;109:969–81. quiz 982
6. Petrov MS, Chong V, Windsor JA. Infected pancreatic necrosis: not
necessarily a late event in acute pancreatitis. World J Gastroenterol.
2011;17:3173.
7. Forsmark CE, Vege SS, Wilcox CM. Acute pancreatitis. N Engl J Med.
2016;375:1972–81.
8. Santvoort HC, van, Bakker OJ, Bollen TL, et al. A conservative and mini-
mally invasive approach to necrotizing pancreatitis improves outcome.
Gastroenterology. 2011;141:1254–63.
9. Santvoort HC, van, Besselink MG, Bakker OJ, et al. A step-up approach
or open necrosectomy for necrotizing pancreatitis. N Engl J Med.
2010;362:1491–502.
10. Bang JY, Holt BA, Hawes RH, et al. Outcomes aer implementing a
tailored endoscopic step-up approach to walled-o necrosis in acute
pancreatitis. Br J Surg. 2014;101:1729–38.
11. Costa DW, da, Boerma D, Santvoort HCvan, et al. Staged multidisci-
plinary step-up management for necrotizing pancreatitis. Br J Surg.
2014;101:e65–79.
12. Brunschot S, van, Grinsven J, van, Voermans RP, et al. Transluminal
endoscopic step-up approach versus minimally invasive surgical step-up
approach in patients with infected necrotising pancreatitis (TENSION
trial): design and rationale of a randomised controlled multicenter trial
[ISRCTN09186711]. BMC Gastroenterol. 2013;13:161.
13. Bakker OJ, Santvoort HC, van, Brunschot Svan, et al. Endoscopic
transgastric vs surgical necrosectomy for infected necrotizing pancreatitis:
a randomized trial. JAMA. 2012;307:1053–61.
14. Brunschot S, van, Grinsven J, van, Santvoort HCvan, et al. Endoscopic or
surgical step-up approach for infected necrotising pancreatitis: a multi-
centre randomised trial. Lancet. 2018;391:51–58.
15. Brunschot S, van, Hollemans RA, Bakker OJ, et al. Minimally invasive
and endoscopic versus open necrosectomy for necrotising pancreatitis: a
pooled analysis of individual data for 1980 patients. Gut. 2018;67:697–706.
16. Hollemans RA, Bollen TL, Brunschot Svan, et al. Predicting success
of catheter drainage in infected necrotizing pancreatitis. Ann Surg.
2016;263:787–92.
17. Babu RY, Gupta R, Kang M, et al. Predictors of surgery in patients with
severe acute pancreatitis managed by the step-up approach. Ann Surg.
2013;257:737–50.
18. Raraty MGT, Halloran CM, Dodd S, et al. Minimal access retroperitoneal
pancreatic necrosectomy: improvement in morbidity and mortality with a
less invasive approach. Ann Surg. 2010;251:787–93.
19. Gomatos IP, Halloran CM, Ghaneh P, et al. Outcomes from minimal
access retroperitoneal and open pancreatic necrosectomy in 394 patients
with necrotizing pancreatitis. Ann Surg. 2016;263:992–1001.
20. Carter CR, McKay CJ, Imrie CW. Percutaneous necrosectomy and sinus
tract endoscopy in the management of infected pancreatic necrosis: an
initial experience. Ann Surg. 2000;232:175–80.
21. Working Party of the British Society of Gastroenterology, Association of
Surgeons of Great Britain and Ireland, Pancreatic Society of Great Britain
and Ireland. et al. UK guidelines for the management of acute pancreati-
tis. Gut. 2005;54:iii1–9.
22. Cotton PB, Eisen G, Romagnuolo J, et al. Grading the complexity of
endoscopic procedures: results of an ASGE working party. Gastrointest
Endosc. 2011;73:868–74.
23. Cotton PB, Eisen GM, Aabakken L, et al. A lexicon for endoscopic
adverse events: report of an ASGE workshop. Gastrointest Endosc.
2010;71:446–54.
24. Manrai M, Kochhar R, Gupta V, et al. Outcome of acute pancreatic and
peripancreatic collections occurring in patients with acute pancreatitis.
Ann Surg. 2016;267:357–63.
25. Grinsven J, van, Santvoort HC, van, Boermeester MA, et al. Timing of
catheter drainage in infected necrotizing pancreatitis. Nat Rev Gastroen-
terol Hepatol. 2016;13:306–12.
26. Grinsven J, van, Brunschot S, van, Bakker OJ, et al. Diagnostic
strategy and timing of intervention in infected necrotizing pancreatitis:
an international expert survey and case vignette study. HPB.
2016;18:49–56.
27. Garg PK, Madan K, Pande GK, et al. Association of extent and infection
of pancreatic necrosis with organ failure and death in acute necrotizing
pancreatitis. Clin Gastroenterol Hepatol. 2005;3:159–66.
28. Isenmann R, Rau B, Beger HG. Bacterial infection and extent of necrosis
are determinants of organ failure in patients with acute necrotizing pan-
creatitis. Br J Surg. 1999;86:1020–4.
29. Padhan RK, Jain S, Agarwal S, et al. Primary and secondary organ failures
cause mortality dierentially in acute pancreatitis and should be distin-
guished. Pancreas. 2018;47:302–7.
30. Kumar N, Conwell DL, ompson CC. Direct endoscopic necrosectomy
versus step-up approach for walled-o pancreatic necrosis. Pancreas.
2014;43:1334–9.
31. Petrov MS, Shanbhag S, Chakraborty M, et al. Organ failure and infection
of pancreatic necrosis as determinants of mortality in patients with acute
pancreatitis. Gastroenterology. 2010;139:813–20.
32. Johnson CD, Abu-Hilal M. Persistent organ failure during the rst week
as a marker of fatal outcome in acute pancreatitis. Gut. 2004;53:1340–4.
33. Siddiqui AA, Kowalski TE, Loren DE, et al. Fully covered self-expanding
metal stents versus lumen-apposing fully covered self-expanding
metal stent versus plastic stents for endoscopic drainage of pancreatic
walled-o necrosis: clinical outcomes and success. Gastrointest Endosc.
2017;85:758–65.
34. Sharaiha RZ, Tyberg A, Khashab MA, et al. Endoscopic therapy with
lumen-apposing metal stents is safe and eective for patients with pancre-
atic walled-o necrosis. Clin Gastroenterol Hepatol. 2016;14:1797–803.
35. Bang JY, Hasan M, Navaneethan U, et al. Non-superiority of lumen-ap-
posing metal stents over plastic stents for drainage of walled-o necrosis
in a randomised trial. Gut 2018 (epub ahead of print).
36. Brimhall B, Han S, Tatman PD, et al. Increased incidence of pseudoaneu-
rysm bleeding with lumen-apposing metal stents compared to double-
pigtail plastic stents in patients with peripancreatic uid collections. Clin
Gastroenterol Hepatol. 2018; (epub ahead of print).
37. Mier J, León EL, Castillo A, et al. Early versus late necrosectomy in severe
necrotizing pancreatitis. Am J Surg. 1997;173:71–75.
38. Besselink MGH, Verwer TJ, Schoenmaeckers EJP, et al. Timing of surgical
intervention in necrotizing pancreatitis. Arch Surg. 2007;142:1194–201.
39. Horvath K, Freeny P, Escallon J, et al. Safety and ecacy of video-assisted
retroperitoneal debridement for infected pancreatic collections: a multi-
center, prospective, single-arm phase 2 study. Arch Surg. 2010;145:817–25.
40. Rodriguez JR, Razo AO, Targarona J, et al. Debridement and closed pack-
ing for sterile or infected necrotizing pancreatitis: insights into indications
and outcomes in 167 patients. Ann Surg. 2008;247:294–9.