University of Groningen
A Step-up Approach or Open Necrosectomy for Necrotizing Pancreatitis
van Santvoort, Hjalmar C.; Besselink, Marc G.; Bakker, Olaf J.; Hofker, H. Sijbrand;
Boermeester, Marja A.; Dejong, Cornelis H.; van Goor, Harry; Schaapherder, Alexander F.;
van Eijck, Casper H.; Bollen, Thomas L.
Published in:
New England Journal of Medicine
DOI:
10.1056/NEJMoa0908821
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Publication date:
2010
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Citation for published version (APA):
van Santvoort, H. C., Besselink, M. G., Bakker, O. J., Hofker, H. S., Boermeester, M. A., Dejong, C. H., van
Goor, H., Schaapherder, A. F., van Eijck, C. H., Bollen, T. L., van Ramshorst, B., Nieuwenhuijs, V. B.,
Timmer, R., Lameris, J. S., Kruyt, P. M., Manusama, E. R., van der Harst, E., van der Schelling, G. P.,
Karsten, T., ... Dutch Pancreatitis Study Grp (2010). A Step-up Approach or Open Necrosectomy for
Necrotizing Pancreatitis.
New England Journal of Medicine
,
362
(16), 1491-1502.
https://doi.org/10.1056/NEJMoa0908821
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1491
original article
A Step-up Approach or Open Necrosectomy
for Necrotizing Pancreatitis
Hjalmar C. van Santvoort, M.D., Marc G. Besselink, M.D., Ph.D.,
Olaf J. Bakker, M.D., H. Sijbrand Hofker, M.D., Marja A. Boermeester, M.D., Ph.D.,
Cornelis H. Dejong, M.D., Ph.D., Harry van Goor, M.D., Ph.D.,
Alexander F. Schaapherder, M.D., Ph.D., Casper H. van Eijck, M.D., Ph.D.,
Thomas L. Bollen, M.D., Bert van Ramshorst, M.D., Ph.D.,
Vincent B. Nieuwenhuijs, M.D., Ph.D., Robin Timmer, M.D., Ph.D.,
Johan S. Laméris, M.D., Ph.D., Philip M. Kruyt, M.D., Eric R. Manusama, M.D., Ph.D.,
Erwin van der Harst, M.D., Ph.D., George P. van der Schelling, M.D., Ph.D.,
Tom Karsten, M.D., Ph.D., Eric J. Hesselink, M.D., Ph.D.,
Cornelis J. van Laarhoven, M.D., Ph.D., Camiel Rosman, M.D., Ph.D.,
Koop Bosscha, M.D., Ph.D., Ralph J. de Wit, M.D., Ph.D.,
Alexander P. Houdijk, M.D., Ph.D., Maarten S. van Leeuwen, M.D., Ph.D.,
Erik Buskens, M.D., Ph.D., and Hein G. Gooszen, M.D., Ph.D.,
for the Dutch Pancreatitis Study Group*
From the University Medical Center,
Utrecht (H.C.S., M.G.B., O.J.B., M.S.L.,
E.B., H.G.G.); University Medical Center,
Groningen (H.S.H., V.B.N., E.B.); Academ-
ic Medical Center, Amsterdam (M.A.B.,
J.S.L.); Maastricht University Medical Cen-
ter, Maastricht (C.H.D.); Radboud Uni-
versity Nijmegen Medical Center (H.G.,
C.J.L.) and Canisius–Wilhelmina Hospital
(C.R.) — both in Nijmegen; Leiden Uni-
versity Medical Center, Leiden (A.F.S.);
Erasmus Medical Center, Rotterdam
(C.H.E.); St. Antonius Hospital, Nieu-
wegein (T.L.B., B.R., R.T.); Gelderse Vallei
Hospital, Ede (P.M.K.); Leeuwarden Medi-
cal Center, Leeuwarden (E.R.M.); Maasstad
Hospital, Rotterdam (E.H.); Amphia Hos-
pital, Breda (G.P.S.); Reinier de Graaf Hos-
pital, Delft (T.K.); Gelre Hospital, Apel-
doorn (E.J.H.); Jeroen Bosch Hospital, Den
Bosch (K.B.); Medical Spectrum Twente,
Enschede (R.J.W.); and Medical Center
Alkmaar, Alkmaar (A.P.H.) — all in the
Netherlands. Address reprint requests to
Dr. Gooszen at Radboud University Nijme-
gen Medical Center
,
Nijmegen, the Neth-
erlands, or at h.gooszen@ok.umcn.nl.
*Other study investigators are listed in the
Appendix.
N Engl J Med 2010;362:1491-502.
Copyright © 2010 Massachusetts Medical Society.
ABSTRACT
Background
Necrotizing pancreatitis with infected necrotic tissue is associated with a high rate
of complications and death. Standard treatment is open necrosectomy. The outcome
may be improved by a minimally invasive step-up approach.
Methods
In this multicenter study, we randomly assigned 88 patients with necrotizing pan-
creatitis and suspected or confirmed infected necrotic tissue to undergo primary
open necrosectomy or a step-up approach to treatment. The step-up approach consisted
of percutaneous drainage followed, if necessary, by minimally invasive retroperito-
neal necrosectomy. The primary end point was a composite of major complications
(new-onset multiple-organ failure or multiple systemic complications, perforation
of a visceral organ or enterocutaneous fistula, or bleeding) or death.
Result s
The primary end point occurred in 31 of 45 patients (69%) assigned to open necro-
sectomy and in 17 of 43 patients (40%) assigned to the step-up approach (risk ratio
with the step-up approach, 0.57; 95% confidence interval, 0.38 to 0.87; P = 0.006). Of
the patients assigned to the step-up approach, 35% were treated with percutaneous
drainage only. New-onset multiple-organ failure occurred less often in patients as-
signed to the step-up approach than in those assigned to open necrosectomy (12% vs.
40%, P = 0.002). The rate of death did not differ significantly between groups (19% vs.
16%, P = 0.70). Patients assigned to the step-up approach had a lower rate of inci-
sional hernias (7% vs. 24%, P = 0.03) and new-onset diabetes (16% vs. 38%, P = 0.02).
Conclusions
A minimally invasive step-up approach, as compared with open necrosectomy, re-
duced the rate of the composite end point of major complications or death among
patients with necrotizing pancreatitis and infected necrotic tissue. (Current Controlled
Trials number, ISRCTN13975868.)
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A
cute pancreatitis is the third most
common gastrointestinal disorder requir-
ing hospitalization in the United States,
with annual costs exceeding $2 billion.
1,2
Necro-
tizing pancreatitis, which is associated with an
8 to 39% rate of death, develops in approximately
20% of patients.
3
The major cause of death, next
to early organ failure, is secondary infection of
pancreatic or peripancreatic necrotic tissue, lead-
ing to sepsis and mult iple organ failure.
4
Second-
ary infection of necrotic tissue in patients with
necrotizing pancreatitis is virtually always an in-
dication for intervention.
3,5-7
The traditional approach to the treatment of
necrotizing pancreatitis with secondary infection
of necrotic tissue is open necrosectomy to com-
pletely remove the infected necrotic tissue.
8,9
This
invasive approach is associated with high rates of
complications (34 to 95%) and death (11 to 39%)
and with a risk of long-term pancreatic insuffi-
ciency.
10-16
As an alternative to open necrosectomy,
less invasive techniques, including percutaneous
drainage,
17,18
endoscopic (transgastric) drainage,
19
and minimally invasive retroperitoneal necrosec-
tomy, are increasingly being used.
14,20 -2 2
These
techniques can be performed in a so-called step-up
approach.
23
As compared with open necrosecto-
my, the step-up approach aims at control of the
source of infection, rather than complete removal
of the infected necrotic tissue. The first step is
percutaneous or endoscopic drainage of the col-
lection of infected fluid to mitigate sepsis; this
step may postpone or even obviate surgical necro-
sectomy.
17-19
If drainage does not lead to clinical
improvement, the next step is minimally invasive
retroperitoneal necrosectomy.
14,20 -2 2
The step-up
approach may reduce the rates of complications
and death by minimizing surgical trauma (i.e., tis-
sue damage and a systemic proinflammatory re-
sponse) in already critically ill patients.
14,21
It remains uncertain which intervention in
these patients is optimal in terms of clinical out-
comes, health care resource utilization, and costs.
We performed a nationwide randomized trial
called Minimally Invasive Step Up Approach ver-
sus Maximal Necrosectomy in Patients with Acute
Necrotising Pancreatitis (PANTER).
Methods
Study Design
The design and rationale of the PANTER study have
been described previously.
24
Adults with acute pan-
creatitis and signs of pancreatic necrosis, peri-
pancreatic necrosis, or both, as detected on con-
trast-enhanced computed tomography (CT), were
enrolled in 7 university medical centers and 12
large teaching hospit als of the Dutch Pancreat it is
Study Group. Patients with confirmed or suspect-
ed infected pancreatic or peripancreatic necrosis
were eligible for randomization once a decision
to perfor m a su rg ic al int er vent ion had been m ade
and percutaneous or endoscopic drainage of the
fluid collection was deemed possible.
Infected necrotic tissue was defined as a posi-
tive culture of pancreatic or peripancreatic necrotic
tissue obtained by means of fine-needle aspiration
or from the first drainage procedure or operation,
or the presence of gas in the fluid collection on
contrast-enhanced CT. Suspected infected necro-
sis was defined as persistent sepsis or progressive
clinical deterioration despite maximal support in
the intensive care unit (ICU), without documenta-
tion of infected necrosis.
The exclusion criteria were a f lare-up of chron-
ic pancreatitis, previous exploratory laparotomy
during the current episode of pancreatitis, previ-
ous drainage or surgery for confirmed or sus-
pected infected necrosis, pancreatitis caused by
abdominal surgery, and an acute intraabdominal
event (e.g., perforation of a visceral organ, bleed-
ing, or the abdominal compartment syndrome).
Patients were randomly assigned to either pri-
mary open necrosectomy or the minimally invasive
step-up approach. Randomization was performed
centrally by the study coordinator. Permuted-block
randomization was used with a concealed block
size of four. Randomization was stratified accord-
ing to the treatment center and the access route
that could be used for drainage (i.e., a retroperi-
toneal route or only a transabdominal or endo-
scopic transgastric route).
Study Oversight
All patients or their legal representatives provided
written informed consent before randomization.
This investigator-initiated study was conducted in
accordance with the principles of the Declaration
of Helsinki. The inst itutional review board of each
participating hospital approved the protocol.
Quality Control
The indication for intervention and the optimal
timing of intervention in necrotizing pancreatitis
are frequently subject to discussion.
25
Therefore,
an expert panel consisting of eight gastrointesti-
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Step-up Approach vs. Necrosectomy for Necrotizing Pancreatitis
n engl j med 362;16 nejm.org april 22, 2010
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nal surgeons, one gastroenterologist, and three
radiologists was formed. Whenever infected necro-
sis was suspected or there was any other indica-
tion for intervention in a patient, the expert panel
received a case description, including CT images,
on a standardized form by e-mail. Within 24 hours,
the members of the expert panel individually as-
sessed the indication for intervention and the pa-
tient’s eligibility for randomization.
Whenever possible, the randomization and in-
tervention were postponed until approximately
4 weeks after the onset of disease.
5,6,26,27
All in-
terventions were performed by gastrointestinal
surgeons who were experienced in pancreatic sur-
gery and by experienced interventional radiologists
and endoscopists. Whenever necessary, the most
experienced study clinicians visited the participat-
ing centers to assist with interventions.
Open Necrosectomy
The open necrosectomy, originally described by
Beger et al.,
8
consisted of a laparotomy through a
bilateral subcostal incision. After blunt removal of
all necrotic tissue, two large-bore drains for post-
operative lavage were inserted, and the abdomen
was closed.
Minimally Invasive Step-up Approach
The first step was percutaneous or endoscopic
transgastric drainage. The preferred route was
through the left retroperitoneum, thereby facili-
tating minimally invasive retroperitoneal necro-
sectomy at a later stage, if necessary. If there was
no clinical improvement (according to prespeci-
fied criteria
24
) after 72 hours and if the position
of the drain (or drains) was inadequate or other
f luid collections could be drained, a second drain-
age procedure was performed. If this was not pos-
sible, or if there was no clinical improvement after
an additional 72 hours, the second step, video-
assisted retroperitoneal débridement (VARD) with
postoperative lavage,
21,22
was performed. (Details
on the step-up approach and postoperative man-
agement in both groups are included in the Sup-
plementary Appendix, available with the full text
of this article at NEJM.org.)
End Points and Data Collection
The predefined primary end point was a composite
of major complications (i.e., new-onset multiple
organ failure or systemic complications, enterocu-
taneous fistula or perforation of a visceral organ
requiring intervention, or intraabdominal bleeding
requiring intervention) (
Table 1
) or death during
admission or during the 3 months after discharge.
The individual components of the primary end
point were analyzed as secondary end points. Sec-
ondary end points also included other complica-
tions (
Table 1
), health care resource utilization, and
tot al direct medical costs and indirect costs from
admission unt il 6 months after discharge (detai ls
are available in the Supplementary Appendix).
Follow-up visits took place 3 and 6 months
after discharge. Data collection was performed by
local physicians using Internet-based case-record
forms. An independent auditor who was unaware
of the treatment assignments checked all com-
pleted case-record forms against on-site source
data. Discrepancies detected by the auditor were
resolved on the basis of a consensus by two in-
vestigators who were unaware of the study-group
assignments and were not involved in patient care.
All CT scans were prospectively evaluated by one
experienced radiologist who was unaware of the
treatment assignments and outcomes.
A blinded outcome assessment was performed
by an adjudication committee consisting of eight
experienced gastrointestinal surgeons who inde-
pendently reviewed all data regarding complica-
tions. Disagreements were resolved during a ple-
nary consensus meeting with concealment of the
treatment assignments.
Statistical Analysis
We calculated that we would need to enroll 88 pa-
tients
24
in order to detect a 64% relative reduction
in the rate of the composite primary end point with
the step-up approach (from 45% to 16%), with a
power of 80% and a t wo-sided alpha level of 0.05.
The large risk reduct ion wit h t he step-up approach
was expected on t he basis of results from a Dutch
nationwide retrospective multicenter study
30
and
other previous studies.
17, 31
Moreover, a larger sam-
ple was not thought to be feasible because necro-
tizing pancreatitis with secondary infection is un-
common.
All analyses were performed according to the
intention-to-treat principle. The occurrences of the
primary and secondary end points were compared
between the treatment groups. Results are pre-
sented as risk ratios with corresponding 95% con-
fidence intervals. Differences in other outcomes
were assessed with the use of the Mann–Whitney
U test.
Predef i ned subg roup an alyses were performed
for the presence or absence of organ failure at
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Table 1. Definitions of the Primary and Secondary End Points.*
End Point Definition Comment
Major complication
New-onset multiple-organ failure
or systemic complications
New-onset failure (i.e., not present at any time in the
24 hr before first intervention) of two or more or-
gans or occurrence of two or more systemic com-
plications at the same time
Organ failure Adapted from Bradley
28
Pulmonary failure PaO
2
<60 mm Hg, despite F
I
O
2
of 0.30, or need for
mechanical ventilation
Circulatory failure Circulatory systolic blood pressure <90 mm Hg,
despite adequate fluid resuscitation, or need for
inotropic catecholamine support
Renal failure Creatinine level >177 μmol/liter after rehydration or
new need for hemofiltration or hemodialysis
Systemic complication Adapted from Bradley
28
Disseminated intravascular
coagulation
Platelet count <100×10
9
/liter
Severe metabolic disturbance Calcium level <1.87 mmol/liter
Gastrointestinal bleeding >500 ml of blood/24 hr
Enterocutaneous fistula Secretion of fecal material from a percutaneous drain
or drainage canal after removal of drains or from a
surgical wound, either from small or large bowel;
confirmed by imaging or during surgery
Before any analysis, the adjudication committee
decided to combine the end points of en-
terocutaneous fistula and perforation of a
visceral organ because one is often caused
by the other and they may occur in the same
patient
Perforation of visceral organ Perforation requiring surgical, radiologic, or endo-
scopic intervention
Before any analysis, the adjudication committee
decided to combine the end points of en-
terocutaneous fistula and perforation of a
visceral organ because one is often caused
by the other and they may occur in the same
patient
Intraabdominal bleeding Requiring surgical, radiologic, or endoscopic inter-
vention
Other outcome
Pancreatic fistula Output, through a percutaneous drain or drainage
canal after removal of drains or from a surgical
wound, of any measurable volume of fluid with an
amylase content >3 times the serum amylase level
Adapted from Bassi et al.
29
New-onset diabetes Insulin or oral antidiabetic drugs required 6 mo after
discharge; this requirement was not present before
onset of pancreatitis
Use of pancreatic enzymes Oral pancreatic-enzyme supplementation required to
treat clinical symptoms of steatorrhea 6 mo after
discharge; this requirement was not present before
onset of pancreatitis
Incisional hernia Full-thickness discontinuity in abdominal wall and
bulging of abdominal contents, with or without
obstruction, 6 mo after discharge
The original study protocol
24
stated “incisional
hernia requiring intervention”; before any
analysis, the adjudication committee decid-
ed to report incisional hernias with or with-
out intervention because surgical recon-
struction of the abdominal wall is usually
not performed within 6 mo after recovery
from necrotizing pancreatitis
* FIO
2
denotes fraction of inspired oxygen, and PaO
2
partial pressure of arterial oxygen.
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