A step-up approach or open necrosectomy for necrotizing pancreatitis.

Abstract

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.
In this multicenter study, we randomly assigned 88 patients with necrotizing pancreatitis 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 retroperitoneal 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.
The primary end point occurred in 31 of 45 patients (69%) assigned to open necrosectomy 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 assigned 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 incisional hernias (7% vs. 24%, P=0.03) and new-onset diabetes (16% vs. 38%, P=0.02).
A minimally invasive step-up approach, as compared with open necrosectomy, reduced 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.)

Full text

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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.
Results
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
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 multiple 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.14,20-22 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.14,20-22 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).
cute pancreatitis is the third most
common gastrointestinal disorder requir-
ing hospitalization in the United States,
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 hospitals of the Dutch Pancreatitis
Study Group. Patients with confirmed or suspect-
ed infected pancreatic or peripancreatic necrosis
were eligible for randomization once a decision
to perform a surgical intervention had been made
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 flare-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 institutional 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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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 criteria24) after 72 hours and if the position
of the drain (or drains) was inadequate or other
fluid 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
total direct medical costs and indirect costs from
admission until 6 months after discharge (details
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-
tients24 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 two-sided alpha level of 0.05.
The large risk reduction with the step-up approach
was expected on the basis of results from a Dutch
nationwide retrospective multicenter study30 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.
Predefined subgroup analyses 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 DefinitionComment
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 failureAdapted from Bradley28
Pulmonary failurePaO2 <60 mm Hg, despite FIO2 of 0.30, or need for
mechanical ventilation
Circulatory failureCirculatory 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 complicationAdapted from Bradley28
Disseminated intravascular
coagulation
Platelet count <100×109/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 organPerforation 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 bleedingRequiring surgical, radiologic, or endoscopic inter-
vention
Other outcome
Pancreatic fistulaOutput, 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 diabetesInsulin or oral antidiabetic drugs required 6 mo after
discharge; this requirement was not present before
onset of pancreatitis
Use of pancreatic enzymesOral 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 protocol24 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
* FIO2 denotes fraction of inspired oxygen, and PaO2 partial pressure of arterial oxygen.
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randomization and the timing of intervention (≤28
days or >28 days after the onset of symptoms).
A formal test of interaction in a logistic-regres-
sion model was used to assess whether treat-
ment effects differed significantly between the
subgroups.
No interim analysis was performed. As a pre-
cautionary measure, an independent biostatisti-
cian who was unaware of the study-group assign-
ments performed sequential monitoring32 of the
major complications and deaths reported during
the trial (details are available in the Supplemen-
tary Appendix).
All reported P values are two-sided and have
not been adjusted for multiple testing.
Results
Study Participants
Between November 3, 2005, and October 29, 2008,
a total of 378 patients with acute pancreatitis who
had signs of pancreatic necrosis, peripancreatic ne-
crosis, or both were enrolled in the study. A total
of 88 patients were randomly assigned to a treat-
ment group (Fig. 1). Baseline characteristics of the
treatment groups were similar (Table 2).
Primary Open Necrosectomy
Of the 45 patients assigned to primary open ne-
crosectomy, 44 underwent a primary laparotomy.
In one patient, who had previously undergone
esophagectomy, it was decided after randomiza-
tion that laparotomy would potentially compro-
mise the gastric conduit. Therefore, primary VARD
without previous percutaneous drainage was per-
formed.
Patients underwent a median of 1 open necro-
sectomy (range, 1 to 7). Nineteen patients (42%)
required one or more additional laparotomies for
additional necrosectomy because of ongoing sep-
sis (in eight patients), complications (in five pa-
tients) or both (in six patients). Fifteen patients
88 Underwent randomization
378 Patients with acute pancreatitis and signs
of pancreatic necrosis, peripancreatic necrosis,
or both were assessed for eligibility
290 Were excluded
229 Did not meet inclusion criteria
45 Met exclusion criteria
11 Underwent previous exploratory
laparotomy
26 Underwent previous drainage
or surgery for infected necrosis
(19 in referring hospitals)
4 Had acute complication as indica-
tion for surgery
1 Could not undergo drain placement
3 Had other reasons
16 Declined to participate
45 Were assigned to undergo primary
open necrosectomy
43 Were assigned to undergo the
minimally invasive step-up approach
1 Underwent VARD without previous
percutaneous drainage
45 Were included in the analysis 43 Were included in the analysis
Figure 1. Enrollment, Randomization, and Follow-up of the Study Patients.
VARD denotes video-assisted retroperitoneal débridement.
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(33%) required additional percutaneous drainage
after laparotomy.
Minimally Invasive Step-up Approach
Forty of 43 patients assigned to the step-up ap-
proach (93%) underwent retroperitoneal percuta-
neous drainage; 1 patient (2%) underwent trans-
abdominal percutaneous drainage and 2 patients
(5%) underwent endoscopic transgastric drainage.
After the first 72 hours of observation, 19 patients
(44%) underwent a second drainage procedure.
Details of the drainage procedures are available
in the Supplementary Appendix.
Fifteen patients (35%) survived after percuta-
Table 2. Baseline Characteristics of the Patients.*
Characteristic
Minimally Invasive
Step-up Approach
(N = 43)
Primary Open
Necrosectomy
(N = 45)P Value
Age — yr57.6±2.157.4±2.00.94
Male sex — no. (%)31 (72)33 (73)0.89
Cause of pancreatitis — no. (%)0.98
Gallstones26 (60) 29 (64)
Alcohol abuse 3 (7) 5 (11)
Other 14 (33)11 (24)
Coexisting condition — no. (%)
Cardiovascular disease19 (44)21 (47)0.82
Pulmonary disease4 (9) 4 (9) 0.95
Chronic renal insufficiency3 (7)2 (4)0.61
Diabetes5 (12)4 (9)0.67
ASA class on admission — no. (%)0.99
I: healthy status 11 (26) 11 (24)
II: mild systemic disease19 (44) 20 (44)
III: severe systemic disease 13 (30)14 (31)
Body-mass index on admission†0.12
Median 2827
Range20–5522–39
CT severity index‡0.95
Median88
Range 4–10 4–10
Extent of pancreatic necrosis — no. (%) 0.52
<30% 17 (40) 19 (42)
30% to 50%14 (33) 10 (22)
>50%12 (28) 16 (36)
Necrosis extending >5 cm down the paracolic gutter — no. (%) 24 (56)27 (60) 0.69
Retroperitoneal access route to necrosis possible — no. (%) 40 (93)40 (89)0.50
Disease severity — no. (%)§
SIRS¶42 (98) 45 (100)0.49
Admitted to ICU at time of randomization 23 (54) 21 (47) 0.52
Admitted to ICU at any time before randomization28 (65) 29 (64)0.95
Single-organ failure21 (49) 22 (49)0.99
Multiple-organ failure15 (35) 13 (29)0.55
Positive blood culture within previous 7 days14 (33) 15 (33)0.94
Positive blood culture at any time before randomization 22 (51)25 (56) 0.68
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neous or endoscopic drainage only, without the
need for necrosectomy. The condition of two pa-
tients with progressive multiple organ failure was
too unstable for surgery, and they subsequently
died. The remaining 26 patients (60%) underwent
necrosectomy a median of 10 days (range, 1 to 52)
after percutaneous drainage. A VARD procedure
was performed in 24 of the patients, and the other
2 patients underwent primary laparotomy accord-
ing to the protocol because there was no retroperi-
toneal access route. A median of 1 VARD proce-
dure (range, 0 to 3) was performed in each patient.
In one patient, VARD was intraoperatively con-
verted to laparotomy because it was not possible
to reach the pancreatic necrosis through the ret-
roperitoneum.
Fourteen patients (33%) required one or more
additional operations for further necrosectomy
Table 2. (Continued.)
Characteristic
Minimally Invasive
Step-up Approach
(N = 43)
Primary Open
Necrosectomy
(N = 45) P Value
APACHE II score‖║14.6±6.115.0±5.30.75
APACHE II score ≥20 — no. (%) 10 (23)9 (20) 0.71
MODS**0.71
Median21
Range 0–9 0–10
SOFA score‡‡0.39
Median32
Range 0–11 0–12
C-reactive protein — mg/liter
White-cell count — ×10−9/liter
213.6±106 215.9±1110.93
17.6±10.615.9±6.3 0.38
Time since onset of symptoms — days0.86
Median30 29
Range11–71 12–155
Antibiotic treatment at any time before randomization — no. (%)37 (86)38 (84)0.83
Nutritional support at any time before randomization — no. (%)0.92
Enteral feeding only23 (54)23 (51)
Parenteral feeding only3 (7)4 (9)
Enteral and parenteral feeding 12 (28)11 (24)
Oral diet5 (12) 7 (16)
Tertiary referral — no. (%)21 (49)23 (51)0.83
Confirmed infected necrotic tissue — no. (%)§§ 39 (91)42 (93)0.65
* Plus–minus values are means ±SD. ASA denotes American Society of Anesthesiologists, CT computed tomography,
and ICU intensive care unit.
† The body-mass index is the weight in kilograms divided by the square of the height in meters.
‡ Data were derived from the CT performed just before randomization. Scores on the CT severity index range from 0 to
10, with higher scores indicating more extensive pancreatic necrosis and peripancreatic fluid collections.
§ Data were based on maximum values during the 24 hours before randomization unless stated otherwise.
¶ The systemic inflammatory response syndrome (SIRS) was defined according to the consensus-conference criteria of
the American College of Chest Physicians and the Society of Critical Care Medicine.
‖ Scores on the Acute Physiologic and Chronic Health Evaluation II (APACHE II) scale range from 0 to 71, with higher
scores indicating more severe disease.
** The Multiple Organ Dysfunction Score (MODS) ranges from 0 to 24, with higher scores indicating more severe organ
dysfunction.
‡‡ Scores on the Sequential Organ Failure Assessment (SOFA) scale range from 0 to 24, with higher scores indicating
more severe organ dysfunction.
§§ Infected necrotic tissue was defined as a positive 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.
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(five patients), complications (seven patients), or
both (two patients). Seven of the 26 patients who
underwent necrosectomy (27%) required percuta-
neous drainage afterward.
Clinical End Points
The primary and secondary end points are listed
in Table 3. The composite primary end point of
major complications or death occurred in 31 of
45 patients after primary open necrosectomy (69%)
and in 17 of 43 patients after the step-up ap-
proach (40%) (risk ratio with the step-up ap-
proach, 0.57; 95% confidence interval [CI], 0.38
to 0.87; P = 0.006). All major complications tend-
ed to occur more frequently after primary open
necrosectomy than after the step-up approach, al-
though the difference was significant only for
the composite end point of new-onset multiple
organ failure or multiple systemic complications
(P = 0.001). This difference was mainly driven by
the occurrence of organ failure (Table 3).
The rate of death between the two study groups
did not differ significantly (P = 0.70) (Table 3).
A total of 15 patients in the study died (17%):
8 patients in the step-up group (19%) and 7 pa-
tients in the open-necrosectomy group (16%). The
causes of death were multiple organ failure in
seven patients in the step-up group and six pa-
tients in the open-necrosectomy group, postop-
erative bleeding in one patient in the step-up
group and no patients in the open-necrosectomy
group, and respiratory failure due to pneumonia
in no patients in the step-up group and one
patient in the open-necrosectomy group.
At the 6-month follow-up, patients who had
undergone primary open necrosectomy, as com-
pared with patients who had been treated with
the step-up approach, had a higher rate of inci-
sional hernias (24% vs. 7%, P = 0.03), new-onset
diabetes (38% vs. 16%, P = 0.02), and use of pan-
creatic enzymes (33% vs. 7%, P = 0.002).
Health Care Resource Utilization and Costs
Utilization of health care resources for operations
(i.e., necrosectomies and reinterventions for com-
plications) was lower in the group of patients who
were treated with the step-up approach than in the
group of patients who underwent primary open
necrosectomy (P = 0.004) (Table 3). After primary
open necrosectomy, 40% of patients required a new
ICU admission, as compared with 16% of patients
who had been treated with the step-up approach
(P = 0.01).
The mean total of direct medical costs and in-
direct costs per patient during admission and at
the 6-month follow-up was €78,775 ($116,016) for
the step-up approach and €89,614 ($131,979) for
open necrosectomy, for a mean absolute difference
of €10,839 ($15,963) per patient. Thus, the step-up
approach reduced costs by 12% (details of costs
are available in the Table in the Supplementary
Appendix).
Predefined Subgroup Analyses
Treatment effects with respect to the primary end
point were similar across the subgroups on the
basis of organ failure at the time of randomiza-
tion and the timing of intervention (≤28 days or
>28 days after the onset of symptoms). None of the
tests for interaction were significant (P>0.05).
Discussion
This study showed that the minimally invasive
step-up approach, as compared with primary open
necrosectomy, reduced the rate of the composite
end point of major complications or death, as well
as long-term complications, health care resource
utilization, and total costs, among patients who
had necrotizing pancreatitis and confirmed or sus-
pected secondary infection. With the step-up ap-
proach, more than one third of patients were suc-
cessfully treated with percutaneous drainage and
did not require major abdominal surgery.
There are several possible explanations for the
favorable outcome of the step-up approach. First,
as we postulated when designing the study,24 in-
fected necrosis may be similar to an abscess be-
cause both contain infected fluid (pus) under
pressure. Although a true abscess is more easily
resolved with percutaneous drainage because it is
composed entirely of liquid, simple drainage may
also be sufficient to treat infected necrotic tissue.
After the infected fluid is drained, the pancreatic
necrosis can be left in situ, an approach that is
similar to the treatment of necrotizing pancrea-
titis without infection. This hypothesis apparently
holds true, since 35% of our patients who were
treated with the step-up approach did not require
necrosectomy.
Second, it has been suggested that minimally
invasive techniques provoke less surgical trauma
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Step-up Approach vs. Necrosectomy for Necrotizing Pancreatitis
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1499
Table 3. Primary and Secondary End Points.*
Outcome
Minimally Invasive
Step-up Approach
(N = 43)
Primary Open
Necrosectomy
(N = 45)
Risk Ratio
(95% CI)P Value
Primary composite end point: major complications or death — no. (%)†
17 (40)31 (69) 0.57 (0.38–0.87)0.006
Secondary end points
Major complication — no. (%)
New-onset multiple-organ failure or systemic complications‡5 (12)19 (42) 0.28 (0.11–0.67) 0.001
Multiple-organ failure5 (12)18 (40)
Multiple systemic complications0 1 (2)
Intraabdominal bleeding requiring intervention7 (16) 10 (22)0.73 (0.31–1.75)0.48
Enterocutaneous fistula or perforation of a visceral organ requiring
intervention
6 (14)10 (22) 0.63 (0.25–1.58)0.32
Death — no. (%)8 (19) 7 (16)1.20 (0.48–3.01)0.70
Other outcome — no. (%)
Pancreatic fistula12 (28)17 (38)0.74 (0.40–1.36) 0.33
Incisional hernia§3 (7) 11 (24) 0.29 (0.09–0.95)0.03
New-onset diabetes§7 (16) 17 (38)0.43 (0.20–0.94)0.02
Use of pancreatic enzymes§ 3 (7) 15 (33)0.21 (0.07–0.67) 0.002
Health care resource utilization
Necrosectomies (laparotomy or VARD) — no. (%)<0.001
017 (40)0
1 19 (44)31 (69)
26 (14)8 (18)
≥31 (2) 6 (13)
Total no. of operations¶ 0.004
Per study group53 91
Range per patient 0–61–7
Total no. of drainage procedures‖║ <0.001
Per study group 8232
Range per patient 1–70–6
New ICU admission at any time after first intervention — no. (%)**7 (16)18 (40) 0.41 (0.19–0.88) 0.01
Days in ICU0.26
Median9 11
Range 0–2810–111
Days in hospital0.53
Median5060
Range 1–287 1–247
* ICU denotes intensive care unit, and VARD video-assisted retroperitoneal débridement.
† Multiple events in the same patient were considered as one end point.
‡ This category included only patients without multiple-organ failure or multiple systemic complications at any time in the 24 hours before
the first intervention.
§ Patients were assessed 6 months after discharge from the index admission (readmission within 10 days was considered the same admission).
¶ This category included necrosectomies (laparotomy or VARD procedure) and additional operations to treat complications (e.g., repeated
laparotomy for abdominal bleeding) during the index admission.
║‖ This category included primary drainage procedures as part of the minimally invasive step-up approach and additional drainage proce-
dures after necrosectomy in both treatment groups during the index admission.
** This category included only patients who were not admitted to the ICU at any time in the 24 hours before the first intervention.
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The new england journal of medicine
n engl j med 362;16 nejm.org april 22, 2010
1500
(i.e., tissue injury and a proinflammatory response)
in patients who are already severely ill.14,20,21 This
hypothesis is supported by the substantial reduc-
tion in the incidence of new-onset multiple organ
failure in our step-up group. Third, in the attempt
to completely débride necrosis, viable pancreatic
parenchyma may be unintentionally removed. This
could explain why, at the 6-month follow-up, sig-
nificantly more patients who underwent primary
open necrosectomy had new-onset diabetes or
were taking pancreatic enzymes. For pragmatic
reasons, we defined pancreatic insufficiency on
the basis of the use of pancreatic-enzyme sup-
plements to treat clinical symptoms of pancreatic
insufficiency instead of objective analyses of exo-
crine insufficiency (e.g., the fecal elastase test).
It is possible that some of these patients did not
have exocrine insufficiency, although the rate of
pancreatic-enzyme supplementation in the open-
necrosectomy group is consistent with data on
exocrine insufficiency after open necrosectomy.15
Our findings are consistent with observations
from several retrospective studies. It has been sug-
gested previously that percutaneous drainage can
be performed in almost every patient who has
necrotizing pancreatitis with infection and obvi-
ates the need for necrosectomy in approximately
half the patients.17,18,33 Several authors have re-
ported promising results of minimally invasive
necrosectomy,14,20,22 including endoscopic proce-
dures.19,34-36 Most studies, however, included only
a small number of patients and may have unin-
tentionally selected patients who were less ill than
the patients treated with open necrosectomy or
were better candidates for minimally invasive tech-
niques. In contrast, the current study was ran-
domized and included a relatively large number of
patients, with a high incidence of confirmed in-
fected necrotic tissue and organ failure at the time
of intervention.
The benefit of the step-up approach in terms of
preventing major abdominal surgery and associ-
ated complications, such as multiple organ failure
requiring ICU admission, is of obvious impor-
tance. The reduction in long-term complications,
including new-onset diabetes and incisional her-
nias, is also clinically relevant. Diabetes due to
necrotizing pancreatitis is known to worsen over
time.15 Moreover, secondary complications from
diabetes have a considerable effect on the quality
of life and potentially on life expectancy. Inci-
sional hernias often cause disabling discomfort
and pain, carry a risk of small-bowel strangula-
tion, and frequently require surgical intervention.37
Aside from these clinical implications, the esti-
mated economic benefit from reduced health care
resource utilization and costs may be substantial.
Approximately 233,000 patients are admitted with
a new diagnosis of acute pancreatitis in the United
States each year,38 and necrotizing pancreatitis
with secondary infection develops in about 5% of
these patients.3,28 On the basis of these numbers,
the step-up approach may reduce annual costs in
the United States by $185 million.
The nationwide multicenter setting of our
study and the applicability of the minimally in-
vasive techniques provide support for the gener-
alizability of its results. Percutaneous catheter
drainage is a relatively easy and well-established
radiolo gic procedure. VARD is considered a fairly
straightforward procedure that can be performed
by any gastrointestinal surgeon with basic laparo-
scopic skills and experience in pancreatic necro-
sectomy.21,22
Our study specifically compared two treatment
strategies and does not provide a direct compari-
son of open necrosectomy with minimally inva-
sive retroperitoneal necrosectomy. Although there
are theoretical advantages of a minimally inva-
sive approach, we have not proved that VARD is
superior to open necrosectomy in patients in
whom percutaneous drainage has failed.
This study was not designed or powered to
demonstrate a difference in the rate of death be-
tween the two treatment strategies. A study show-
ing a clinically relevant difference in mortality
would require thousands of patients and is not
likely to be performed.
Our results indicate that the preferred treat-
ment strategy for patients with necrotizing pan-
creatitis and secondary infection, from both a
clinical and an economic point of view, is a mini-
mally invasive step-up approach consisting of per-
cutaneous drainage followed, if necessary, by min-
imally invasive retroperitoneal necrosectomy.
Supported by a grant (945-06-910) from the Dutch Organiza-
tion for Health Research and Development.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the study research nurses, Anneke Roeterdink and
Vera Zeguers, for their tremendous work, all medical and nurs-
ing staff in the participating centers for their assistance in en-
rollment and care of patients in this study, the patients and their
families for their contributions to the study, and Ale Algra and
Marco Bruno for critically reviewing an earlier version of the
manuscript.
Copyright © 2010 Massachusetts Medical Society. All rights reserved.
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Step-up Approach vs. Necrosectomy for Necrotizing Pancreatitis
n engl j med 362;16 nejm.org april 22, 2010
1501
Appendix
The following investigators participated in the study: Steering committee: M.G. Besselink, M.A. Boermeester, T.L. Bollen, E. Buskens,
C.H. Dejong, C.H. van Eijck, H. van Goor, H.G. Gooszen (chair), H.S. Hofker, J.S. Laméris, M.S. van Leeuwen, V.B. Nieuwenhuijs, R.J.
Ploeg, B. van Ramshorst, H.C. van Santvoort, A.F. Schaapherder. Expert panel: M.A. Boermeester, T.L. Bollen, C.H. Dejong, C.H. van
Eijck, H. van Goor, H.G. Gooszen, H.S. Hofker, J.S. Laméris, M.S. van Leeuwen, A.F. Schaapherder, R. Timmer, V.B. Nieuwenhuijs.
Independent data and safety monitoring committee: F.L. Moll (chair), K.G. Moons, M. Prokop, M. Samsom, P.B. Soeters. Independent
biostatistician: I. vd Tweel. Independent data auditor: J. Oors. Adjudication committee: M.A. Boermeester, C.H. Dejong, C.H. van Eijck,
H. van Goor, H.G. Gooszen, H.S. Hofker, B. van Ramshorst, A.F. Schaapherder. In addition to the authors, the following clinicians
participated in the study: Maastricht University Medical Center, Maastricht — R.M. van Dam, J.P. Rutten, J.H. Stoot, Y. Keulemans, R. Vliegen;
University Medical Center, Utrecht — A. Roeterdink, V. Zeguers, U. Ahmed Ali, H.G. Rijnhart, G.A. Cirkel, K.J. van Erpecum, F.P. Vleggaar,
M. van Baal, M. Schrijver, L.M. Akkermans, E.J. Hazebroek; St. Antonius Hospital, Nieuwegein — M.J. Wiezer, B.L. Weusten, H.D. Biemond;
University Medical Center, Groningen — R.J. Ploeg, H.T. Buitenhuis, S.U. van Vliet, S. Ramcharan, H.M. van Dullemen; Academic Medical Center,
Amsterdam — O. van Ruler, W. Laméris, D.J. Gouma, O.R. Busch, P. Fockens; Leiden University Medical Center, Leiden — A. Haasnoot, R.
Veenendaal; Gelderse Vallei Hospital, Ede — B.J. Witteman; Leeuwarden Medical Center, Leeuwarden — J.P. Pierie, P. Spoelstra, J.A. Dol, R.T. Ger-
ritsen; Maasstad Hospital, Rotterdam — J.F. Lange, N.A. Wijffels, L.A. van Walraven, P.P. Coene, F.J. Kubben; Amphia Hospital, Breda — J.H.
Wijsman, R.M. Crolla, A.W. van Milligen de Wit, M.C. Rijk; Reinier de Graaf Hospital, Delft — L.P. Stassen; Gelre Hospital, Apeldoorn — H.
Buscher; St. Elisabeth Hospital, Tilburg — J. Heisterkamp, H. van Oostvogel, M.J. Grubben; Canisius–Wilhelmina Hospital, Nijmegen — A.C. Tan;
Erasmus Medical Center, Rotterdam — J.B. van der Wal, M.J. Morak, C.J. Pek, J.J. Hermans, E.J. Kuipers, J.W. Poley, M. Bruno; Radboud Uni-
versity Nijmegen Medical Center, Nijmegen — J.B. Jansen, S.P. Strijk; Jeroen Bosch Hospital, Den Bosch — D. Lips, J.G. Olsman, I.P. van Munster;
Medical Spectrum Twente, Enschede — J.J. Kolkman, A.B. Huisman; Medical Center Alkmaar, Alkmaar — H.A. Tuynman, B.M. Wiarda.
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