REVIEW ARTICLE
Enteral Nutrition and the Risk of Mortality
and Infectious Complications in Patients
With Severe Acute Pancreatitis
A Meta-analysis of Randomized Trials
Maxim S. Petrov, MD; Hjalmar C. van Santvoort, MD; Marc G. H. Besselink, MD;
Geert J. M. G. van der Heijden, PhD; John A. Windsor, MD, FRACS; Hein G. Gooszen, MD, PhD
Objective: To compare the effect of enteral vs parenteral nutrition in patients with severe acute pancreatitis
for clinically relevant outcomes.
Data Sources: A computerized literature search was per-
formed in the MEDLINE, EMBASE, and Cochrane databases for articles published from January 1, 1966, until December 15, 2006.
Study Selection: From 253 publications screened, 5
randomized controlled trials comparing enteral and parenteral nutrition in patients with predicted severe acute
pancreatitis met the inclusion criteria.
Data Synthesis: A meta-analysis of randomized con-
trolled trials was performed using a random-effects model.
Enteral feeding reduced the risk of infectious complications (relative risk, 0.47; 95% confidence interval, 0.280.77; P ⬍.001), pancreatic infections (0.48; 0.26-0.91;
P=.02), and mortality (0.32; 0.11-0.98; P=.03). The risk
reduction for organ failure was not statistically significant (0.67; 0.30-1.52; P=.34).
Data Extraction: Information on study design, pa-
Conclusions: Enteral nutrition results in clinically
relevant and statistically significant risk reduction for
infectious complications, pancreatic infections, and
mortality in patients with predicted severe acute
pancreatitis.
tient characteristics, and acute pancreatitis outcomes were
independently extracted by two of us using a standardized protocol.
Arch Surg. 2008;143(11):1111-1117
I
Author Affiliations:
Department of Surgery
(Drs Petrov, van Santvoort,
Besselink, and Gooszen) and
Julius Center for Health
Sciences and Primary Care
(Dr van der Heijden),
University Medical Center
Utrecht, Utrecht, the
Netherlands; and Department of
Surgery, University of
Auckland, Auckland,
New Zealand (Dr Windsor).
NFECTIOUS COMPLICATIONS OCcur in approximately 10% of patients with acute pancreatitis and
account for at least 50% of the
mortality in these patients.1-3 Animal and human studies4-6 suggest that a
loss of the gut barrier function is instrumental in the local and systemic infectious complications associated with a severe course of disease. Attempts to reduce
the failure of the gut barrier, to potentially decrease the incidence of infectious
complications of acute pancreatitis, have
largely consisted of enteral nutrition
(EN).7,8 The protective role of EN, compared with parenteral nutritional (PN), in
maintaining the integrity of the gut barrier has been demonstrated in a rat model
of acute pancreatitis.9 The EN group was
found to have significantly less bacterial
translocation and a lower blood endotoxin level than the PN group.
These experimental findings, however,
have not been convincingly supported by
results from randomized clinical trials
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(RCTs). Thereby, on the basis of previous
meta-analyses,10,11 the latest guidelines of the
American College of Gastroenterology state
that “it is reasonable to conclude that enteral feeding is safer and less expensive than
PN, but there is not yet convincing findings that there are major improvements in
morbidity and mortality of acute pancreatitis.”12(p2388) However, the previous metaanalyses were not stratified according to the
severity of disease and included 46% to 58%
patients with mild acute pancreatitis. This
limits the conclusions that can be drawn because it is believed that only patients with
severe acute pancreatitis need nutritional
support.12-14 Moreover, the most comprehensive meta-analysis, by Marik and
Zaloga,11 included 4 of 6 trials in which the
allocation of patients to the EN or PN group
either was not stated15,16 or was performed
via quasi-randomization (medical record
number17 or date of birth18), thereby potentially leading to the selection biases. Lastly,
3 new trials have been published since
then.19-21 In light of these issues, the pres-
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STATISTICAL ANALYSIS
253 Potentially relevant
publications identified
224 Excluded after review
of title and abstract
29 Potentially appropriate
RCTs to be included in
meta-analysis
24 RCTs excluded from
meta-analysis
5 RCTs included in
meta-analysis
Statistical analysis was conducted using meta-analysis software (Comprehensive Meta-analysis, version 2; Biostat, Englewood, New Jersey; and MIX: Comprehensive Free Software for
Meta-analysis of Causal Research Data, version 1.51).23 Metaanalysis was performed with a random-effects model as the most
conservative. The presence of heterogeneity was assessed using
the I2 measure, with an I2 value greater than 20 indicating marked
heterogeneity. We also used funnel plots to determine the presence of publication bias and related biases and performed a statistical test of funnel plot asymmetry.
RESULTS
Figure 1. The study selection process. RCT indicates randomized clinical
trial.
ent meta-analysis aimed to provide an evidence-based appraisal of the effects of enteral feeding compared with parenteral feeding in patients with severe acute pancreatitis.
METHODS
STUDY SELECTION
The MEDLINE, EMBASE, and Cochrane databases were crosssearched for articles published from January 1, 1966, until December 15, 2006. A bibliographic search of the Cochrane database was
made using the following predefined terms: acute pancreatitis AND
(enteral nutrition OR enteral feeding) AND (parenteral nutrition OR
parenteralfeeding).TermsusedforthesearchinEMBASEwereacute
pancreatitis AND (enteral nutrition OR enteral feeding) AND (parenteral nutrition OR parenteral feeding) AND [humans]/lim. Terms
usedforthesearchinMEDLINEwereacutepancreatitis[title/abstract]
ORpancreatitis[title/abstract])AND(enteralnutrition[title/abstract]
OR enteral feeding [title/abstract]) AND (parenteral nutrition [title/
abstract] OR parenteral feeding [title/abstract]). No language restrictions were applied.
Full-text articles were included in this systematic review if
the title and/or abstract of the article reported (1) an RCT study
design; (2) a population of patients with predicted severe acute
pancreatitis (in the case of a mixed study population, ie, patients with both mild and severe acute pancreatitis, included
trials should present separate outcome data for patients with
severe acute pancreatitis); (3) EN and PN interventions (EN
was defined as the nasogastric or nasojejunal delivery of nutritional formula not supplemented with any immuneenhancing ingredients); and (4) at least 3 of the following outcome variables: total infectious complications, pancreatic
infections, need for surgery, nonpancreatic infections, organ
failure, and in-hospital mortality.
DATA EXTRACTION
Data from full-text articles were retrieved and checked for consistency by two of us (M.S.P. and H.C.v.S.) independently. Data
on baseline characteristics and numbers of events for each end
point were extracted. Disagreements about values were resolved by discussion between the two of us.
The methodologic quality of the studies was assessed using
a previously published scoring system, with a quality scale range
of 0 to 5 points.22 This quality scale incorporates method of randomization, masking, and dropouts and withdrawals. A score
of 2 or less represents a low-quality study, whereas a score of
at least 3 represents a high-quality study. Differences in assessment were resolved by consensus among the authors of this
review.
Overall, we identified 253 publications. After initial eligibility screening, 29 potentially eligible RCTs on artificial nutrition in acute pancreatitis were retrieved
(Figure 1). Twenty-four studies were subsequently excluded for the following reasons: EN was compared with
no artificial nutrition,24 PN was compared with no artificial nutrition,25 fat glucose–based PN was compared with
glucose-based PN,26 fructose-glucose-xylitol–based PN
was compared with glucose-based PN,27 the effects of PN
compared with immune-enriched PN were studied,28-30
the effects of probiotics and immune-enriched enteral nutritional formulas were studied,31-34 nasojejunal EN was
compared with nasogastric EN,35,36 nasojejunal refeeding was compared with oral refeeding,37 polymeric enteral feeding formula was compared with semielemental formula,38 PN was compared with the combined use
of EN and PN,39,40 or the trials considered postoperative
patients only41-43 or included patients with both mild and
severe acute pancreatitis without presenting data separately.15-18 Finally, 5 RCTs,19-21,44,45 in which 95 patients
were randomly allocated to the EN group and 107 to the
PN group, met all inclusion criteria. The characteristics
of included trials are detailed in Table 1. All RCTs
reached a Jadad quality score of 3. Table 2 demonstrates the feeding regimens for all RTCs. A summary of
the outcome data for the included RCTs are listed in
Table 3. The funnel plots for the different outcomes show
no clear pattern of bias (data not presented). Table 4
summarizes the results of the meta-analysis for the respective end points reported herein.
TOTAL INFECTIOUS COMPLICATIONS
The risk of total infectious complications was reported
in all 5 RCTs. Sixty-seven of 202 patients (33.2%) had
infections: 21 of 95 (22.1%) in the EN group and 46 of
107 (43.0%) in the PN group. In absence of marked
heterogeneity across RCTs, EN resulted in a clinically relevant and statistically significant reduction in risk for total
infectious complications (relative risk [RR], 0.47; 95%
confidence interval [CI], 0.28-0.77; P⬍.001) (Figure 2).
PANCREATIC INFECTIONS
Pancreatic infections included infected pancreatic necrosis and pancreatic abscess and were reported in all
RCTs. In the absence of marked heterogeneity across stud-
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Table 1. Study Characteristics of the Included Trials
Years of
Study
Year of
Publication
Kalfarentzos
et al44
Gupta et al45
Louie et al19
Eckerwall et al20
1990-1995
1997
Greece
Not stated
1996-1998
1999-2001
2002-2004
2003
2005
2006
United Kingdom
Canada
Sweden
Not stated
Not stated
25 (22-35) h/
30 (20-35) h
Petrov et al21
2002-2004
2006
Russia
⬍72 h
Source
Onset of
Symptoms
Setting
Severity at the
Time of Inclusion
in Trial (APACHE II
Score), EN/PN Groups a
Criteria of Severity
APACHE II score ⱖ8 and/or
Imrie score ⱖ3
APACHE II score ⱖ6
Ranson score ⱖ3
APACHE II score ⱖ8 and/or
CRP level ⱖ150 mg/L
and/or peripancreatic liquid
on CT
APACHE II score ⱖ8 and/or
CRP level ⱖ150 mg/L
Prophylactic
Antibiotics, %
12.7 (2.6)/11.8 (1.9)
100
8 [6-12]/10 [7-14]
11.8 (8.3)/12.7 (5.5)
10 [8-13]/9 [8-10]
100
79
73
12 (10-14)/12.5 (11-16)
100
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CRP, C-reactive protein; CT, computed tomography; EN, enteral nutrition;
PN, parenteral nutrition.
SI conversion factor: To convert CRP to nanomoles per liters, multiply by 9.524.
a Data are presented as median [range] or mean (SD).
Table 2. Summary of Feeding Regimens for the Included Trials
Feeding Start
Days Receiving Feeding,
EN/PN Groups a
Parenteral Feeding
Formula
Kalfarentzos et al44
⬍48 h after admission
34.8/32.8
Gupta et al45
⬍6 h after admission
2 [2-7]/4 [2-7]
Louie et al19
Eckerwall et al20
⬎96 h after admission
⬍24 h after admission
13.1 (10.5)/14.6 (10.3)
6 [5-9]/6 [5-9]
Petrov et al21
⬍24 h after admission
14 [8-20]/14 [10-21]
Dextrose and amino acid solutions,
fat emulsion, vitamins, minerals
Amino acid (Synthamin 14; Baxter
Nutrition Ltd, Wallingford, United
Kingdom), lipid and glucose
solutions, trace elements
Dextrose solution, fat emulsion
Glucose, amino acid solutions and fat
emulsion (Kabiven PI; Fresenius-Kabi,
Uppsala, Sweden)
Dextrose and amino acid solutions,
fat emulsion
Source
Enteral Feeding
Formula
Semielemental
Polymeric
Semielemental
Polymeric
Semielemental
Abbreviations: EN, enteral nutrition; PN, parenteral nutrition.
are presented as median [range] or mean (SD).
a Data
Table 3. Summary of Outcome Data of Trials Included in the Meta-analysis
EN/PN Groups
Source
Kalfarentzos et al44
Gupta et al45
Louie et al19
Eckerwall et al20
Petrov et al21
No. of
Patients
18/20
8/9
10/18
24/26
35/34
Mortality
Total No.
of Infectious
Complications
No. of
Pancreatic
Infections
No. of Patients
With Organ
Failure
No. of Patients
Undergoing
Surgery
1/2
0/0
0/3
1/0 b
2/12
5/10
1/2
1/7
3/0 b
11/27
2/4
0/0
1/4
1/0 b
7/16
Not stated
0/6
7/13
3/2
4/10
2/4
0 (2)/0 (2) a
1/4
1/0 (1) a
8/25
Abbreviations: EN, enteral nutrition; PN, parenteral nutrition.
a Number of cholecystectomies in parentheses (data were not included
b After exclusion of protocol violators (1 patient from each group).
in meta-analysis).
ies, EN resulted in a clinically relevant and statistically
significant reduction in risk of pancreatic infections (RR,
0.48; 95% CI, 0.26-0.91; P = .02).
heterogeneity across studies, EN resulted in a clinically
relevant and statistically significant reduction in the need
for surgery (RR, 0.37; 95% CI, 0.21-0.65; P=.001).
SURGICAL INTERVENTION
NONPANCREATIC INFECTIONS
Pancreatic infections were an absolute indication for surgery as reported in all 5 RCTs. In the absence of marked
Nonpancreatic infections, reported in 3 RCTs, included infections of the respiratory and urinary systems. In the ab-
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Table 4. Results of the Meta-analysis
Outcome
No. of Events,
EN/PN Groups
Relative Risk
(95% Confidence Interval)
P Value
Heterogeneity, I 2
21/46
4/17
12/33
11/24
7/16
4/8
14/31 a
4/9
7/16
3/5
0.47 (0.28-0.77)
0.32 (0.11-0.98)
0.37 (0.21-0.65)
0.48 (0.26-0.91)
0.44 (0.19-1.06)
0.62 (0.19-2.03)
0.67 (0.30-1.52)
0.66 (0.23-1.88)
0.78 (0.38-1.62)
0.80 (0.21-3.07)
⬍.001
.03
.001
.02
.05
.34
.21
.44
.51
.75
0.00
6.43
0.00
0.00
0.00
46.15
62.79
0.00
0.00
0.00
Infectious complication
Death
Surgical intervention
Pancreatic infections
Infected pancreatic necrosis
Pancreatic abscess
Organ failure
Renal
Respiratory
Shock
Abbreviations: EN, enteral nutrition; PN, parenteral nutrition.
a There was 1 patient with coagulopathy.
Year
EN Group
PN Group
Kalfarentzos et al44
1997
5/18
10/20
6.30
||||||||
0.556 (0.234-1.318)
Gupta et al45
2003
1/8
2/9
4.90
|
0.563 (0.062-5.094)
Louie et al19
2005
1/10
7/18
6.30
|
0.257 (0.037-1.803)
Eckerwall et al20
2006
3/23
0/25
2.90
|
7.583 (0.413-139.315)
2006
11/35
27/34
58.50
||||||||||||||||||||
0.396 (0.236-0.665)
21/94
46/106
100
|||||||||||||||||||||||||||||
0.468 (0.285-0.769)
Petrov et
al21
Meta-analysis
Forest Plot – RR (IV+t)
Association Measure
(95% CI)
Source
0.01
0.1
1
10
Weight, %
100
1000
RR (Log Scale)
Figure 2. Forest plot for total infectious complications. CI indicates confidence interval; EN, enteral nutrition; IV, inverse variance; PN, parenteral nutrition;
and RR, relative risk.
Year
EN Group
PN Group
Kalfarentzos et al44
1997
1/18
2/20
12.00
||||||||
0.556 (0.055-5.622)
Louie et al19
2005
0/10
3/18
14.40
||||
0.247 (0.014-4.346)
Eckerwall et al20
2006
1/23
0/25
12.00
||||
3.25 (0.139-76.006)
Petrov et al21
2006
2/35
12/34
52.00
||||||||||||||||||||
0.162 (0.039-0.67)
4/86
17/97
100
|||||||||||||||||||||||||||||
0.322 (0.106-0.98)
Meta-analysis
Forest Plot – RR (IV+t)
Association Measure
(95% CI)
Source
0.01
0.1
1
Weight, %
10
100
RR (Log Scale)
Figure 3. Forest plot for mortality. CI indicates confidence interval; EN, enteral nutrition; IV, inverse variance; PN, parenteral nutrition; and RR, relative risk.
sence of marked heterogeneity across studies, EN was not
associated with a statistically significant reduction in risk
of urinary tract infections (RR, 0.70; 95% CI, 0.21-2.36;
P=.56). The same holds for the risk reduction for respiratory tract infections (RR, 0.70; 95% CI, 0.21-2.34; P=.56).
a statistically significant reduction in risk of organ failure (RR, 0.67; 95% CI, 0.30-1.52; P=.34). Results of subgroup analysis of types of organ failure are presented in
Table 4.
MORTALITY
ORGAN FAILURE
Data on organ failure were reported in 4 trials. A total of
49 patients had any type of organ failure. With a marked
heterogeneity across studies, EN was not associated with
Mortality was reported in all RTCs. Twenty-one patients died, 4 of 95 (4%) in the EN group and 17 of 107
(15.9%) in the PN group. With a marginal heterogeneity across studies, EN resulted in a clinically relevant
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and statistically significant reduction in mortality risk (RR,
0.32; 95% CI, 0.11-0.98; P = .03) (Figure 3).
COMMENT
This meta-analysis shows that EN, compared with PN,
has important beneficial effects in patients with predicted severe acute pancreatitis, notably, clinically relevant and statistically significant risk reduction in infectious complications and mortality. The present study is
stronger than previous meta-analyses10,11,46 in its adherence to strict methodologic criteria. The quality of studies has an effect on the estimates of treatment efficacy.47
The trials included in the previous meta-analyses were
of relatively poor quality, with 1 of 2 (50%),10 4 of 7
(57%),46 and 4 of 6 (67%)11 studies having a Jadad score
less than 3. Because of the nature of the treatment arms,
it was essentially impossible to double blind studies. Consequently, the maximally possible Jadad score was 3.
Thereby, this meta-analysis, including only trials with
Jadad scores of 3, summarizes the best available evidencebased data. Another strength of this meta-analysis is that
it includes a more homogeneous subgroup of patients (ie,
we only included trials that reported effect estimates for
patients with predicted severe acute pancreatitis). All previous meta-analyses included mixed populations, with
32 of 70 (46%),10 152 of 291 (52%),46 and 152 of 263
(58%)11 predicted mild cases.
This meta-analysis has several potential weaknesses.
The ability to accurately predict the course of an attack
of acute pancreatitis remains a challenge12,13 as evidenced by the range (57%-92%) of positive predictive
value for scoring systems.48,49 However, the selection of
patients for a trial without the use of a scoring system
will lead to inclusion of only 10% to 15% with a poor
outcome. However, when a scoring system is used to select the patients with predicted severe acute pancreatitis, 57% to 92% of the patients will have a poor outcome. Although this is far from an ideal prediction, it will
help to improve the statistical power of the study. Furthermore, there was clear heterogeneity for organ failure (I 2 =46.15). Different definitions of organ failure, variability in scores, and other reasons may contribute to the
observed heterogeneity. In addition, there was minimal
heterogeneity for mortality (I2 = 6.43). It is believed that
mortality in acute pancreatitis has a bimodal distribution (organ failure within 1-2 weeks and infectious complications later).50 Taking this into account, the heterogeneity in mortality may have been influenced by
differences across studies with respect to organ failure.
However, the trial publications do not provide sufficient data to test for such sources of heterogeneity by metaregression. By its relatively high weight, the trial from
Russia21 added much information to the meta-analysis of
infectious complications and mortality. In contrast to other
trials included, the statistical power of this particular study
was adequate for these outcomes, whereas no heterogeneity was found among trials in terms of the risk of infectious complications. Still, sensitivity analyses on the
influence of different trials on the pooled outcomes did
not show a clear pattern (data not shown).
Common to all meta-analyses, publication bias is a concern. Reports of trials with statistically significant results are more likely to be published than those with negative outcomes.51 The funnel plots show no clear pattern
of such biases. Variation also occurred among the studies in terms of the location of the feeding tube. At the
same time, it is unlikely that the difference between nasogastric and nasojejunal feeding would confound the results because 2 recent trials showed no difference in the
outcomes between these approaches.35,36
Despite the clear clinical benefits of EN, the exact
mechanism of its favorable effect remains unclear. It is
considered that EN acts to reduce the failure of the gut
barrier and diminish subsequent bacterial translocation
that plays a pivotal role in the development of infectious complications during severe acute pancreatitis.7,8
The clinical measurement of the failure of gut barrier function remains a challenge, and the measurement of intestinal permeability is most often performed. Apart from
experimental studies,4,5 3 clinical studies have shown that
there is increased intestinal permeability to both micromolecules (sugar probes) and macromolecules (polyethylene glycol) in patients with severe acute pancreatitis
compared with those with mild disease and healthy volunteers.6,52,53 The issue remains unresolved, however, because 2 trials have suggested that EN is associated with
increased intestinal permeability. The trial by Powell et
al,24 in which patients with predicted severe acute pancreatitis were randomized to receive either nasojejunal
EN or no nutritional support, showed significantly increased intestinal permeability (using a differential sugar
permeability test) by day 4 in patients allocated to the
EN group. Another trial comparing nasogastric EN vs PN
in patients with predicted severe acute pancreatitis demonstrated increased intestinal permeability (using the urinary excretion of orally administered polyethylene glycol) on day 3 in the EN group.20 However, both trials
included a considerable number of patients with mild
acute pancreatitis (11 of 27 and 26 of 48, respectively),
for which it has not been shown that intestinal permeability will change considerably.6,52,53
Another marker of impaired gut barrier function is the
finding of endotoxemia. The serum concentration of antiendotoxin core antibodies (both IgM and IgG) can be used
as an indicator of severity and an indirect marker for intestinal permeability.54 Results of an early trial from the
United Kingdom17 showed that levels of serum IgM antibodies decreased significantly after 7 days of EN when compared with the PN group (P⬍.05). The trial by Gupta et
al45 demonstrated that IgM antibody levels decreased significantly in the EN group (P=.03) and tended to increase
in the PN group during the week of treatment. Conversely, the recent trial by Eckerwall et al20 found decreasing levels of IgM antibodies in both the EN and PN groups
without significant differences at any time point within the
10 days of follow-up. The IgG antibody may be a better
marker of gut barrier failure than IgM,54 but, unfortunately, it was not measured in the trial from Sweden.20 The
influence of EN on intestinal barrier function in severe acute
pancreatitis merits further investigation.
A number of other issues should be addressed when
considering EN in the setting of severe acute pancreati-
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tis. The patients included in all 5 RCTs received prophylactic antibiotics. Theoretically, either a synergistic effect
of antibiotics with EN or an antagonistic effect of antibiotics with PN cannot be ruled out. Thereby, to ascribe
a decrease in the infectious complications and mortality
to the enteral feeding, ultimately, a trial on EN vs EN plus
antibiotics would be useful. In addition, future trials
should also focus on different aspects of feeding methods, notably, the safety of nasogastric vs nasojejunal delivery of nutrients, the optimal timing for initiation of
feeding, and the composition of enteral formulations.
In conclusion, since the pioneer trial by McClave et
al15 in 1997, the present meta-analysis of high-quality studies has summarized the decennial endeavors to define the
best nutritional strategy in acute pancreatitis. This metaanalysis has demonstrated strong evidence of the benefits of enteral over parenteral feeding in patients with
severe acute pancreatitis in terms of clinically relevant
and statistically significant reductions in the risk of infectious complications and mortality.
Accepted for Publication: June 20, 2007.
Correspondence: Hein G. Gooszen, MD, PhD, University Medical Center Utrecht, PO Box 85500, HP G04.228,
3508 GA Utrecht, The Netherlands (h.gooszen
@umcutrecht.nl).
Author Contributions: Drs Petrov and van Santvoort had
full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of
the data analysis. Study concept and design: Petrov,
Windsor, and Gooszen. Acquisition of data: Petrov and
van Santvoort. Analysis and interpretation of data: Petrov,
Besselink, van der Heijden. Drafting of the manuscript:
Petrov. Critical revision of the manuscript for important intellectual content: van Santvoort, Besselink, van der
Heijden, Windsor, and Gooszen. Statistical analysis: Petrov
and van der Heijden. Administrative, technical, or material support: Van Santvoort, Besselink, van der Heijden,
and Gooszen. Study supervision: Petrov, Windsor, and
Gooszen.
Financial Disclosure: None reported.
Previous Presentation: This study was presented in part
at the 39th meeting of the European Pancreatic Club; July
2007; Newcastle upon Tyne, England, and published as
an abstract in Pancreatology. 2007;7:254.
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