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Impact of the Reconstruction Method on Delayed GastricEmptying After Pylorus-Preserving Pancreaticoduodenectomy:A Prospective Randomized Study
Dietmar Tamandl • Klaus Sahora • Johannes Prucker •
Rainer Schmid • Jens-Juul Holst • Johannes Miholic •
Peter Goetzinger • Michael Gnant
Published online: 12 October 2013
� Societe Internationale de Chirurgie 2013
Abstract
Background Delayed gastric emptying (DGE) is of con-
siderable concern in patients undergoing pylorus-preserv-
ing pancreaticoduodenectomy (PPPD). Prolonged hospital
stay, increased cost, and decreased quality of life add on to
interventions needed to treat DGE. This study was con-
ducted to determine if performing duodenojejunostomy via
the antecolic rather than the retrocolic route improved
incidence of DGE.
Methods Patients undergoing PPPD between April 2007
and November 2009 were randomized for either antecolic
or retrocolic reconstruction of the duodenojejunostomy.
DGE was then assessed by clinical criteria on postoperative
day (POD) 10. A paracetamol absorption test was also
administered with a liquid meal, and serial plasma levels of
intestinal peptides were measured.
Results Overall, 64 patients were amenable for analysis:
36 in the antecolic group and 28 in the retrocolic group.
The incidences of DGE on POD 10 were 17.6 and 23.1 %
(antecolic vs. retrocolic, respectively) (p = 0.628). The
two groups did not differ in regard to their median
(interquartile range) postoperative hospital length of stay
[13.0 (10.0–17.5) vs. 12.5 (11.0–17.0) days; p = 0.446],
time to regular diet [5 (5–7) vs. 5 (4–6) days; p = 0.353],
or morbidity (52.9 vs. 50.0 %; p = 0.777). The median
length of nasogastric tube decompression was similar in the
two groups [4 (3–7) vs. 3 (3–5) days; p = 0.600]. Levels of
paracetamol and glucagon-like peptide-1 were markedly
decreased in patients with DGE.
Conclusions Antecolic reconstruction after PPPD does
not improve the occurrence/the incidence of DGE and is
similar to retrocolic reconstruction with regard to second-
ary outcome parameters.
Introduction
Pancreaticoduodenectomy (PD) is the standard operation
for tumors of the pancreatic head, ampulla, and distal
common bile duct [1, 2]. Pylorus-preserving pancreatico-
duodenectomy (PPPD) is a procedure with equal short- and
long-term outcomes compared to the classic Whipple
pancreaticoduodenectomy, which has been demonstrated
by several randomized trials [3, 4]. However, PPPD seems
to be associated with a shorter operation time and less
intraoperative blood loss [4]. The idea of organ-preserving
surgery has led to the fact that whenever possible PPPD is
the standard operation instead of PD at many centers [5].
Delayed gastric emptying (DGE) is a common compli-
cation after PPPD, occurring in 5–70 % of patients after the
operation [5–9]. This high variation in incidence is due to
different use of definitions throughout the literature [6, 10,
11] and the fact that most studies dealing with this topic are
retrospective in nature. DGE is usually not a life-threat-
ening complication, but it prolongs hospital stay, decreases
quality of life, and increases treatment costs [6, 12].
D. Tamandl (&) � K. Sahora � J. Prucker � J. Miholic �P. Goetzinger � M. Gnant
Department of Surgery, Medical University of Vienna,
Waehringer Guertel 18-20, 10990 Vienna, Austria
e-mail: dietmar.tamandl@meduniwien.ac.at
M. Gnant
e-mail: michael.gnant@meduniwien.ac.at
R. Schmid
Clinical Institute of Medical and Chemical Laboratory
Diagnostics, Medical University of Vienna, Vienna, Austria
J.-J. Holst
Department of Biomedical Sciences, The Panum Institute,
University of Copenhagen, Copenhagen, Denmark
123
World J Surg (2014) 38:465–475
DOI 10.1007/s00268-013-2274-4
Several attempts to alleviate DGE have been reported,
most of which are applied postoperatively [13]. To our
knowledge, there are three randomized controlled trials
(RCTs) dealing with a modification of the operative pro-
cedure to improve the incidence of DGE [6, 14, 15]. The
first trial conducted in Japan was available at the time of
setting up the current study. It randomized patients to
undergo either antecolic or retrocolic reconstruction of the
duodenojejunostomy and found striking improvement of
DGE in the antecolic group (5 % antecolic vs. 50 % ret-
rocolic). Together with retrospective evidence [5, 7–9],
their results led to the belief in the surgical community that
antecolic reconstruction seems to be a safer method with
respect to decreased DGE. However, some shortcomings in
the RCT and some natural limitations in the retrospective
analyses raises the question of whether these findings can
be applied to all patients.
The paracetamol absorption test is a reliable method for
determining gastric emptying in healthy individuals [16,
17] and surgical patients [18, 19]. Because paracetamol is
absorbed only in the small intestine, gastric emptying is the
rate-limiting step in paracetamol uptake [16]. Therefore,
the profile of paracetamol concentration in plasma can be
used to assess how quickly a meal passes through the
stomach. Also, plasma levels of intestinal peptides, which
are secreted upon nutrient ingestion, have been used to
analyze the regulation of gastric emptying in previous
studies [19–21]. Glucagon-like peptide-1 (GLP-1), an in-
cretin that is secreted into the bloodstream within minutes
after nutrients reach the small intestine, has been shown to
correlate with gastric emptying [20]. GLP-1 levels rapidly
increased after a meal in patients who exhibited dumping
as a result of rapid gastric emptying after distal gastrec-
tomy, whereas patients without dumping showed an
attenuated peak of GLP-1 secretion [21]. Peptide YY (PYY
3-36) is secreted into the bloodstream upon contact of
nutrients with L-cells in the distal intestine [22]. It is
therefore a ‘‘late’’ indicator of gastric emptying.
We designed the current trial to determine if antecolic
reconstruction of the duodenojejunostomy was able to
decrease the incidence of DGE using clinical criteria. In
addition, patients had a test meal with a paracetamol
absorption test at postoperative day (POD) 10, which fur-
ther helped to elucidate the biology of gastric emptying in
these patients.
Materials and methods
This open, randomized trial was performed at a single
center in Austria. The study was conducted between April
2007 and November 2009 at the General Hospital of
Vienna, a tertiary referral center of the Medical University
of Vienna (MUV). The local ethics committee approved
this study (EK-No. 539/2006). All patients gave written
informed consent.
Eligible participants were adults between the ages of 18
and 90 years undergoing PPPD for cancer either of the
pancreatic head/uncinate process/ampulla or distal com-
mon bile duct or with a radiographically suspicious solid or
cystic tumor requiring pancreaticoduodenectomy. Exclu-
sion criteria were as follows: (1) distant metastases; (2)
locally unresectable tumors (arterial involvement or[1808involvement of the portal vein or superior mesenteric vein);
(3) invasion of the stomach; (4) prior surgical resection of
the stomach or duodenum. Exclusion criteria for the test
meal at POD 10 were (1) clinically significant anastomotic
dehiscence of any anastomosis or (2) postoperative pan-
creatitis that had been present for more than 10 days and
(3) hypersensitivity to paracetamol.
Patients were randomized preoperatively to undergo
either antecolic or retrocolic reconstruction of the duode-
nojejunostomy after the resection. The surgical procedure
and postoperative management were conducted according
to standard operating procedures of the MUV. On POD 10,
patients received a test meal consisting of 200 ml Fresubin
Protein Energy� (Fresenius Kabi, Graz, Austria), 50 ml
cream (36 % fat), and 1 g paracetamol (Ratiopharm Arz-
neimittel Vertriebs-GmbH, Vienna, Austria) according to a
protocol described by Strommer et al. [19]. This 250-ml
liquid meal was composed of 26.5 g carbohydrates, 21.1 g
proteins, and 31.4 g fat. It contained a total of 472 kcal. If
patients were discharged before POD 10, the meal was
administered at the day of discharge. Patients were fasted
overnight and received the test meal instead of breakfast on
POD 10. They were not allowed to take metoclopramide or
erythromycin before the meal for a period of 12 h. In case
of nausea, intravenous ondansetron was administered. All
patients were able to drink the meal within 5 min. Patients
remained sitting in bed and were not allowed to take
anything per mouth throughout the measurement period.
Blood samples were obtained before and 15, 30, 60, and
90 min after the meal. After that, patients resumed their
respective diet as planned for that day.
On POD 10, clinical parameters were observed and
recorded, including the type of diet, day of first full diet,
days of nasogastric tube (NGT) decompression, reinsertion
of an NGT, daily and total output of the NGT, and utili-
zation of prokinetic drugs (metoclopramide and erythro-
mycin). Data were recorded for up to 90 days after surgery
regarding the hospital length of stay (LOS), postoperative
complications, and mortality after discharge. Complica-
tions were graded using the Clavien-Dindo [23] staging
system. Other data acquired were demographic variables,
such as sex and date of birth, operating surgeon, histology
of removed specimen, and operating room LOS.
466 World J Surg (2014) 38:465–475
123
Surgery and postoperative care
After completion of the pancreaticoduodenectomy, the
reconstruction was performed as follows: The first jejunal
loop was brought up through a separate incision in the
transverse mesocolon usually to the right to the middle colic
vein. An end-to-side pancreaticojejunostomy was performed
in a single-layer fashion with 5-0 PDS-II� sutures (John-
son&Johnson Medical Products GmbH, Vienna, Austria).
The bile duct was then anastomosed end-to-side to the same
loop of jejunum with one layer of 5-0 PDS-II�. The stapled
duodenal remnant (usually 1–3 cm) was reopened, and the
pylorus was dilated with a blunt clamp from the luminal side.
Either antecolic or retrocolic end-to-side duodenojejunos-
tomy was then performed according to the randomization. A
single-layer anastomosis was performed, with the type of
suture and technique used (interrupted vs. running) at the
discretion of the operating surgeon. Silicone drains were
placed at the site of the pancreatic and bile duct anastomosis
and were managed as described below.
After surgery, patients typically recovered in the inten-
sive care unit overnight and were transferred to the floor on
POD 1. Patients received antibiotics only perioperatively.
They were not given somatostatin or prokinetics (meto-
clopramide and erythromycin) postoperatively on a routine
basis. Clear liquids were started on POD 1, and the diet was
advanced as tolerated by the patient. The NGT was
removed in the operating room and was reinserted only in
case of repeated vomiting or abdominal distension and the
inability to ingest food. Amylase and lipase were measured
in the drainage fluid on POD 5. If one of those levels
(amylase or lipase) was elevated, the drains remained in
place regardless of output. Serial measurements of pan-
creatic enzymes were performed at the discretion of the
treating surgeon, and the drains were removed if there was
no evidence of fistula.
Laboratory tests
Paracetamol plasma levels
For the paracetamol measurements, 5 ml of blood was
drawn into heparin-coated collection tubes (Vacutainer;
Becton–Dickinson Austria, Schwechat, Austria) at the
indicated time points. Paracetamol levels were measured as
described in an earlier study [24] (available upon request).
GLP-1 and PYY (3–36) plasma levels For the GLP-1 and
PYY (3–36) measurements, 4 ml of blood was drawn into
collection tubes containing 15 % K-EDTA and 250 kIU
aprotinin (Vacutainer) at the indicated time points, which
were placed on ice immediately. After centrifugation at
2,200 g for 10 min, plasma samples were aliquoted and
stored at -80 �C for later analysis. The methods to
measure plasma concentrations of GLP-1 and PYY (3–36)
have been described elsewhere in detail [25] (available
upon request).
Primary endpoint
The primary endpoint of this study was delayed gastric
emptying as defined by clinical criteria on POD 10. DGE is
defined as the NGT remaining in place beyond POD 10 and
one of the following criteria: (1) emesis after NGT
removal; (2) NGT reinsertion; (3) failure to progress with
the diet; (4) use of prokinetics after POD 10. If the NGT
was removed before day 10, two of the previous criteria
had to be fulfilled to qualify for DGE to be present.
Secondary endpoints
Secondary endpoints for this study included evaluation and
results of the following: (1) gastric emptying determined
by the paracetamol absorption test; (2) the kinetics of
intestinal peptides (GLP-1 and PYY) after ingestion of a
test meal; (3) postoperative LOS; (4) morbidity and
mortality.
Statistics and sample size calculation
The hypothesis was that antecolic reconstruction of the
duodenojejunostomy decreased the incidence of DGE after
PPPD. Based on the single prospective trial on this topic
that was available during our study designing [6], we
estimated the rate of DGE in the control arm (retrocolic) at
50 %, whereas the rate of DGE in the antecolic arm was
estimated at 10 %. We arrived at these figures because the
reported 5 % in the former reported trial was lower than in
all but one of the previous retrospective series [5]. With a
power of 80 % and a two-sided alpha of 0.05, we calcu-
lated that we required 20 patients per arm to demonstrate a
clinical significant difference. It was planned to accrue
patients for this protocol until 40 patients had undergone
the paracetamol test. However, because of the high post-
operative dropout rate we decided to analyze the entire
cohort on an intention-to-treat basis and reported the results
of the biochemical analyses as a subcohort. Randomization
was conducted prior to surgery, patients with an uneven
birth date (e.g., February 1) were allocated to the antecolic
arm. Patients who had an even birth date were treated with
retrocolic reconstruction.
SPSS 17.0 solftware (SPSS, Chicago, IL, USA) was
used for statistical analyses. Continuous data are repre-
sented as the median and interquartile range unless other-
wise indicated and were compared using Student’s t test.
For dichotomous variables, a v2 test was used. To compare
levels of paracetamol or intestinal peptides, the area under
World J Surg (2014) 38:465–475 467
123
the curve (AUC) was calculated and was used as a con-
tinuous variable to compare between groups. A value of
p \ 0.05 was considered to indicate significance in all
analyses.
Results
Patient recruitment
Between April 2007 and November 2009, a total of 82
patients who were scheduled to undergo PPPD at the
Department of Surgery at the Vienna General Hospital
were assessed for this study (Fig. 1). Among them, 71 were
randomized to undergo reconstruction using either ante-
colic (n = 38) or retrocolic (n = 33) duodenojejunostomy.
Two and three patients, respectively, in the antecolic and
retrocolic groups were not operated on according to pro-
tocol because the attending surgeon thought that the
randomized reconstruction method was technically not
feasible or was not possible for anatomic reasons (n = 2,
retrocolic group). Hence, 36 patients underwent the allo-
cated intervention in the antecolic group and 28 patients in
the retrocolic group. On POD 10, DGE was assessed
according to clinical criteria. However, two patients in each
group could not be evaluated owing to early discharge,
leaving 34 patients in the antecolic and 26 patients in the
retrocolic group for clinical analysis of DGE.
A test meal including a paracetamol absorption test was
conducted on or around POD 10. A significant number of
patients (eight in the antecolic group, six in the retrocolic
group) withdrew consent for this test meal at the day of
intervention. In six patients it was due to inability to ingest
the meal (n = 2), technical issues (n = 3), or other reasons
(n = 1). In all, 22 patients in the antecolic group and 18
patients in the retrocolic group underwent the test meal and
paracetamol absorption test. Two samples could not be
processed because of logistic reasons and one sample did
Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) flow chart of all screened and randomized patients. DGE delayed gastric
emptying
468 World J Surg (2014) 38:465–475
123
not have enough blood for analysis, Thus, 21 (antecolic)
and 16 (retrocolic) patient samples were available for
measurement of plasma intestinal peptides. These numbers
are summarized in Fig. 1.
Patient characteristics
Demographic and tumor-specific details according to the
reconstruction method are presented in Table 1. Age, sex,
and operation duration were similarly distributed between
groups. A nonsignificant trend of more patients (20 vs. 13)
with ductal adenocarcinoma was observed in the antecolic
group.
Primary endpoint
At POD 10, six patients in the antecolic group (17.6 %) and
six in the retrocolic group (23.1 %) had clinically evident
DGE (p = 0.628). There was no difference in the absolute
number of patients requiring NGT reinsertion (seven in each
group). The duration of decompression and the median daily
and total NGT output were similar in the two groups. Patients
in the antecolic arm resumed a regular diet at POD 5 (med-
ian), similar to patients in the retrocolic reconstruction arm.
There was no difference in administration of prokinetic
drugs between the two groups (Table 2).
Secondary endpoints
Eighteen (52.9 %) patients in the antecolic group devel-
oped some kind of postoperative complication compared to
13 (50.0 %) of patients in the retrocolic group (p = 0.777).
The nature and grading of complications is summarized in
Table 2. One patient in each group died within 90 days
after the operation. The median postoperative LOS was
also not different between the treatment groups (Table 2).
The characteristics of patients with DGE (n = 12)
compared to patients without DGE (n = 48) are depicted
In Table 3. Patients with DGE had more complications
than patients without DGE (12 vs. 19, p \ 0.001), although
there was no specific pattern of these complications. The
median hospital LOS was 17.5 days in patients with DGE
compared to 12.0 days in patients without DGE. As
expected, the DGE patients resumed their regular diet later,
received prokinetics longer, and had more days of NGT
decompression than patients without DGE.
Paracetamol absorption test and plasma levels
of intestinal peptides as surrogate parameters for DGE
A test meal also containing 1 g paracetamol was admin-
istered on POD 10 (see Methods). Paracetamol levels were
measured at baseline and 15, 30, 60, and 90 min after
ingestion of the meal. Patients with DGE had less uptake of
paracetamol, which indicates that the drug remained longer
in the stomach since paracetamol is solely absorbed in the
jejunum. At any time point after ingestion of the test meal,
the paracetamol levels were lower in patients with DGE
(Fig. 2a). The AUC in the group of patients with DGE was
lower than that in patients without DGE. The maximum
concentration of paracetamol was reached later when DGE
was present.
With respect to the reconstruction method, there was no
difference in the uptake or plasma levels of paracetamol.
The plasma levels were similar if compared at individual
time points, and the AUCs in the antecolic and retrocolic
groups were not different. A similar trend was observed for
GLP-1, which is secreted by intestinal L-cells when
nutrients reach the upper jejunum. Patients with DGE had a
slower rise of plasma levels and a lower AUC than patients
with no clinical evidence of DGE (Fig. 2b). There was no
difference in GLP-1 levels with regard to treatment groups.
Table 1 Patient characteristics
according to groups
IQR interquartile range, IPMN
intraductal papillary mucinous
neoplasm, SCN/MCN serous/
mucinous cystic neoplasm
* The p values are derived from
the v2 test for categoric
variables and from Student’s
t-test for continuous variables
Characteristic Antecolic group (n = 36) Retrocolic group (n = 28) p*
Age (years), median and IQR 67.1 (55.7–75.3) 65.4 (55.6–70.6) 0.688
Sex (M/F) 17/19 12/16 0.803
Histology: malignant/benign 28/8 20/8 0.561
Pathology
Ductal adenocarcinoma 20 13 0.267
Distal cholangiocarcinoma 1 1
Ampullary cancer 4 5
IPMN 2 0
SCN/MCN 1 1
Chronic pancreatitis 5 7
Other 3 1
Surgery duration (min), median
and IQR
273 (245–300) 280 (243–340) 0.970
World J Surg (2014) 38:465–475 469
123
For PYY, the AUC in patients with DGE was slightly
lower than in patients without DGE, but the difference did
not reach statistical significance (p = 0.060) (Fig. 2c). The
AUC for PYY was similar in the antecolic and retrocolic
groups. These findings are summarized in Table 4.
Discussion
We report the outcomes of a prospective study investigat-
ing the effect of antecolic versus retrocolic reconstruction
on the incidence of DGE in patients who underwent PPPD.
In contrast to the existing literature [5–9], we did not find a
difference between these groups (Table 5). Furthermore,
we performed a paracetamol absorption test and measured
plasma levels of intestinal peptides, which confirmed these
findings.
So far, one well-designed RCT from Japan has investi-
gated this topic and found a relevant improvement of DGE
in patients with antecolic reconstruction (5 vs. 50 % in the
retrocolic group). Some of the findings of their study,
however, limit applicability to our patients [6]. First, their
study had to be stopped early because of the extensive
benefit in the intervention group that ethically would not
allow proceeding with treatment in the control group. This
observed difference could also be due to temporary fluc-
tuations, which would have leveled out more during the
course of the trial. Second, the median postoperative stay in
Table 2 Parameters of delayed gastric emptying and postoperative morbidity according to treatment arms
Parameter Antecolic group (n = 34) Retrocolic group (n = 26) p
Section A: generala
No. of patients requiring
NGT
7 (20.6 %) 7 (26.9 %) 0.788
NGT (days) 4 (3–7) 3 (3–5) 0.600
Daily retention (ml) 474 (42–1,366) 800 (0–1,936) 0.482
Median total retention
(ml)
2,370 (300–4,100) 1,050 (0–5,810) 0.650
Section B: with vs.
without NGTaAll patients Patients with
NGT
Patients without
NGT
All patients Patients with
NGT
Patients without
NGT
p*
Regular diet resumed
(POD)
5 (5–7) 8 (3–8) 5 (4–6) 5 (4–6) 5 (5–13) 5 (4–6) 0.353**
Metoclopramide (days) 0 (0–3) 6 (3–10) 0 (0–1) 2 (0–3) 5 (3–7) 0 (0–3) 0.269**
Erythromycin (days) 0 0 (0–6) 0 0 0 (0–2) 0 0.576**
Hospital LOS (days) 13 (10.5–17.5) 17 (11–29) 12 (9–15) 12.5 (11–17) 17 (12–20) 12 (10.5–15.0) 0.446**
Section C: postoperative complications
Any complications 18 (52.9 %) 13 (50.0 %) 0.777
Grade I 2 (5.9 %) 1 (3.8 %)
Grade II 11 (32.3 %) 8 (30.8 %)
Grade III 4 (11.8 %) 3 (11.5 %)
Grade IV 0 0
Grade V 1 (2.9 %) 1 (3.8 %)
Delayed gastric
emptying
6 (17.6 %) 6 (23.1 %) 0.628
Bile leak 2 (5.9 %) 2 (7.7 %) 0.593
Pancreatic fistula 5 (14.7 %) 4 (15.4 %) 0.629
Intraabdominal abscess 2 (5.9 %) 2 (7.7 %) 0.491
Infection 7 (20.6 %) 1 (3.8 %) 0.157
Bleeding 2 (5.9 %) 1 (3.8 %) 0.552
Ileus 2 (5.9 %) 0 0.138
Other 1 (2.9 %) 1 (3.8 %) 0.420
Two patients in each group were not amenable for analysis of postoperative outcome (see Fig. 1)
NGT nasogastric tube, IQR interquartile range, POD postoperative day, LOS length of staya Unless otherwise stated, the results are expressed as the median and the interquartile range (IQR)
* The p values were derived from v2 test for categoric variables and from Student’s t-test for continuous variables
** These p values apply to the comparison of all patients
470 World J Surg (2014) 38:465–475
123
the antecolic group was 28 days compared to 48 days in
the retrocolic group, a number that is more than double the
reported average hospital stay after PPPD in Europe [5]
and even more if compared to that in the United States
[26].
Other studies dealing with this topic include the series of
Hartel et al. [5], who analyzed 100 patients between 1996
and 2001 while practicing in Bern, when retrocolic
reconstruction was always performed. They compared their
findings to a cohort of 100 patients with antecolic recon-
struction treated by the same surgeons in Heidelberg
between 2002 and 2003. They found an improvement in
their DGE rates from 24 to 5 % and concluded that this
difference was due to the antecolic reconstruction method.
It is, however, difficult to dissect all those differences in
perioperative management between two centers in two
Table 3 Postoperative
parameters in relation to
delayed gastric emptying
Unless otherwise stated, the
results are expressed as the
median and the interquartile
range (IQR)
Some patients had more than
one complication
DGE delayed gastric emptying
* The p values are derived from
the v2 test for categoric
variables and from Student’s
t-test for continuous variables
Parameter DGE according to clinical criteria p*
Yes (n = 12) No (n = 48)
NGT (days) 4 (3–7) 0 \0.001
Daily retention (ml) 887 (42–1,936) 0 \0.001
Total retention (ml) 2,875 (300–4,250) 0 \0.001
Regular diet resumed (POD) 8 (5–10) 5 (4–6) 0.003
Metoclopramide (days) 6 (3–10) 0 (0–3) \0.001
Erythromycin (days) 0 (0–6) 0 \0.001
Hospital LOS (days) 17.5 (13.5–25.0) 12 (10.5–15.5) 0.003
Postoperative complications (no.)
Any 12 19 \0.001
Bile leak 0 4 0.321
Pancreatic fistula 3 6 0.227
Intraabdominal abscess 2 2 0.085
Infection 2 6 0.108
Bleeding 1 2 0.090
Ileus 1 1 0.100
Other 1 1 0.465
Fig. 2 Plasma levels of paracetamol (a), glucagon-like peptide-1 (b),
and peptide YY (3–36) (c) according to the reconstruction group (top
panels) and to patients with or without delayed gastric emptying after
pylorus-preserving pancreaticoduodenectomy (bottom panels). Val-
ues are the means. Error bars represent the standard error of the mean
World J Surg (2014) 38:465–475 471
123
countries, let alone the effect of the learning curve, the case
load (100 PPPDs in 6 vs. 2 years), the difference in med-
ical complications (17 vs. 8 %, p = 0.054), and so on. The
rest of the relevant literature comprises retrospective
studies with sometimes exceedingly high rates of DGE (up
to 70 and 80 %) [7–9].
Table 4 Plasma levels of paracetamol, GLP-1, and PYY after the test meal on POD 10
Parameter Reconstruction method p* Delayed gastric emptying p*
Antecolic (n = 22) Retrocolic (n = 18) Yes (n = 8) No (n = 32)
Paracetamol
Level (lmol/l)
Baseline 0.14 (0–0.60) 0.20 (0–0.88) 0.267 0.13 (0–0.38) 0.14 (0–0.61) 0.325
15 min 2.33 (0.69–5.72) 1.98 (1.37–2.80) 0.757 1.10 (0.53–2.28) 2.33 (1.37–6.50) 0.002
30 min 2.20 (1.73–6.55) 3.85 (2.19–5.30) 0.779 2.38 (0.51–3.00) 4.26 (1.75–6.60) 0.006
60 min 3.20 (2.56–6.00) 3.92 (2.30–5.40) 0.943 2.83 (1.30–3.75) 3.77 (2.70–6.53) 0.025
90 min 3.57 (2.25–6.72) 4.15 (3.00–5.70) 0.508 3.08 (1.94–4.39) 4.02 (2.94–6.80) 0.043
AUCa 13.24 (7.01–27.78) 16.13 (11.28–23.0) 0.827 10.53 (6.50–16.13) 18.0 (10.04–29.37) 0.004
Cmax
At 15 min 3/22 5/18 0/8 8/32
At 30 min 4/22 3/18 1/8 6/32
At or after 60 min 15/22 10/18 7/8 18/32
GLP-1
Level (pmol/l)
Baseline 16 (11–25) 11.5 (7.5–27.5) 0.795 11 (5–25) 15 (10–26) 0.352
15 min 36 (18–91) 31.5 (13–61.5) 0.275 21 (13–42) 44 (17–91) 0.008
30 min 62 (20–187) 49.5 (22–82) 0.296 21 (11–55) 60 (24–187) 0.001
60 min 37 (22–68) 30 (17.5–59.0) 0.401 30 (10–49) 35.5 (24–68) 0.034
90 min 30 (22–54) 42 (19.5–70) 0.955 27 (13–54) 37.5 (23–70) 0.131
AUCb 5.69 (1.29–21.12) 3.62 (1.34–11.41) 0.240 1.26 (0.68–9.07) 6.62 (2.54–23.97) 0.006
Cmax
At 15 min 9/20 5/16 1/6 13/30
At 30 min 7/20 6/16 1/6 12/30
At or after 60 min 4/20 5/16 4/6 5/30
PYY
Level (pg/ml)
Baseline 40 (30–64) 30 (30–43) 0.288 30 (30–43) 36 (30–61) 0.155
15 min 57 (30–82) 37 (30–52) 0.209 45 (30–71) 50 (30–75) 0.333
30 min 56 (37–112) 49 (35–67) 0.268 49 (38–58) 52 (35–110) 0.014
60 min 66 (48–124) 51 (40–85) 0.109 63 (48–64) 65 (40–118) 0.073
90 min 72 (36.0–119.5) 51.5 (43–84) 0.216 53.5 (45–57) 64 (34–111) 0.063
AUCb 15.58 (6.65–39.08) 6.96 (3.60–14.147) 0.226 6.54 (6.52–10.29) 14.17 (3.63–7.74) 0.060
Cmax
At or before 30 min 5/19 8/15 3/7 10/27
At 60 min 9/19 5/15 3/7 11/27
At 90 min 5/19 2/15 1/7 6/27
The results are expressed as the median and the interquartile range (IQR) except for Cmas, which are absolute numbers
GLP-1 glucagon-like peptide-1, PYY peptide YY (3–36), AUC area under the curve, Cmax maximum serum concentration reached at the
indicated time pointa Arbitrary unitsb Arbitrary units 910-3
* The p values are derived from Student’s t-test for comparison of continuous variables
472 World J Surg (2014) 38:465–475
123
During the final analyses for our study, a group from
India published the results of an RCT with similar design
[15]. It did not show any influence of the gastroenteric
anastomosis with regard to DGE. Their trial, however, also
included patients who underwent a classic Whipple pro-
cedure, so the impact on patients with an intact pylorus
after PD was still unclear.
The current study was conducted at a single center and
87 % of the procedures were performed or assisted by a
single surgeon (P.G.). Although the randomization method
was simple and did not balance for any potential differ-
ences, the two treatment groups were homogeneously dis-
tributed and did not show any evident differences in
preoperative or intraoperative properties. The difference in
the final number of patients in the two arms is explained by
patients dropping out of the trial after being screened for
eligibility. One way to overcome this issue would have
been to blind patients to the intervention, which we did not
plan to do when we assembled this study.
The addition of the functional test of paracetamol
absorption and measurement of intestinal peptide plasma
levels further strengthened our observations, although they
were not standardized and ubiquitously available tests [16,
19]. We decided not to perform an invasive test such as
scintigraphy [13] because we thought that it was not feasible
in our patients. We anticipated that such a test could decrease
compliance and that we would not be able to accrue enough
patients for this protocol. In fact, even with this noninvasive
intervention we used for this study, eight and six patients,
respectively, withdrew consent for the test meal around POD
10. The plasma paracetamol concentration after the test meal
closely mirrored our clinical impression of DGE in this patient
population. However, we found that the interpretation of the
paracetamol uptake test did not have a better predictive value
in the individual patient. Prolonged LOS was better estimated
with clinical criteria for DGE (data not shown).
The biology of intestinal peptides such as GLP-1 and
PYY (3-36) is complex, and many physiologic effects and
interactions have been described [22, 27]. Therefore, we
decided not to interpret any of our baseline findings based
on their plasma levels because there is little evidence about
their meaning after PPPD. We chose to use only the time
course of GLP-1 and PYY concentration as a surrogate for
passage of nutrients to the proximal and distal intestine,
respectively [19]. A sampling period longer than 90 min
would probably have been more appropriate for better
understanding the PYY levels. Similar to other studies [20,
21, 28], the early GLP-1 peak correlated well with the
clinical impression of gastric emptying. The authors are
aware, however, that this is just an indirect indicator and
cannot replace an imaging study.
A limitation of this trial could be that it was finally
underpowered to assess the observed difference of only
5 % in DGE between groups. Although we chose the
numbers for our sample size calculation based on the
available literature at the time, the estimated improvement
in DGE by the operative intervention was too high. The
incidence of DGE was six patients in each group, or 17.6
and 23.1 %, respectively. For this absolute difference of
5.5 % we would now calculate a sample size of 840
patients for each arm, a number that would not enable us to
perform this trial reasonably. There is a risk that the results
presented here are related to a type II error as the number
of patients who were eventually evaluable for the primary
endpoint was too small to draw definitive conclusions.
Even on an intention-to-treat basis analysis (38 and 33
patients, respectively, in the two groups), there would have
to be at least 12 events in the retrocolic and 6 events in the
antecolic group in order to show a statistically significant
difference.
Another drawback of this study limiting future inter-
pretation is that the definition of DGE has since become
outdated because of the consensus definition proposed by
the International Study Group of Pancreatic Surgery
(ISGPS) published in November of 2007 [11]. We decided
in 2006 to use the definition of the Johns Hopkins group
Table 5 Series dealing with reconstruction of the duodenojejunostomy after PPPD
Study Region Study type Total patients
(antecolic/retrocolic)
DGE antecolic
(%)
DGE retrocolic
(%)
Tani [6] Japan RCT 20/20 5 50
Gangavatiker [15]a India RCT 32/36 34 28
Horstmann [9] Germany Retrospective 51/0 12 NA
Sugiyama [7] Japan Retrospective 12/18 8 72
Hartel [5] Germany Retrospective 100/100 5 24
Murakami [8] Japan Retrospective 78/54 10 81
Current series Austria Prospective 36/28 17.6 23.1
PPPD pylorus-preserving pancreaticoduodenectomy; RCT randomized controlled trial; NA not applicablea Includes patients with PPPD and a Whipple operation
World J Surg (2014) 38:465–475 473
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because we found it to be a well-published and very useful
way of evaluating DGE [10]. We identified 13 individuals
who qualified for the diagnosis of DGE using the ISGPS
definition, 13 patients with the NGT in place longer than
3 days, and 11 with failure to eat a regular diet after POD
7. In summary, we had 11 patients with grade A DGE, 1
patient with grade B DGE, and 1 with grade C DGE.
Because this definition of DGE was not designated in the
methods that were prospectively established, we did not
report these findings in the ‘‘Results’’ section. However,
this new definition seems to be applicable and is used
internationally [29, 30], so we wanted to report these data
at this point.
Conclusions
We have performed the first prospective trial in a Western
center regarding the effect of the duodenojejunal recon-
struction method on the incidence of postoperative DGE
after PPPD. We found no differences in the results regardless
of whether the duodenojejunostomy was performed via the
antecolic route or the retrocolic route. We confirmed the
clinical findings with a test meal performed on POD 10.
However, to truly and finally answer this question, a trial
with a noninferiority design is probably necessary, which is
of questionable feasibility in this setting.
Conflict of interest The authors do not disclose any potential
conflict of interest.
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