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doi:10.1111/j.1440-1746.2012.07191.x

GASTROENTEROLOGY

jgh_7191

1473..1479

Effect of intravenous proton pump inhibitor regimens

and timing of endoscopy on clinical outcomes of
peptic ulcer bleeding
Na Liu,*,1 Lili Liu,*,1 HongBo Zhang,* Prakash Chandra Gyawali, Dexin Zhang,* Liping Yao,*
Yan Yang,* KaiChun Wu,* Jie Ding* and DaiMing Fan*
*State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xian, China; and Division of
Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA

Key words
endoscopy, peptic ulcer, proton pump
inhibitor.
Accepted for publication 24 April 2012.
Correspondence
Dr Hongbo Zhang and Dr Daiming Fan, State
Key Laboratory of Cancer Biology, Xijing
Hospital of Digestive Diseases, Fourth
Military Medical University, Xian 710032,
Shanxi Province, China. Email:
zhanghb59@hotmail.com,
fandaim@fmmu.edu.cn
1

These two authors contributed equally to this

work.

Abstract
Background and Aim: The most effective schedule of proton pump inhibitor (PPI)
administration and the optimal timing of endoscopy in acute peptic ulcer bleeding remain
uncertain. The aim of this study was to determine the most efficient PPI regimen and
optimal timing of endoscopy.
Methods: Consecutive patients with suspected bleeding peptic ulcers were enrolled and
randomized to receive either a standard regimen or a high-dose intensive intravenous
regimen. Only patients with bleeding peptic ulcers diagnosed at initial endoscopy continued the study. High-risk patients received endoscopic hemostasis. The primary outcome
measure of recurrent bleeding was compared between the two dosage regimens and
between early and late endoscopy. Secondary outcome measures compared included need
for endoscopic treatment, blood transfusion, hospital stay, surgery and mortality.
Results: A total of 875 patients completed the study. Recurrent bleeding occurred in
11.0% in the standard regimen group, statistically higher than that in the intensive regimen
group (6.4%, P = 0.02). Mean units of blood transfused and duration of hospital stay were
also higher in the standard regimen group (P < 0.001 for each compared to intensive
regimen group). However, no significant differences were noted between the two groups in
the need for endoscopic hemostasis, need for surgery, and mortality. Recurrence of bleeding was similar between the early and late endoscopy groups. Units of blood transfused and
length of hospital stay were both significantly reduced with early endoscopy.
Conclusion: High-dose PPI infusion is more efficacious in reducing rebleeding rate, blood
transfusion requirements and hospital stay. Early endoscopy is safe and more effective than
late endoscopy.

Introduction
Peptic ulcer bleeding is the most serious complication of peptic
ulcer disease,1 with incidence in the general population ranging
from 19.4 to 79.0 per 100 000 per year in Europe.2 Peptic ulcer
bleeding is life threatening, and mortality has not improved from
78% in 4 decades. Furthermore, patients with peptic ulcer bleeding have significantly lower health-related quality of life compared
to the general population.3 Consequently, this complication incurs
significant costs to health-care systems and employers, estimated
to be as high as $5.7bn per year in the USA.4
In the past few years, advances in delivery of acid suppression
and timing of endoscopy have improved the management of peptic
ulcer bleeding. Several studies have demonstrated the effectiveness of the combination of early endoscopy and pharmacologic
treatment with a proton pump inhibitor (PPI); these therapies

reduce the need for surgical intervention and blood transfusion,

and thereby reduce the cost of management of acute peptic ulcer
57
bleeding. However, the optimal regimen for PPI administration
and optimal timing of endoscopic intervention still remain
unclear8,9 and defining these issues will have important cost-saving
implications for health-care systems.
In this prospective study, we compared the clinical effectiveness
of two different intravenous PPI dosing regimens head-to-head;
further, we assessed the effects of the timing of endoscopy in the
outcome of patients with acute peptic ulcer bleeding.

Methods
Study design. This is a randomized, single-center, prospective, double blind study conducted in a busy tertiary teaching

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hospital. Consecutive patients with suspected acute peptic ulcer

bleeding presenting to the Emergency Department of Xijing Hospital of Digestive Diseases over a 5-year period (May 2005May
2010) were eligible for study entry. The study protocol was
approved by the institutional review board at Xijing Hospital. All
study subjects gave written informed consent before study entry.
The study was conducted by the faculty of the institution, with no
industry support in the planning, design, and conduct of the trial or
in the analysis of study data.
Study patients. Consecutive adult patients (age 18 years)
presenting with overt gastrointestinal bleeding (hematemesis
and/or melena) from suspected peptic ulcers who visited the emergency department at Xijing Hospital of Digestive Diseases were
eligible to enter the trial. Inclusion into the study required a documentation of peptic ulcer at the index endoscopy. Exclusion criteria included malignant-appearing ulcers, bleeding from alternate
(non-ulcer) sources, severe comorbid conditions (including
advanced cardiac and pulmonary disease, chronic renal insufficiency), coagulopathy (platelet count < 100 000; international normalized ratio > 1.5), and need for continuous anticoagulation.10
Patients who were pregnant, in hemodynamic shock (systolic
blood pressure less than 90 mmHg), or with a known allergy to PPI
were also excluded. Offending medications were discontinued at
presentation in patients with bleeding ulcers associated with ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs).

Procedures. Patients without exclusion criteria were randomized to receive one of the following two PPI regimens at presentation: Group A: standard regimen, consisting of intravenous bolus
of 40 mg of PPI twice a day, with a continuous infusion of saline
for 72 h; and Group B: intensive regimen, consisting of 80 mg PPI
bolus at the outset, followed by a continuous infusion of 8 mg/h for
72 h. Investigators were provided with a computer-generated list
of random numbers and sealed envelopes were opened to reveal
the randomized regimen. As this study was not supported financially by a pharmaceutical company, individual investigators were
allowed to use either omeprazole or esomeprazole depending on
drug availability at our institution. From May 2005 to August
2008, omeprazole was the PPI that was exclusively used. After
August 2008 until the end of study, the intravenous formulation
available in our hospital was esomeprazole.
A diagnostic endoscopy was performed when the patient clinical status was deemed stable and the professional procedure team
available. According to the timing of endoscopy, the patients were
also divided into two groups: early endoscopy group, where endoscopy was performed within 24 h of presentation, and late endoscopy group, where endoscopy was performed from 2472 h after
presentation. Patients who had bleeding ulcers with high-risk stigmata (active bleeding, non-bleeding visible vessel or adherent clot;
Forrest Ia to IIb) at initial endoscopy received endoscopic
therapy.11 This included epinephrine injection (at a 1 : 5000 ratio
of epinephrine to normal saline), thermal therapy (electrocoagulation or argon plasma coagulation), and mechanical therapy with
clips. The actual method of endoscopic therapy used, alone or in
combination, was at the discretion of the treating endoscopist who
was well experienced with endoscopic hemostasis. Patients who
1474

had recurrent bleeding were offered a second attempt at endoscopic hemostasis. Surgery was used as a last resort for persistent
bleeding despite medical and endoscopic therapy.
After the initial 72 h, all patients were switched to oral PPI
therapy (20 mg twice daily) until discharge. Patients were followed until 180 days after randomization. Research nurses contacted patients or their families. Records of hospital readmissions
were obtained and verified through a regional computerized
hospital-record system. Endoscopists who performed endoscopic
procedures and physicians attending and treating study subjects
were blinded to the group assignments and therapies administered
in this study.
Outcomes. Our primary outcome of the study was the occurrence of rebleeding, confirmed at a repeat endoscopy. Criteria for
clinical suspicion of rebleeding were established a priori and
included at least one of the following signs after initial stabilization: decrease in blood pressure ( 100 mmHg), increase in pulse
rate ( 100 beats per min), decline in hemoglobin (> 2.0 g/dL), no
change in hemoglobin levels with red blood cell transfusions, and
reappearance of overt bleeding (new hematemesis or melena).
Patients with a clinical suspicion of rebleeding underwent a
second attempt at endoscopic hemostasis.10 Secondary outcomes
assessed included the need for endoscopic therapy at the first
endoscopic examination, number of instances of endoscopic
therapy, transfusion requirements, duration of hospital stay, need
for surgery, and mortality.
Statistical analysis. All patients who completed the study
were included in the analysis. Categorical data were expressed as
proportions (%), and continuous data as means standard deviation (SD). P-values for the primary end-point were obtained from
two-sided c2 Pearsons tests. For other P-values, the two-sample
t-test was used for continuous variables and Fishers exact test
used for discrete variables. All analyses were performed using spss
statistical software (Chicago, IL, USA).

Results
During the 5-year study period, a total of 1534 patients were
screened for inclusion; and 1092 patients were enrolled and
randomized. Of the randomized patients, 875 (age range,
3291 years) completed the study, while 217 patients (120 in the
standard regimen group and 97 in the intensive regimen group)
were excluded from analysis. Reasons for exclusion included 108
patients diagnosed with non-peptic ulcer bleeding, 90 lost to
follow up and 19 with protocol violations. Of the 875 patients
included in the analysis, 456 were randomly assigned to receive
the standard regimen (Group A) and 419 to receive the high-dose
intensive regimen (Group B) (Fig. 1). Demographics and clinical
characteristics were similar in the two groups (Table 1). Similar
proportions of patients underwent early and late endoscopy in the
two groups (Table 1). There were no significant differences
between the two groups with respect to hemoglobin levels at
admission, risk factors, ulcer location and size, previous ulcer
disease history and type of PPI administered. No drug-related
side-effects were noted in either group.

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N Liu et al.

Figure 1
study.

Table 1

Peptic ulcer bleeding

Flow chart of patients through the

Demographics and clinical characteristics of study patients

Characteristic

Standard regimen (n = 456)

Intensive regimen (n = 419)

P-value

Age (years)
Men n (%)
Hemoglobin (g/dL)
Risk factors n (%)
NSAID use
Corticosteroid use
Timing of endoscopy n (%)
Early ( 24 h)
Late (> 24 h)
Previous ulcer disease n (%)
Ulcer size 10 mm n (%)
Peptic ulcer as source of bleeding n (%)
Duodenal ulcer
Gastric ulcer
Type of PPI administered n (%)
Omeprazole
Esomeprazole

55.3 17.8
318 (69.7)
85.8 9.1

53.8 19.9
299 (71.3)
84.8 9.9

0.24
0.53
0.12

107 (23.5)
13 (2.9)

121 (28.9)
18 (4.3)

0.07
0.25

182
274
49
133

183
236
54
130

0.26

(39.9)
(60.1)
(10.7)
(29.2)

(45.2)
(54.8)
(12.9)
(31.0)

0.33
0.55

292 (64.0)
164 (36.0)

285 (68.0)
134 (32.0)

0.21

263 (57.7)
193 (42.3)

250 (59.7)
169 (40.3)

0.55

NSAID, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitor.

At the initial endoscopy, actively bleeding peptic ulcers were

observed at a similar frequency between the two treatment groups,
standard regimen versus intensive regimen (9.0% vs 9.5%,
P = 0.78) (Table 2). Further, proportions of ulcers with and
without stigmata of recent bleeding also did not differ significantly

between the two groups. Consequently, proportions of patients

undergoing endoscopic therapy were 29.8% (Group A, standard
regimen) and 25.5% (Group B, intensive regimen, P = 0.20).
These parameters were no different in between subgroups of early
and late endoscopy within the two treatment groups.

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Peptic ulcer bleeding

Table 2

N Liu et al.

Clinical outcomes compared by PPI regimen administered

Characteristic

Standard regimen
Group A (n = 456)

Forrest classification of endoscopic stigmata of hemorrhage n (%)

Iactive bleeding
IIanon-bleeding visible vessel
IIbadherent clot
IIcflat, pigmented spot
IIIclean base
Endoscopic therapy n (%)
Early endoscopic therapy
Late endoscopic therapy
Rebleeding n (%)
Early endoscopic examination
Late endoscopic examination
Number of endoscopic therapies n (%)
1
2
Rebleeding after endoscopic therapy n / total n received endoscopic therapy (%)
Early endoscopic therapy
Late endoscopic therapy
No. of units of blood transfused
Early endoscopic examination
Late endoscopic examination
Hospital stay (days)
Early endoscopic examination
Late endoscopic examination
Surgery n (%)
Death within 180 days n (%)

Recurrent bleeding as defined by study parameters occurred in

50 patients (11.0%) with the standard regimen (Group A), statistically higher than in the intensive regimen group (Group B, 27
patients, 6.4%, P = 0.02 compared to Group A). Subgroup analyses indicated that this difference was driven by patients who
received late endoscopy (P = 0.03). There was no benefit noted
from the intensive PPI regimen in patients who underwent early
endoscopy (P = 0.32). Repeat endoscopic therapy was performed
in 22 patients (4.8%) in Group A (standard regimen), significantly
higher than in Group B (eight patients, 1.9%, P = 0.02). Further
analysis demonstrated that among patients who needed repeat
endoscopic intervention, 22 patients (17, 3.7% in Group A, five,
1.2% in Group B, P = 0.03) had risk factors of NSAID and corticosteroid use for cardiovascular and autoimmune conditions.
Among patients who underwent endoscopic hemostasis, bleeding
recurred in 22 of 136 patients (16.2%) in Group A, as compared
with eight of 107 (7.5%) in Group B (P = 0.04). However, timing
of endoscopy (early vs late) did not impact rebleeding rates
between the two treatment groups.
The mean number of units of blood transfused was 1.93 2.12
in Group A and 1.23 2.13 in Group B (P < 0.001). Duration
of hospitalization was significantly longer in Group A
(9.4 5.7 days), compared with that in Group B (6.2 4.6 days,
P < 0.001). The benefit of intensive PPI regimen on these outcomes remained significant upon separate analysis of early and
late endoscopy subgroups. Nineteen patients (4.2%) in Group A
underwent surgery because of failure of endoscopic therapy,
1476

41
50
45
156
164
136
76
60
50
16
34

(9.0)
(11.0)
(9.9)
(32.0)
(36.0)
(29.8)
(16.7)
(13.2)
(11.0)
(3.5)
(7.5)

Intensive regimen
Group B (n = 419)

40
38
29
152
159
107
65
42
27
10
17

114 (25.0)
22 (4.8)
22/136 (16.2)
12 (8.8)
10 (7.4)
1.93 2.12
1.15 1.89
2.71 2.35
9.4 5.7
8.5 5.1
10.3 6.3
19 (4.2)
6 (1.3)

(9.5)
(9.1)
(6.9)
(36.3)
(37.9)
(25.5)
(15.9)
(10.0)
(6.4)
(2.4)
(4.0)

99 (23.6)
8 (1.9)
8/107 (7.5)
5 (4.7)
3 (2.8)
1.23 2.13
0.65 1.64
1.81 2.62
6.2 4.6
5.2 4.0
7.2 5.2
13 (3.1)
1 (0.2)

P-value

0.78
0.35
0.12
0.59
0.54
0.20
0.64
0.50
0.02
0.32
0.03
0.64
0.02
0.04
0.31
0.20
0.000
0.007
0.000
0.000
0.000
0.000
0.40
0.16

Table 3 Clinical outcomes according to the timing of endoscopy

examination
Characteristic

Early (n = 365)

Late (n = 510)

P-value

Rebleeding n (%)
Standard regimen
Intensive regimen
No. of units of blood
transfused
Standard regimen
Intensive regimen
Hospital stay (days)
Standard regimen
Intensive regimen

26 (7.1)
16 (4.4)
10 (2.7)
0.90 1.76

51 (10)
34 (6.7)
17 (3.3)
2.26 2.48

0.14
0.29
0.60
0.000

1.15 1.89
0.65 1.64
6.8 4.6
8.5 5.1
5.2 4.0

2.71 2.35
1.81 2.62
8.8 5.8
10.3 6.3
7.2 5.2

0.000
0.000
0.000
0.000
0.000

similar to that in Group B (13 [3.1%], P = 0.40). Six patients

(1.3%) in Group A and one patient (0.2%) in Group B died within
180 days after randomization (P = 0.16). All the patients who died
had history of NSAIDs or corticosteroids therapy.
We further compared the clinical outcomes of early versus late
endoscopy in our patient cohorts. There was no significant difference in recurrence of bleeding between the early and late endoscopy (7.1% vs 10.0%, P = 0.14) (Table 3). However, blood
transfusion (0.90 1.76 unit) was significantly lower in the early
endoscopy group, compared to the late endoscopy group
(2.26 2.48 unit, P < 0.001). Duration of hospital stay was sigJournal of Gastroenterology and Hepatology 27 (2012) 14731479

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N Liu et al.

nificantly shorter in the early endoscopy group (6.8 4.6 days vs

8.8 5.8 days, P < 0.001). Similar results were obtained from a
separate analysis of standard and intensive regimen subgroups
(Table 3). No serious endoscopic complications occurred in either
group during the study.

Discussion
In this prospective randomized study at a busy tertiary care center,
we demonstrated reductions in clinical rebleeding, transfusion
requirements, and hospital stay with PPI infusion regimen in acute
peptic ulcer bleeding, although need for endoscopic hemostasis,
surgery and mortality were not impacted. Further, early endoscopy
within the first 24 h of presentation provided demonstrable benefit
in blood transfusion requirements and hospital stay, regardless of
PPI regimen, but not rebleeding rates. Our results therefore
support the use of PPI infusions in patients with active peptic ulcer
bleeding in clinical practice.
Several clinical trials have demonstrated that pre-endoscopic
PPI treatment downstages endoscopic lesions and decreases the
need for endoscopic intervention, superior to placebo or a
histamine-2 receptor antagonist (H2RA).1215 A recent consensus
statement also recommends administration of PPI while the
patients with acute non-variceal upper gastrointestinal bleeding
are awaiting endoscopy (Grade: Moderate, 1b), but the optimal
dose is not clarified.16 One review on management of acute peptic
ulcer bleeding suggests a high-dose intensive regimen,11 but little
is known as to whether this high-dose regimen of PPI administration is more effective than a standard approach. In this study, we
found that a high-dose PPI strategy did not significantly reduce the
proportion of patients with actively bleeding peptic ulcers and the
need for endoscopic therapy as assessed at index endoscopy (performed early or late), compared to a standard regimen.
A recent Cochrane meta-analysis17,18 showed that PPI treatment
with or without endoscopic therapy significantly reduces rebleeding rates in patients with peptic ulcer bleeding compared with
H2RA or placebo, which is in agreement with other metaanalyses1921 and randomized controlled trials.2224 However, the
optimal dose of PPI treatment in the acute bleed setting remains a
controversial issue. Udd et al. report that a standard omeprazole
dose is as successful as a high-dose regimen in preventing peptic
ulcer rebleeding.25 This study involved 142 patients with acute
peptic ulcer bleeding (Forrest classification III) who were randomly assigned to receive the regular dose of omeprazole intravenously (20 mg once a day for 3 days) or a high dose of omeprazole
(80 mg bolus followed by 8 mg/h). Andriulli et al. also showed
that standard-dose PPI infusion was as effective as a high-dose
regimen in reducing the risk of recurrent bleeding following endoscopic hemostasis of bleeding ulcers.10 However, in a retrospective
study, Simon-Rudler and colleagues found that high-dose omeprazole reduced the occurrence of rebleeding, need for surgery and
mortality due to hemorrhagic shock in patients with high-risk
peptic ulcer bleeding, when compared to standard-dose omeprazole.26 Even the latest consensus16 and meta-analyses have not
resolved this highly debated issue.27 More powered clinical trials
are needed to define the minimum effective dose of PPI.
In our randomized comparative study, we found that rebleeding
rates were significantly higher with standard-dose PPI therapy
compared to the high-dose intensive regimen, but this difference

Peptic ulcer bleeding

was restricted to patients who were in the late endoscopy subgroup, where endoscopy was delayed over 24 h from presentation.
This suggests the special role of high-dose PPI infusion in situations wherein early endoscopy may be delayed or when available
endoscopic expertise may be suboptimal. The requirement for
repeated endoscopic therapy due to recurrent bleeding was also
reduced in those administered the high-dose regimen. On the contrary, in patients where endoscopic hemostasis was successful, the
rebleeding rate was similar between the two doses of intravenous
PPI therapy, which similar to that reported by Andriulli et al.10 We
also compared other clinical outcomes, including blood transfusion, duration of hospital stay, the need for surgery, and mortality
between the two groups in this study. High-dose intravenous PPI
administration significantly reduced blood transfusion and hospital stay compared with the standard regimen, but need for surgery
and mortality rates were not different in the two groups.
Endoscopy is firmly established as an effective treatment for
bleeding peptic ulcers, and is currently the standard of care.9,28,29 A
systematic review29 found that early endoscopy is safe and effective for patients in all risk groups. Despite this, the optimal timing
of endoscopy remains debated, with conflicting data in the literature. Cho et al. report that the effectiveness of interventional endoscopy in bleeding peptic ulcer disease is not significantly affected
by the timing of endoscopy.9 Moreover, there is indirect evidence
to suggest that early endoscopy may be associated with more
complications than delayed endoscopy.29 Further, early endoscopy
may not be practical or convenient in all instances. A nationwide
analysis conducted in the USA suggests that patients with nonvariceal upper gastrointestinal bleeding admitted on weekends are
less likely to undergo early endoscopy within 1 day of hospitalization.30 Similar findings have been reported from the UK,31 and
Korea9 and we attest to a similar approach in China. Therefore, we
thought it was appropriate and meaningful for us to assess the
clinical effectiveness of early versus delayed endoscopy, especially since evidence from China regarding this is scant. We
confirm the clear clinical benefit of early endoscopy in reducing
transfusion requirements and length of hospital stay; further, we
document that early endoscopy is safe. These results are in agreement with the recent consensus that early endoscopy (within 24 h
of presentation) is recommended for most patients with acute
upper gastrointestinal bleeding.16
We acknowledge there are some limitations in our study. First,
the PPI formulation used varied throughout the duration of the
study, for hospital formulary reasons that were beyond our control.
However, in our opinion, this likely has not affected the validity of
our findings, especially since subgroup analysis showed no difference in outcomes based on PPI formulation. Further, pharmacologic data in the literature indicate a class effect of PPI therapy in
inhibiting gastric secretion,10 with no evidence that any one PPI
was more efficacious than the others on meta-analysis.8 Second,
various different contemporary methods of endoscopic hemostasis
were used that were not standardized for the study, and were left to
the discretion of endoscopists. There is evidence in meta-analyses
that epinephrine injection alone is inferior to combined endoscopic
therapies.16,32 However, we felt that subgrouping according to the
precise technique of endoscopic intervention would make the
study results difficult to analyze. Also, our endoscopists were well
experienced with endoscopic hemostasis and we felt they had good
judgment to perform the most appropriate treatment. Third, not all

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patients underwent Helicobacter pylori testing, considering that in

the context of acute bleeding, tests for H. pylori may show high
false-negative rates16 and make the results unreliable. Another
limitation is that the early and late endoscopy groups were not
segregated by randomization, but instead allowed to follow clinical practice algorithms of the treating physicians. This could have
generated a selection bias, with more severe bleeding segregated to
the early endoscopy group. However, this represents current clinical practice, which the study was trying to emulate. Finally, the
trial was conducted in a single hospital in China, and a multicenter
trial would have strengthened our results. Currently, it is argued
that PPI therapy seems more efficacious in Asia,8 and therefore the
direct applicability of our results to wider geographic areas, such
as the USA and Europe, can be debated. Despite this, we feel our
findings add evidence for the applicability of consensus recommendations for effective management of peptic ulcer bleeding in
China. Further well-designed, multi-center trials are needed to
verify our results.
In conclusion, our study demonstrates that high-dose intravenous PPI therapy reduces rebleeding rates, blood transfusion
volume and hospital stay, especially when endoscopy is delayed
beyond 24 h of presentation; it does not alter the need for endoscopic treatment, need for surgery and mortality rates when compared to standard intravenous bolus dosing of PPI in acute peptic
ulcer bleeding. Further, our findings reaffirm the important role of
early endoscopy in management of acute peptic ulcer bleeding.

Acknowledgments
The authors would like to thank Professor Guo Xuegang, Professor
Sun Anhua, Chief Nurse Li Caining and other colleagues in Endoscopy Center of our hospital. We also thank the nurse team in our
ward for their excellent work.

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