Journal of the Formosan Medical Association (2016) 115, 19e24

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ORIGINAL ARTICLE

Stress ulcer prophylaxis in patients being

weaned from the ventilator in a respiratory
care center: A randomized control trial
Chien-Chu Lin a,b, Yeong-Long Hsu b,c, Chen-Shuan Chung a,b,d,
Tzong-Hsi Lee a,b,*
a

Division of Gastroenterology and Hepatology, Far Eastern Memorial Hospital, New Taipei City, Taiwan
Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
c
Division of Thoracic Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
d
College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
b

Received 13 July 2014; received in revised form 20 October 2014; accepted 27 October 2014

KEYWORDS
lansoprazole OD;
proton pump
inhibitor;
respiratory care
center;
stress ulcer
prophylaxis;
weaning

Background/Purpose: No data has been available on prophylaxis for stress ulcer development
during the process of weaning patients off mechanical ventilators. We conducted a randomized
study to evaluate the efficacy of stress ulcer prophylaxis with lansoprazole OD in patients being
weaned from mechanical ventilators.
Methods: A total of 120 patients were randomly allocated into two groups using blocked
randomization, with 60 patients in each group. Group A was the treatment group, receiving
lansoprazole OD 30 mg from a nasogastric tube for 14 days, while Group B, the control group,
received no proton pump inhibitors or other medications for treating peptic ulcers. The primary end point of our study was apparent upper gastrointestinal bleeding within 2 weeks of
enrollment.
Results: Apparent upper gastrointestinal bleeding occurred in zero patients and five patients in
Groups A and B, respectively (Group A: 0% vs. Group B: 8.3%, p Z 0.057). There was no significant difference between the two groups in ventilator-associated pneumonia (Group A: 6.7%
vs. Group B: 10.0%, p Z 0.509) and 30-day survival rates (Group A: 96.7% vs. Group B: 100%,
p Z 0.496).
Conclusion: Stress ulcer prophylaxis with lansoprazole in patients being weaned from mechanical ventilators led to a lower but not statistically significant incidence of apparent upper
gastrointestinal bleeding. There was no significant increase of incidence of ventilator-

Conflicts of interest: The authors have no conflicts of interest relevant to this article.
* Corresponding author. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Far Eastern Memorial Hospital,
Number 21, Section 2, Nan-Ya South Road, Banciao District, New Taipei City 22060, Taiwan.
E-mail address: thleekimo@yahoo.com.tw (T.-H. Lee).
http://dx.doi.org/10.1016/j.jfma.2014.10.006
0929-6646/Copyright 2015, Formosan Medical Association. Published by Elsevier Taiwan LLC. All rights reserved.

20

C.-C. Lin et al.

associated pneumonia in the prophylaxis group. Further larger scale studies are needed to
clarify the benefit of stress ulcer prophylaxis in such patients.
Copyright 2015, Formosan Medical Association. Published by Elsevier Taiwan LLC. All rights
reserved.

Introduction
Stress ulcer prophylaxis (SUP) has been recommended for
the prevention of upper gastrointestinal (UGI) bleeding and
has become a standard of care in critical patients admitted
to the intensive care unit (ICU).1 Prolonged mechanical
ventilation for >48 hours and coagulopathy were two independent risk factors for gastrointestinal bleeding.2 Both
histamine-2 receptor antagonists (H2RAs) and proton pump
inhibitors (PPIs) are commonly used as antisecretory agents
in the treatment of acid-related disease in clinical practice.3,4 In previous studies, the H2RAs were the most
common agents used in SUP.5 In a recent meta-analysis,
H2RAs offered no advantage for stress ulcer prophylaxis
as compared to sucralfate in patients with mechanical
ventilation, but had the disadvantage of higher rates of
ventilator-associated pneumonia (VAP).6 PPIs have been
demonstrated to maintain better acid suppression than
H2RAs7 and have good prophylactic effects for stress ulcers.8 In a cost-effectiveness analysis, PPI prophylaxis
produced a more efficient prophylactic strategy for stress
ulcer bleeding (SUB) than H2RAs.9
In clinical practice, the weaning program has sometimes
been deferred due to UGI bleeding. During weaning from a
mechanical ventilator, the weaning process will increase the
oxygen cost of breathing10 and generate a major energy
demand to support the respiratory muscles.11 As an organ,
the gut is very sensitive to hypoxia.12e14 Gastric mucosal
acidosis and mucosal ischemia will develop when blood flow
is diverted from the splanchnic vasculature to other tissues,15,16 disturbing the defense mechanism of the gastric
mucosa. Therefore, stress ulcers may occur as a manifestation of focal mucosal ischemia17 during the weaning process.
SUP is commonly used in patients on a ventilator to
prevent SUB.18 However, no single strategy is preferred for
SUP when mortality is used as the outcome in such patients.5 In addition, medications for SUP in critically ill
patients, including those on a ventilator, are not routinely
recommended by the national insurance system in Taiwan.
No data is currently available on the incidence of SUB and
prophylaxis of stress ulcer development during the process
of weaning patients from mechanical ventilators. Therefore, we conducted this study to investigate the efficacy of
SUP and the incidence of VAP in patients being weaned
from mechanical ventilators in a respiratory care center.

Patients and methods

Study design
This study was a prospective, randomized, non double-blind
trial performed in a medical center, the Far Eastern

Memorial Hospital, in New Taipei City, Taiwan. The study

was designed in a respiratory care center using a weaning
program for those difficult to wean patients in the medical
or surgical ICUs. Patients who had received mechanical
ventilation for >48 hours, had undergone nasogastric (NG)
tube intubation, and were prepared to be weaned from the
ventilator were included. Patients who were pregnant, <18
years old, allergic to lansoprazole, having active UGI
bleeding, or receiving PPIs or H2RAs within 1 week were
excluded. Surgical tracheostomy should be performed after
11e14 days of mechanical ventilation.19 The study period
was defined as 2 weeks. The mechanical ventilation settings of the patients fulfilling the criteria for weaning were
as follows: SIMV (synchronized intermittent mandatory
ventilation) plus PSV (pressure support ventilation) mode,
respiration rate (f) 6/min, pressure support level
16 cmH2O, and tidal volume 5 mL/kg.

Patients
From June 1, 2009 to February 29, 2012, 758 patients were
admitted to the respiratory care center (RCC) due to difficulties being weaned off ventilators in the medical or
surgical ICUs, and 534 patients were excluded due to recent
use of PPIs, H2Ras, or death prior to enrollment. The
definition of difficult weaning was patients who were not
weaned off the mechanical ventilator 48e72 hours after
the resolution of their underlying disease process. Among
the 224 patients who started to be weaned and fulfilled the
enrollment criteria, 104 patients were excluded because
their families refused to sign the informed consent form.
Finally, 120 patients were enrolled in this study (Fig. 1).

Study procedures
After obtaining written consent from their families, the
patients were enrolled within 24 hours after beginning the
weaning from the ventilator. They were randomly allocated
into two groups using blocked randomization. Treatment
Group A was given lansoprazole OD 30 mg once daily
(takepron OD 30 mg/tab, TAKEDA Pharmaceutical Company, Ltd., Osaka, Japan) via NG tube for 14 days, while
control Group B received no PPIs or other medications for
treating peptic ulcers. We collected the following data: the
use of ulcerogenic medications [such as, nonsteroidal antiinflammatory drugs (NSAIDs), aspirin, steroids, and anticoagulants], comorbidities (including coronary artery disease,
recent cerebrovascular accident, chronic obstructive pulmonary disease, diabetes mellitus, hypertension, heart
failure, liver cirrhosis, uremia, and malignancy), histories
of recent operations, peptic ulcer disease and UGI
bleeding, initial APACHE II (Acute Physiology and Chronic
Health Evaluation II) scores in the medical or surgical ICUs,

Stress ulcer prophylaxis in RCC

Figure 1

21

Study protocol. H2-blocker Z histamine receptor-2 blocker; PPI: proton pump inhibitor; RCC Z respiratory care center.

GCS (Glasgow Coma Scale) scores in the RCC before

weaning (score of verbal response under endotracheal tube
was counted as 1), ventilator-dependent days prior to
starting the weaning process, as well as the baseline albumin and hemoglobin levels prior to weaning. We also
monitored the following data: the color of nasogastric (NG)
aspirate and stool every day; the weaning parameters; the
complete blood count; a chest X-ray; and, a stool occult
blood test every week and as needed. All patients received
bolus feeding from the NG tube. If there was clinical evidence of UGI bleeding, an endoscopy was performed after
an 8-hour fast. The protocol was approved by the Research
Ethics Review Committee of the Far Eastern Memorial
Hospital (ClinicalTrials.gov ID: NCT00708149).

Outcome measures
The primary end point of our study was apparent UGI
bleeding2,20 within 2 weeks of enrollment, which was
defined as follows: (1) a coffee ground substance from the
NG aspirate 60 mL; (2) fresh blood from the NG tube; or
(3) passage of tarry stool. Secondary end points included
clinically significant UGI bleeding2,20 (definition: UGI
bleeding with hemoglobin level decrease 2 gm/dL or in
need of a blood transfusion of >2 units), successful weaning
rate, ventilator-associated pneumonia (definition: clinical
pulmonary infection score21 >6, a scoring system composed
of body temperature, white blood cell count, purulent secretions, diffuse or localized pulmonary infiltrate in CXR,
progression of infiltrate, and culture of secretions), and a
30-day survival rate.

From 74% to 100% of critically ill patients showed evidence of mucosal damage within 24 hours of admission to
the ICU.22 The incidence of overt SUB was 4.0w5.7%.2,23,24
In an earlier study, 17% of the patients not receiving prophylactic therapy for stress ulceration reported apparent
bleeding.25 The reported incidence of stress ulcer bleeding
without prophylaxis was even as high as 45.5% in cases of
prolonged mechanical ventilation.26 In our previous study,
overt bleeding was reported at a rate of 3% in those
receiving proton pump inhibitors for prophylactic therapy
for stress ulceration in the medical ICU.27 Based on this
data, the bleeding rate was assumed to be 3% in Group A
and 20% in Group B. Consequently, about 55 patients were
required in each group to achieve a power of 0.8 at a significance level 0.05 to statistically assess the differences
between these two groups. We decided to enroll 60 patients in each group.

Statistical analysis
Quantitative data were presented as mean  standard deviation. A c2 test or Fishers exact test was used to examine
differences in gender, use of ulcerogenic medications,
histories of recent operations, peptic ulcer disease, and
UGI bleeding, while the ManneWhitney U test was used for
the other variables, including age, initial APACHE II score,
GCS score in the RCC, rapid shallow breathing index,
ventilator-dependent days, and baseline albumin and hemoglobin levels prior to weaning. Either a c2 test or Fishers
exact test was used to compare the primary and secondary
end points between these two groups. Univariate and

22

C.-C. Lin et al.

multivariate analysis were performed for all parameters of

baseline characteristics to find out possible significant differences of outcome under some specific conditions.

Table 2 Comparisons of primary and secondary outcomes

between two groups of patients.
Outcome evaluations Group A
(n Z 60)

Results
Table 1 shows the baseline characteristics of the 120 patients enrolled in this prospective study and randomized
into either Group A or Group B. There was no difference in
gender, age, and mean number of comorbidities between
the two groups. The use of ulcerogenic medications was
similar between the two groups. There was no significant
difference between the two groups in their GCS scores in
the RCC, initial APACHE II score in the medical or surgical
ICUs, ventilator-dependent days prior to starting to be
weaned, rapid shallow index (a weaning parameter), and
the baseline albumin and hemoglobin levels prior to
weaning.
Apparent UGI bleeding developed in zero patients and
five patients in Groups A and B, respectively (0% vs. 8.3%,
p Z 0.057). Clinically significant UGI bleeding developed in
zero patients and one patient in Groups A and B, respectively (0% vs. 1.7%, p Z 1.00; Table 2). Two of the five

Table 1 Distributions of baseline characteristics in two

groups of patients.
Baseline
characteristics

Group A
(n Z 60)

Male (%)
38 (63.3)
Age
66.7  16.8
Medicine with risk of ulcer bleeding
NSAID
6 (10.0)
Aspirin
6 (10.0)
Steroid
3 (5.0)
Anticoagulant
11 (18.3)
Comorbidities
1.78  1.26
Operation within
33 (55.0)
last
2 months
Peptic ulcer history 4 (6.7)
UGI bleeding history 1 (1.7)
APACHE II
21.3  6.7
GCS at RCC
9.2  3.0
Rapid shallow index 106.3  69.9
(breaths/min/L)
Hemoglobin (g/dL) 10.1  1.5
Albumin (gm/dL)
3.01  0.50
Ventilator15.8  7.9
dependent
days

Group B
(n Z 60)

p*

37 (67.2)
64.8  18.6

0.850
0.652

6 (10.0)
13 (21.7)
4 (6.7)
6 (10.0)
1.55  1.31
35 (58.3)

1.000
0.080
1.000
0.191
0.322
0.713

5 (8.3)
1 (1.7)
19.9  6.9
10.1  3.0
112.5  102.9

1.000
1.000
0.242
0.082
0.599

10.3  1.5
2.92  0.55
14.7  11.4

0.477
0.389
0.157

* Comparisons between two groups: c2 test or Fishers exact

test was used to examine the difference in gender, medication,
recent OP status, and peptic ulcer disease and UGI bleeding
histories, while the ManneWhitney U test was used for other
variables.
APACHE II Z Acute Physiology and Chronic Health Evaluation;
GCS Z Glasgow Coma Scale; NSAID Z non-steroidal antiinflammatory drugs; RCC Z respiratory intensive care center;
UGI Z upper gastrointestinal.

Apparent UGI
bleeding
Significant UGI
bleeding
Ventilatorassociated
pneumonia
Weaning success
rate
Survived after 30
days

Group B
(n Z 60)

p*

0 (0)

5 (8.3)

0.057

0 (0)

1 (1.7)

1.000

4 (6.7)

6 (10.0)

0.509

38 (63.3)

36 (60.0)

0.707

58 (96.7)

60 (100)

0.496

Data are presented as n (%).

*c2 test or Fishers exact test was used to compare the proportions of the two groups.
UGI Z upper gastrointestinal.

patients with apparent UGI bleeding in Group B received

UGI endoscopic examination. The endoscopic findings
showed hemorrhagic gastritis and reflux esophagitis in one
patient and gastric and duodenal erosions in another patient. The other three patients did not undergo endoscopic
examinations because their families denied permission,
receiving empirical PPI therapy instead.
The weaning success rate was similar between the two
groups (Group A: 63.3% vs. Group B: 60%, p Z 0.707). The
successful weaning rate without apparent UGI bleeding in
Group B was 63.6% (35/55). Only one patient (20%) in Group
B with apparent UGI bleeding was successfully weaned from
the ventilator. However, the difference did not reach statistical significance (p Z 0.147). There was no significant
difference between the two groups in ventilator-associated
pneumonia (Group A: 6.7% vs. Group B: 10.0%, p Z 0.509)
and 30-day survival rate (Group A: 96.7% vs. Group B: 100%,
p Z 0.496). In the univariate analysis, recent CVA was
associated with higher risk with OR of 7.0 (95% CI
1.04e46.95, p Z 0.045), and albumin was associated with
lower risk with OR of 0.05 (95% CI 0.01e0.49, p Z 0.01)/
every increment of 1 gm/dL for apparent UGI bleeding. In
the multivariate analysis, none of the parameters
mentioned in the method part was the independent risk
factor for apparent UGI bleeding.

Discussion
This prospective randomized trial is the first study of stress
ulcer prophylaxis in patients being weaned from mechanical ventilators. Our data revealed an 8.3% incidence of
apparent UGI bleeding in patients undergoing weaning
without prophylaxis. There was no apparent or clinically
significant UGI bleeding in our patients with prophylaxis
(0%). Although the difference did not reach statistical significance (p Z 0.057), it showed a lower incidence of
apparent UGI bleeding in our SUP patients weaning from
mechanical ventilators. The reported incidence of apparent
and clinically significant UGI bleeding without prophylaxis

Stress ulcer prophylaxis in RCC

in critically ill patients was up to 25% and 4%, respectively.17,22,24,28 Our study showed a lower rate of apparent
or clinically significant UGI bleeding in patients undergoing
weaning as compared to other critically ill patients. One
possible explanation is that those weaning patients were in
a relatively stable condition. From the results of univariate
analysis, recent CVA was associated with higher risk, and
albumin was associated with lower risk/every increment of
1 gm/dL for apparent UGI bleeding.
PPIs have been increasingly used for SUP in critical care
patients due to their ability to maintain good acid suppression.8,29 In a national survey, PPIs have been used as a
first line therapy in more than 25% of American hospitals.30
Lansoprazole OD provides effective acid suppression and
the tablets are soluble for use in tube feeding.31e33
Therefore, we chose it for SUP in our study. The cost is
also much cheaper than intravenous formulations. However, the reason for stress ulcer prophylaxis with lansoprazole
OD in patients being weaned from mechanical ventilators
was not statistically significant; incidence of apparent
upper gastrointestinal bleeding may be due to the efficacy
of oral PPI is low, partly due to the absorption. Concerns
have existed for decades as to whether gastric antisecretory therapy would lead to the development of nosocomial pneumonia.34 Some studies have shown an increased
risk in nosocomial pneumonia with PPI treatment for
SUP.35,36 However, a meta-analysis did not find a difference
in the risk of pneumonia between PPIs and H2RAs.37 In our
data, the incidence of ventilator-associated pneumonia did
not increase significantly in the SUP group.
Significant anemia (hemoglobin level  10 g/dL) is an
important factor in predicting weaning failure.38 UGI
bleeding may result in anemia and weaning failure due to
tissue hypoxia which may impair pulmonary gas exchange
and cause respiratory muscle pump failure.39,40 The successful weaning rate without apparent UGI bleeding in
Group B was 63.6% (35/55). However, only one patient
(20%) in Group B with apparent UGI bleeding successfully
weaned from a ventilator. That is compatible with our
previous observation that UGI bleeding sometimes interferes with the weaning process. Our study showed a
lower but not statistically significant weaning rate in the
Group B patients with apparent UGI bleeding than without
bleeding (20% vs. 63.6%, p Z 0.147). The weaning success
rate was not different between the two groups (Group A
63.3% vs. Group B 60%, p Z 0.707).
Several limitations in our study are worth noting: (1) the
study was a randomized, but not double-blind trial; (2) the
case number was still too small to draw a statistical
conclusion; (3) only two patients with apparent UGI
bleeding received endoscopic examinations. The etiologies
of another three patients with apparent UGI bleeding could
not be identified; (4) the study was performed in a single
referral center and therefore the results may not be
applicable to other hospitals; and (5) importantly, the
occurrence of apparent UGI bleeding (primary end-point)
was lower than the prespecified rate in the sample size
calculation (3% vs. 20%), underpowering the results of this
trial.
In conclusion, stress ulcer prophylaxis with oral PPIs in
patients weaning from mechanical ventilators leads to a
lower but not statistically significant incidence of apparent

23
UGI bleeding. There was no significant increase in the
incidence of ventilator-associated pneumonia in the prophylaxis group. Further larger scale studies are needed to
clarify the benefit of stress ulcer prophylaxis in such
patients.

Acknowledgments
This study was supported by a grant from Far Eastern Memorial Hospital (FEMH) (FEMH-2008-C-043).

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