Stress ulcer prophylaxis ASHP Report
A SHP REPORT
ASHP Therapeutic Guidelines on Stress Ulcer
Prophylaxis
DEVELOPED THROUGH THE ASHP COMMISSION ON THERAPEUTICS AND APPROVED BY THE ASHP BOARD OF DIRECTORS ON
NOVEMBER 14, 1998
Am J Health-Syst Pharm. 1999; 56:347-79
D espite the publication of more than 100 studies
of the frequency, risk factors, and prophylaxis of
stress ulcer bleeding, these subjects continue to
generate controversy. Several meta-analyses pertaining
to stress ulcer bleeding have been published, including
one designed to resolve the discordant results of the
others. Given the sheer volume of published informa-
tion, it is understandable that health care providers
experience frustration when confronting this topic.
Stress ulcers are superficial lesions commonly (but
not exclusively) involving the mucosal layer of the
stomach that appear after major stressful events such as
surgery and trauma.1 Endoscopic studies have found
gastroduodenal erosions (shallow ulcers) to be com-
mon in patients who have had such stressful events,
and these may lead to ulceration and bleeding.1 Micro-
scopic bleeding associated with gastroduodenal lesions
can be detected by occult blood testing (e.g., guaiac test)
in patients with gastric tubes.2 However, other factors
may influence the results of occult testing. Simply
placing tubes in the upper respiratory or GI tract may
injure the mucosa and result in microscopic or macro-
scopic (i.e., overt) bleeding. Because not all episodes of
microscopic bleeding are clinically relevant, studies
using only microscopic bleeding as an endpoint artifi-
cially inflate the reported frequency of GI bleeding.
The following professional organizations and persons submitted
comments on the draft document: the American Association of
Critical-Care Nurses; the American College of Chest Physicians;
the American College of Clinical Pharmacy; the American
Gastroenterological Association; Todd A. Armstrong, Pharm.D.,
BCPS, BCNSP; Douglas B. Coursin, M.D.; John Devlin, Pharm.D.,
BCPS; Jeanne Scott Duke; Douglas Fish, Pharm.D.; Edgar R.
Gonzalez, Pharm.D., FASHP; Emily B. Hak, Pharm.D.; Darrell
Heiselman, D.O.; Annie Herrington, Pharm.D.; Mary Hess,
Pharm.D.; Robert J. Kuhn, Pharm.D.; Marc Lapointe, Pharm.D.;
Robin L. Southwood, Pharm.D., BCPS; and Linda S. Welage,
Making clinical use of these inflated estimates has
patient care implications and cost implications, be-
cause stress ulcer prophylaxis adds to the number of
medications given and increases the risk and cost of
adverse reactions.3,4
It is important to determine the frequency of clini-
cally important bleeding due to stress-induced erosions
or ulcerations. Although endoscopy is a specific and
sensitive test for GI bleeding, it is an invasive and
expensive procedure. For endoscopy to be used as a
diagnostic tool, it would need to be repeated during the
period the patient remains at risk for clinically impor-
tant bleeding. Gastroduodenal bleeding associated
with clinically important complications, such as hemo-
dynamic compromise and the need for blood transfu-
sions or surgery, has been suggested in the literature as
a useful definition for clinically important bleeding.
This definition was used to evaluate the clinical trials in
order to develop these guidelines.5 The reported fre-
quency of clinically important bleeding has varied
widely, although the general perception is that the
frequency of stress-related bleeding has been decreas-
ing in recent years.6 Whether this decrease is related to
the use of stress ulcer prophylaxis medications, im-
provements in technology, or improvements in patient
care is not known, because a variety of factors (e.g., type
Pharm.D.
The bibliographic citation for this document is as follows:
American Society of Health-System Pharmacists. ASHP therapeu-
tic guidelines on stress ulcer prophylaxis. Am J Health-Syst Pharm.
1999; 56:347-79.
Index terms: American Society of Health-System Pharma-
cists; Antacids; Economics; Gastrointestinal drugs; Health profes-
sions; Organizations; Prostaglandin derivatives; Protocols; Ulcers
Copyright 1999, American Society of Health-System Phar-
macists, Inc. All rights reserved. 1079-2082/99/0202-0347$06.00.
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 347
ASHP Report Stress ulcer prophylaxis
ASHP Therapeutic Guidelines
on Stress Ulcer Prophylaxis
Project Coordinators
Brian L. Erstad, Pharm.D., FCCM, FASHP, BCPS
Associate Professor/Assistant Department Head
Department of Pharmacy Practice and Science
College of Pharmacy
University of Arizona
Tucson, AZ 85721
Kathryn L. Grant, Pharm.D., FASHP
Assistant Professor
Department of Pharmacy Practice and Science
College of Pharmacy
University of Arizona
Tucson, AZ 85721
Expert Panel
Bradley A. Boucher, Pharm.D., BCPS
Associate Professor and Director of Research
Department of Clinical Pharmacy
The University of Tennessee
Memphis, TN 38163
Jimmi Hatton, Pharm.D., BCNSP
Associate Professor of Pharmacy and Surgery
University of Kentucky Medical Center
Lexington, KY 40536
Judith Jacobi, Pharm.D., BCPS
Critical Care Clinical Pharmacist
Department of Pharmacy Services
Methodist Hospital of Indiana
Indianapolis, IN 46206
Rick Jones, Jr.
Manager, Strategic Development
Pharmacy Department
Orlando Regional Healthcare System
Orlando, FL 32806
Keith M. Olsen, Pharm.D., FCCP
Associate Professor of Pharmacy
College of Pharmacy
University of Nebraska Medical Center
Omaha, NE 68198
H. David Reines, M.D.
Professor of Surgery
Tufts University School of Medicine
Newton, MA 02162
Andrea Quinn Wilson, APRN, CETN, CS
Clinical Nurse Specialist
Yale New Haven Hospital
New Haven, CT 06504
ASHP Staff Liaison
Leslie Dotson Jaggers, Pharm.D., BCPS
Clinical Affairs Associate
ASHP
Bethesda, MD 20814
348 Am J Health-Syst Pharm Vol 56 Feb 15 1999
of resuscitative technique) may contribute to clinically
important stress-related bleeding.7
The presence of patient risk factors for clinically
important bleeding, not just admission to an intensive
care unit (ICU), should determine the need for stress
ulcer prophylaxis. The purpose of this document is to
help health care professionals to identify appropriate
candidates for stress ulcer prophylaxis and select cost-
effective modalities for prophylaxis when prophylaxis
is indicated. An economic evaluation has been provid-
ed that can be adapted to individual practice sites.
Scope
These guidelines pertain to stress-induced bleeding
associated with events such as trauma, surgery, and
acute organ failure. In general, they apply to the days
immediately after the stressful event, when endoge-
nous healing processes or exogenous manipulations by
health care professionals have yet to substantially im-
prove the underlying disease process. However, a pa-
tient may have resolution of the initial problem but
then have reactivation or initiation of a stressful event
that could precipitate stress-induced bleeding. These
are not unexpected occurrences in patients with ICU
stays of more than a few days and could lead to periodic
institution of prophylaxis to prevent bleeding.
The guidelines focus on agents that are used for
stress ulcer prophylaxis in the United States, whether or
not the agents have FDA-approved labeling for this
indication. A majority of studies have involved hista-
mine H2-receptor antagonists, antacids, or sucralfate,
and these agents are discussed in detail. Few controlled,
comparative studies have been conducted to assess the
efficacy of misoprostol or proton-pump inhibitors (e.g.,
lansoprazole, omeprazole) in preventing clinically im-
portant bleeding. The potential advantages and disad-
vantages of the latter medications for stress ulcer pro-
phylaxis are discussed.
The guidelines include information for patients in
all age groups for which there is literature. When age
groups are not specifically cited, the discussion refers to
the adult patient population. Few prospective, random-
ized studies in the pediatric population have been
published, particularly with regard to clinically impor-
tant bleeding. Where appropriate, the lack of age-spe-
cific data is specified. It is hoped that the guidelines will
stimulate research in these areas.
The guidelines are not intended to apply to the
prevention of bleeding associated with chronic diseases
or long-term medication use. However, the contribu-
tion of pre-existing diseases and the use of ulcerogenic
medications as aggravating risk factors for stress-in-
duced bleeding are considered appropriate issues for
review.
Guideline development and use
The ASHP Therapeutic Guidelines on Stress Ulcer

Prophylaxis were prepared by the University of Arizona
under contract to ASHP. The project was coordinated by
two pharmacy specialists, one with expertise in critical
care and the other with expertise in drug information,
who consulted with two physicians and a nurse special-
ist from the Arizona Health Sciences Center. The
project coordinators worked in conjunction with an
independent multidisciplinary panel of seven clinical
specialists (a surgeon, a nurse, and five pharmacists)
representing adult or pediatric critical care. The panel
was appointed by ASHP. Panel members and contrac-
tors were required to disclose any possible conflicts of
interest before their appointment. The guidelines un-
derwent multidisciplinary field review in order to eval-
uate their validity, reliability, and utility in clinical
practice. The final document was approved by the
ASHP Commission on Therapeutics and the ASHP
Board of Directors.
The recommendations in this document may not be
appropriate for use in all clinical situations.8 Decisions
to follow these recommendations must be based on the
professional judgment of the clinician and must take
into account individual patient circumstances and
available resources. These guidelines reflect current
knowledge (at the time of publication) on the use of
stress ulcer prophylaxis in critically ill patients. Given
the dynamic nature of scientific information and tech-
nology, periodic review, updating, and revision are to
be expected.
Literature search
Detailed and exhaustive literature searches of MED-
LINE from 1966 to 1997 and International Pharmaceu-
tical Abstracts (IPA) from 1970 to 1997 were performed.
The searches of the two databases were compared to
check for duplicates and were subsequently compared
with the references listed in a recent meta-analysis by
Cook et al.5 for completeness.
Ten key articles pertinent to stress ulcer prophylaxis
were identified and entered into MEDLINE to capture
appropriate MeSH headings. Applicable MeSH head-
ings were combined with relevant text words into five
sets. Set A1 combined terms for the condition to be
avoided in broad terms (e.g., peptic ulcer) by using the
subheadings prevention and control and complications. Set
A2 covered terms more specific to the condition being
treated (e.g., peptic ulcer hemorrhage) by using the
same subheadings. Set B included terms describing
patient location (e.g., intensive care) or condition (e.g.,
critical illness). Set C covered terms related to the
treatments to be considered (e.g., H2-receptor antago-
nists) with the subheadings adverse effects and therapeu-
tic use, and set D was the free-text term stress ulcer
prophylaxis. The sets were combined as [(A1 and B) or
(A2 and C) or D]. The search was limited to reports on
humans published in the English language. The search
in IPA differed in that combining set A2 and C de-
Stress ulcer prophylaxis ASHP Report
ASHP Commission on Therapeutics
In late 1990, the ASHP Board of Directors created an advi-
sory body called the Commission on Therapeutics to be
concerned with societal drug use and therapeutic issues.
This is consistent with the ASHP governing documents,
which state that one purpose of ASHP is to foster rational
drug use in society such as through advocating public
policies toward that end. The Commission is charged
with the following:
Identifying new and emerging therapeutic modali-
ties for ASHP consideration,
Developing documents on issues related to rational
and cost-effective drug use in society,
Reviewing and responding to selected therapeutic or
drug-use initiatives of other organizations and agen-
cies, and
Consulting with ASHP on drug-use and therapeutic
issues.
Members of the 19981999 ASHP Commission on Thera-
peutics are Austin J. Lee, Pharm.D., BCPS, FASHP, Chair; C.
Wayne Weart, Pharm.D., FASHP, Vice Chair; G. Dennis
Clifton, Pharm.D.; Matthew A. Fuller, Pharm.D., BCPS,
BCPP; Kent M. Nelson, Pharm.D., BCPS; William L. Green,
Pharm.D., BCPS, FASHP; Mary Beth Gross, Pharm.D.;
Michael D. Katz, Pharm.D.; Shirley J. Reitz, Pharm.D.; Jane
E. DeWitt, Student Member; Donald T. Kishi, Pharm.D.,
Board Liaison; and Leslie Dotson Jaggers, Pharm.D., BCPS,
Secretary.
creased the retrieval. The sets were combined in IPA as
{[(A1 or A2) and B] or D}. All relevant citations were
printed and reviewed for pertinent articles, which were
subsequently retrieved and copied. The reference lists
of the retrieved articles were studied for investigations
that may have been missed through the computerized
search.
Periodic literature searches using the same method
were conducted during the compilation of the guide-
lines. The reference lists of review articles were exam-
ined for potentially pertinent references. Unpublished
abstracts (e.g., those presented at meetings) and ab-
stracts in foreign languages were not included in the
evaluation.
Although all relevant articles were reviewed, they are
not necessarily referenced in this document. In partic-
ular, isolated case reports or case series involving fewer
than 25 patients were not routinely included unless
they provided unique information that would substan-
tially affect the recommendations. Similarly, pharma-
cokinetic and pharmacodynamic studies of medica-
tions were not included unless there was some applica-
bility to stress ulcer prophylaxis.
Level of evidence for recommendations
There are several methods for assessing the literature
by using evidence tables.9-12 The methods of Guyatt et
al.9 and the American College of Chest Physicians (1995
revision)10 were determined to be the most applicable to
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 349
ASHP Report Stress ulcer prophylaxis

the literature to be reviewed because they involved
meta-analysis and distinctions based on confidence
intervals, homogeneity, and heterogeneity. These
methods were modified slightly and expanded to in-
clude a category D that represents a panel consensus
based on the clinical experience of the panel members
and a paucity of quality supporting literature. Before
reviewing the literature, the panel of experts agreed
that a meta-analysis carried more weight than a ran-
domized, controlled trial (RCT) in determining a rec-
ommendation unless at least two RCTs had similar
results or one RCT was designed with a sample large
enough to detect a difference of 50% or less in bleeding
rates (considered the primary outcome) between the
treatment and control groups with a power of 80%
and an of 0.05.
The recommendations in this document were catego-
rized according to the strength of the evidence. Category
A corresponds to levels of evidence I+, I, and I; category
B to levels II+, II, and II; and category C to levels III+, III,
IV+, IV, and V. Table 1 includes definitions for each level
of evidence. The level of evidence was evaluated for each
trial. When there were multiple RCTs of comparable
power pertaining to a particular recommendation and
their levels of evidence differed, the level of evidence for
the least stringent trial was used in determining the
strength of evidence for a recommendation. Recommen-
dations were assigned to category D if they represented
the expert opinion of panel members. For a recommen-
dation based on RCTs to be assigned to category A, there
had to be at least two RCTs or one RCT with a sample size
sufficient for detecting a difference of 50% or less in rates
of clinically important bleeding with a power of 0.8 and
an of 0.05.
One problem with both the grading systems9,10 on
which this system was based is the relative inability to
distinguish the quality of individual investigations.
Two RCTs may each be ranked similarly, but one may
have been better designed and reported than the other.
Therefore, in addition to listing levels of evidence for
the various trials, the superscript wd was used to signify
a well-designed and well-reported trial when the guide-
lines were sent to the panel of experts and other review-
ers to aid them in evaluating the literature presented.
More than 30 criteria, some of which have been pub-
lished, were used in the analysis of the investiga-
tions.13,14 The criteria represented a nonnumerical as-
sessment and were not used as a scoring system for the
formal statistical analysis.15
The levels of evidence were used to evaluate those
studies that assessed the frequency of clinically impor-
tant bleeding (i.e., gastroduodenal bleeding associated
with hemodynamic compromise or the need for blood
transfusion or surgery) and nosocomial pneumonia.
Analysis of the number and type of risk factors associat-
ed with bleeding by a rigid evidence-based evaluation
may be misleading for a number of reasons, including
the following: studies used various definitions of bleed-
ing and risk factors associated with bleeding, various
risk factors were studied, various risk factors were used
as inclusion criteria, the analysis of risk factors often
was not a study objective, and, in many studies, multi-
variate analysis was not used to determine which risk
factors might be independent predictors of bleeding.
Observational trials with large numbers of patients are
often used appropriately to assess risk factors for bleed-
ing, although the strength of evidence would never be
higher than C.

Table 1.
System Used for Defining Levels of Evidence in Stress Ulcer Prophylaxis Guidelinesa
Level of
Evidence Definition
I+ Meta-analysis of randomized, controlled trials (RCTs) with homogeneityb of results and a 95% confidence interval (CI)
that lies entirely on one side of the numerical threshold for clinically important benefit
I Meta-analysis of RCTs with homogeneity of results but with a 95% CI that includes the threshold for clinically
important benefit
I RCT in which the entire 95% CI lies on one side of the threshold for clinically important benefit
II+ Meta-analysis of RCTs with heterogeneity of results and a 95% CI that lies entirely on one side of the threshold for
clinically important benefit
II Meta-analysis of RCTs with heterogeneity of results and a 95% CI that includes the threshold for clinically important
benefit
II RCT in which the 95% CI includes the threshold for clinically important benefit
III+ Nonrandomized concurrent cohort study in which the entire 95% CI lies on one side of the threshold for clinically
important benefitc
III Nonrandomized concurrent cohort study in which the 95% CI includes the threshold for clinically important benefit
IV+ Nonrandomized historic cohort study in which the entire 95% CI lies on one side of the threshold for clinically
important benefit
IV Nonrandomized historic cohort study in which the 95% CI includes the threshold for clinically important benefit
V Case series suggesting clinically important benefit
a
Adapted from references 9 and 10.
b
Various definitions of homogeneity were used in the literature (e.g., the difference between the risk reductions or odds ratios between the two most
disparate trials is less than 20% and the difference between 95% confidence intervals for the two most disparate trials is less than 5%); the fact that
homogeneity was tested for is more important than the precise method used.
c
This assumes the availability of comparative data for calculating 95% CIs.

350 Am J Health-Syst Pharm Vol 56 Feb 15 1999


Pathophysiology of stress-induced lesions
Stress ulceration is a form of hemorrhagic gastritis
that may occur in patients who have had a major
stressful event such as trauma, surgery, organ failure,
sepsis, or thermal injury. In general, the histological
and macroscopic appearance of stress-induced fundal
lesions are similar to those associated with nonsteroidal
anti-inflammatory drugs (NSAIDs) seen in the antrum
and the body of the stomach. However, in contrast to
NSAID-induced lesions, stress-induced lesions often
cause more congestion and bleeding, and they eventu-
ally involve multiple sites in the upper GI tract.16 Cush-
ings ulcer, which is associated with CNS injury, often
presents as a single deep lesion in the duodenum or in
the stomach.16 Curlings ulcer, which is associated with
thermal injury, is morphologically similar to other
stress-induced lesions but may appear in the esopha-
gus, the stomach, the small intestine, or the colon.16
The pathogenesis of stress-induced lesions is proba-
bly multifactorial.17 Acid hypersecretion is often stated
as being particularly important in the formation of
ulcers associated with head and thermal injuries.18
However, acid hypersecretion is not a universal finding
in such patients, and higher pH values (>4.5) do not
ensure avoidance of lesions.19-21 During stressful events,
normal protective mechanisms are altered, including
epithelial turnover in the gastric mucosa and secretions
of mucus and bicarbonate. These events, combined
with the release of various mediators (e.g., arachidonic
acid metabolites, cytokines, oxygen free radicals), result
in erosions that may progress to ulceration and bleed-
ing.22 Reductions in mucosal blood flow may also be
important in ulcer formation. Alterations in blood flow
at the microcirculatory level may initiate a series of
changes resulting in erosions that could progress to
ulceration and bleeding. Necrosis and erosions of the
gastric membrane have occurred within 45 minutes of
hemorrhagic shock in experiments in rats.23 In adult
humans, erosions may occur very quickly (i.e., during
the first 24 hours of hospital admission) in association
with a stressful event, although the time from the
inciting event to the diagnosis of bleeding may be
much longer (e.g., >1014 days).
Other less well-studied factors may be involved in the
pathogenesis of stress-related lesions. For example, ele-
vated concentrations of anti-Helicobacter pylori immuno-
globulin A have been found in the serum of critically ill
patients.24 Although the association between H. pylori
and chronic ulceration has been established, few studies
have been performed in acute care settings.
It is not known whether differences in basal or
maximal gastric acid production seen in various age
groups affect the frequency of ulceration and clinically
important bleeding. For example, premature infants
typically produce less gastric acid than full-term in-
fants, albeit with substantial interinfant variability.25,26
Newborns often have slightly acidic gastric pH values
Stress ulcer prophylaxis ASHP Report
that become more acidic within a few hours of birth.27
Gastric pH values in infants begin to approach those of
healthy adults during the first six months of life. How-
ever, stress ulcer lesions may occur at any age, including
in preterm infants, lending additional support to a
multifactorial process.28
The frequency of ulceration, the number of ulcers, and
the sites of ulceration may be different between children
and adults, depending on the stress-related event. In one
retrospective study involving 93 children less than 10
years of age and 178 adults who died of burn-related
injuries, 13 (14.0%) of the children had duodenal ulcer-
ation on postmortem examination compared with 13
(7.3%) of the adults. In addition, 21 (22.6%) of the
children had gastric ulceration compared with 20
(11.2%) of the adults.29 No relationship between sex and
ulceration was found. Another review of infants less than
one year of age with stress ulceration found that single
duodenal ulcers were common, in contrast to the multi-
ple gastric erosions usually found in adults.30
Frequency of bleeding, efficacy
of prophylaxis, and risk factors for bleeding
in general (medical, surgical, respiratory,
pediatric) ICU populations
Acute bleeding in critically ill patients has been
described in the medical literature since the 1800s. To
determine the true frequency of, and risk factors associ-
ated with, stress-induced bleeding in general ICU pop-
ulations, studies that contained at least one defined
group of patients who did not receive prophylaxis were
evaluated.31-63 As will be seen in the following discus-
sion, determining a true frequency of clinically impor-
tant bleeding is complicated by the difficulty in mea-
suring endpoints, the variability in endpoints used, the
variability in definitions of endpoints, and the hetero-
geneity of the patient populations.
In general, the studies included in this section of the
document on general ICU populations determined the
frequency of stress ulcer lesions and the risk factors
associated with clinically important bleeding in pa-
tients in medical, surgical, or respiratory ICUs. Only
two of the studies involved a relatively homogeneous
sample of patients with a single-system disease or sur-
gery. One study was conducted in patients with respira-
tory disease, and the other involved patients undergo-
ing abdominal surgery.36,44 These studies were included
because the patient populations were similar to those
enrolled in other investigations. Studies enrolling pa-
tients with single-system injuries (e.g., head or spinal
cord surgery), patients with thermal injuries, or pa-
tients undergoing transplantation were not included
(see the section on special populations) because of
presumed differences in the pathophysiology or fre-
quency of stress-induced bleeding.
Frequency of bleeding. In all studies conducted
before 1978, the frequency of clinically important
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 351
ASHP Report Stress ulcer prophylaxis
bleeding and related complications ranged from 5.3%
to 33%. From 1978 on, substantial differences in the
frequency of stress-induced bleeding have been record-
ed among trials. For example, in an RCT published by
Pinilla et al.42 in 1985, the frequency of bleeding was
1.6% (1 of 61 patients), and it was not clear whether this
patient had clinically important bleeding. In contrast,
an RCT published by Peura and Johnson43 in the same
year, involving adult patients in a medical ICU, found
a 39% frequency (7 of 18 patients) of endoscopically
confirmed, clinically important, stress-induced bleed-
ing in patients not receiving prophylaxis. Articles pub-
lished from 1984 to 1994 on the frequency of clinically
important bleeding in patients not receiving prophy-
laxis indicate that the average frequency of bleeding is
6% (0.139%).64
With regard to the pediatric population, it is difficult
to estimate the frequency of clinically important bleed-
ing because of the small numbers of patients enrolled in
published investigations and the use of endpoints oth-
er than clinically important bleeding (e.g., endoscopic
evidence of bleeding or overt bleeding). There are im-
portant exceptions, albeit with differing results. In one
study involving 140 children from birth to 20 years of
age, the frequency of clinically important bleeding was
20% in a control group and 5.7% in a combined treat-
ment group.65 In contrast, the frequency of clinically
important bleeding (not defined in the published ab-
stract) was 1.6% in a study of 1006 admissions to a
pediatric ICU, although it was not stated whether the
children received any form of stress ulcer prophylaxis.66
Efficacy. Prophylaxis versus no prophylaxis. Two
studies conducted in the 1990s can be used to illustrate
the disparate results of the more than 20 RCTs of
prophylaxis conducted in general ICU populations.
The first trial, conducted in 1993 by Martin et al.,58 was
a multicenter, double-blind, placebo-controlled study
involving general medical and surgical ICU patients
with an expected length of stay of at least 36 hours and
at least one risk factor (of eight studied) for bleeding.
The study had 90% power to detect a 75% difference in
bleeding between placebo and pH-adjusted cimetidine
therapy. The study was terminated early when an inter-
im analysis revealed a significant difference in bleeding
rates between the control and cimetidine groups. In the
control group, 16 (24.2%) of 66 patients had overt and
clinically important bleeding (some bleeding was not
cleared by lavage, but the patients did not require
transfusion), compared with 5 (7.7%) of 65 patients in
the treatment group (p = 0.009). Six (10.0%) of 66
patients in the control group and 4 (6.2%) of 65 in the
treatment group had clinically important bleeding. Sta-
tistical testing of this endpoint was not performed.
The second study, a single-blind RCT, was conduct-
ed in 1994 by Ben-Menachem et al.59 In that trial, only
medical ICU patients who were expected to have a
length of ICU stay of at least 24 hours were enrolled.
352 Am J Health-Syst Pharm Vol 56 Feb 15 1999
The study was designed to have 80% power to detect a
75% treatment-related reduction in bleeding. Patients
could be randomly assigned to a control (no placebo)
group, a pH-adjusted cimetidine group, or a sucralfate
group. There were no significant differences between
groups with respect to clinically important bleeding
episodes (including some patients whose bleeding did
not clear by lavage): 6 of 100 patients in the control
group, 5 of 100 patients in the cimetidine group, and 5
of 100 patients in the sucralfate group. In addition,
there were no significant differences between groups
when respiratory failure and coagulopathy were stud-
ied as risk factors. If the different findings between this
trial and that of Martin et al. can be attributed to
differences in the populations being studied, it might
be reasonable to consider withholding prophylaxis in
general medical ICU patients. However, it should be
stressed that the trial by Ben-Menachem et al. was not
designed to detect a difference of less than 75% in
bleeding between groups, even though a smaller differ-
ence might be clinically important.
Another study enrolled 90 intensive care patients
with septic shock, severe head injury, and trauma.67 The
patients were randomly assigned to receive pirenzepine
30 mg/day, omeprazole 80 mg/day, or no prophylaxis.
A rating scale of zero (normal mucosa) to four (>25
hemorrhages, erosions, or invasive ulcers) was used to
evaluate all patients at baseline and after five days of
prophylaxis. Although all patients were at high risk for
stress ulcer hemorrhage, no patients developed severe
bleeding from stress lesions, and no difference in endo-
scopic evaluations was noted at baseline or at five days
among the three groups.
Because individual trials have demonstrated con-
flicting results with respect to the frequency of bleeding
with or without prophylaxis, several meta-analyses
have sought to resolve this issue (Table 2).5,68-71 Ab-
stracts and non-English-language articles were fre-
quently included in the data sets of these analyses, as
were reports of studies involving populations that other
studies specifically excluded (e.g., patients with head or
thermal injuries). One meta-analysis was published in
1989, and three were published in 1991, so the number
of trials combined for each analysis was limited.68-71
Despite this difference in time frame, there was definite
overlap among the meta-analyses in the studies that
were included. Only one of the meta-analyses investi-
gated the difference in bleeding rates with sucralfate
compared with no prophylaxis.5
The meta-analysis conducted by Lacroix et al.68 in-
cluded randomized studies only. The frequency of
bleeding in patients receiving no prophylaxis (or place-
bo) ranged from 3.4% to 52.7%. Use of cimetidine and
antacids was associated with a significantly lower fre-
quency of bleeding compared with no prophylaxis.
Among the limitations of this meta-analysis were that
the evaluated studies had methodological problems,
 Stress ulcer prophylaxis ASHP Report

demonstrated heterogeneous effects, and investigated
the frequency of occult or overtbut not necessarily
clinically importantbleeding, defined as hemody-
namic instability or the need for blood transfusion.
In a meta-analysis published by Tryba69 in 1991,
overt and clinically important bleeding (i.e., need for
blood transfusion) were combined in the definition of
upper GI bleeding. Randomized and nonrandomized
studies were included. The odds ratios (ORs) and 95%
confidence intervals (CIs) calculated for H2-receptor
antagonists or antacids compared with no prophylaxis
were all less than one (i.e., treatment was effective in
preventing bleeding). The data were presented only in
the form of figures, so the exact ORs and CIs are not
available. However, the frequency of bleeding was 5.3%
in the group receiving H2-receptor antagonists versus
16.1% with no prophylaxis and 5.6% in the group
receiving antacids versus 14.9% with no prophylaxis. A
second meta-analysis by Tryba71 in 1991 included only
studies with clinically important bleeding. The results
were similar to those of Trybas previous meta-analysis.
Two meta-analyses published by Cook et al.5,70 in
1991 and 1996 included only randomized, controlled
trials. The investigations looked at clinically important
bleeding, defined as overt bleeding with hemodynamic
changes (a 20-mm Hg decrease in blood pressure within
24 hours or a 10-mm Hg decrease plus a 20-beat/min
increase in heart rate on standing) or the need for
transfusion (a decrease in hemoglobin of 2 g/dL plus
transfusion of two units of blood in 24 hours). In the
1991 analysis, H2-receptor antagonists were found to be
more efficacious in preventing clinically important
bleeding than no prophylaxis.
The 1996 meta-analysis was performed to resolve

Table 2.
Meta-analyses Investigating the Risk of Bleeding with and without Stress Ulcer Prophylaxis
Reference Comparisona No. Trials Endpoint Resultsb
68 Cimetidine versus 7 Overt bleeding OR = 0.32, CI = 0.210.49 (lower rate of
control bleeding with cimetidine)
Antacids versus 9 Overt bleeding OR = 0.12, CI = 0.080.19 (lower rate of
control bleeding with antacids)
Cimetidine versus 10 Overt bleeding OR = 1.61, CI = 0.972.65
antacids
69 Antacids versus 6 Overt or clinically important OR and CI < 1 (lower rate of bleeding with
control bleeding antacids)
H2-RAs versus 14 Overt or clinically important OR and CI < 1 (lower rate of bleeding with H2-
control bleeding RAs)
H2-RAs versus 14 Overt or clinically important CI included 1
antacids bleeding
Sucralfate versus 6 Overt or clinically important OR and CI < 1 (lower rate of bleeding with
H2-RAs bleeding sucralfate)
Sucralfate versus 10 Overt or clinically important CI included 1
antacids bleeding
71 Sucralfate versus 9 Clinically important bleeding OR = 0.532, CI = 0.3030.933 (lower rate of
H2-RAs bleeding with sucralfate)
Sucralfate versus 10 Clinically important bleeding OR = 0.868, CI = 0.4521.667
antacids
70 Antacids versus 3 Clinically important bleeding OR = 0.35, CI = 0.081.33
control
H2-RAs versus 6 Clinically important bleeding OR = 0.35, CI = 0.150.76 (lower rate of
control bleeding with H2-RAs)
H2-RAs versus 9 Clinically important bleeding OR = 0.84, CI = 0.451.56
antacids
Antacids versus 5 Clinically important bleeding OR = 0.65, CI = 0.162.49
sucralfate
H2-RAs versus 1 Clinically important bleeding OR = 0.95, CI = 0.0615.40
sucralfate
5 Antacids versus 3 Clinically important bleeding OR = 0.35, CI = 0.091.41
control
H2-RAs versus 10 Clinically important bleeding OR = 0.44, CI = 0.220.88 (lower rate of
control bleeding with H2-RAs)
H2-RAs versus 10 Clinically important bleeding OR = 0.86, CI = 0.461.59
antacids
Sucralfate versus 1 Clinically important bleeding OR = 1.26, CI = 0.1212.87
control
Sucralfate versus 5 Clinically important bleeding OR = 1.49, CI = 0.435.27
antacids
Sucralfate versus 4 Clinically important bleeding OR = 1.28, CI = 0.276.11
H2-RAs
a
H2-RAs = histamine H2-receptor antagonists.
b
OR = odds ratio, CI = 95% confidence interval. Exact values provided when available; some values were extrapolated from figures.

Vol 56 Feb 15 1999 Am J Health-Syst Pharm 353

ASHP Report Stress ulcer prophylaxis
some of the inconsistencies associated with the previ-
ously conducted meta-analyses and to incorporate
more recent studies.5 The methodology was similar to
that of the earlier meta-analysis. Only H2-receptor an-
tagonists were found to have a 95% CI of <1 for prevent-
ing clinically important bleeding compared with no
prophylaxis. However, only three trials with an antacid
group and one with a sucralfate group were available for
comparison with no prophylaxis. Because the 1996
meta-analysis was the most recent and comprehensive,
its results are used in this document whenever the
findings from previous meta-analyses are conflicting.
To date, the study with the largest number of pro-
spectively enrolled patients was published by Cook et
al. in 1994.61 This multicenter follow-up trial enrolled
2252 patients older than 16 years of age who were
admitted to medical and surgical ICUs. Approximately
half of the enrolled patients were admitted for cardio-
vascular surgery. Some subgroups (head or spinal cord
injuries, multiple trauma or thermal injuries, and trans-
plantation) had few patients. This limits the generaliz-
ability of the results to these populations. Lack of
resources at three of the four hospitals prohibited en-
rollment of consecutive patients as intended, and phy-
sicians were not required to withhold prophylaxis.
Various prophylactic medications were used, and the
dosage and duration of prophylaxis were not con-
trolled. Clinically important bleeding occurred in 10
(0.6%) of 1578 patients not receiving prophylaxis and
23 (3.4%) of 674 patients receiving prophylaxis (22 of
the 33 bleeding episodes were confirmed). This suggests
that, in this observational design, physicians were
probably able to predict who was at risk for bleeding
and administer prophylaxis; it does not necessarily
represent failure of prophylaxis.
Prophylaxis in pediatric patients. The number of stress-
induced lesions progressing to clinically important
bleeding with or without prophylaxis is not well stud-
ied in pediatric patients. Lacroix et al.48 compared pro-
phylaxis with no prophylaxis in 40 patients from birth
to 18 years of age. When the results were reported, overt
bleeding was not distinguished from clinically impor-
tant bleeding, and no differences in upper GI bleeding
were noted between the cimetidine group (9 of 19
patients) and the placebo group (8 of 21 patients). Six
patients had massive bleeding, defined as the presence
of nasogastric blood with changes in blood pressure or
hemoglobin levels. It was not stated which groups these
patients were in, and it was noted that five of these
patients had bleeding at other sites due to disseminated
intravascular coagulation. The researchers concluded
that routine prophylaxis in medical pediatric patients is
not warranted.
In another study, 165 pediatric patients admitted to
an ICU were randomly assigned to one of three active-
treatment groups or a no-treatment group.65 The inves-
tigators used clinically important bleeding as an out-
354 Am J Health-Syst Pharm Vol 56 Feb 15 1999
come. A significant (p < 0.05) difference between the
active-treatment groups and the no-treatment group
was achieved only if the results for the three active-
treatment groups were combined. Two studies focused
on a neonatal population but did not use clinically
important bleeding as an endpoint.49,63 In one of these
studies that had a control group, the risk of endoscop-
ically diagnosed gastric lesions in mechanically venti-
lated infants was found to be lower with ranitidine
prophylaxis (OR = 0.03; 95% CI, 0.0030.178). Surfac-
tant therapy, which was used to treat infants with
respiratory distress syndrome, was also associated with
a lower rate of formation of lesions (OR = 0.083; 95% CI,
0.0090.788).63 The mechanism for the apparent pro-
tective effect of surfactant on the GI tract remains to be
elucidated. No RCT conducted to date in pediatric pa-
tients has conclusively demonstrated a significant dif-
ference in clinically important bleeding when prophy-
laxis was compared with no prophylaxis.
Risk factors. In Cooks prospective observational
study, two risk factors were found to be significant
predictors of stress-induced bleeding: respiratory fail-
ure, as defined by mechanical ventilation for at least 48
hours (OR = 15.6; CI not reported, p < 0.001), and
coagulopathy, defined as a platelet count of <50,000
mm3, an International Normalized Ratio of >1.5, or a
partial thromboplastin time of >2 times the control
value (OR = 4.3; CI not reported, p < 0.001).61 The
frequency of bleeding was 3.7% (95% CI, 2.55.2%) if
one or both of these risk factors were present and 0.1%
(95% CI, 0.020.5%) if neither factor was present. Pa-
tients who had received prophylaxis and those who
had not were included. Simple regression analysis
showed that sepsis, renal insufficiency, hepatic failure,
enteral feeding, and the use of glucocorticoids, heparin,
and warfarin were risk factors for bleeding; multiple
regression analysis showed that only mechanical venti-
lation and coagulopathy were independently predic-
tive of clinically important bleeding.
The finding that enteral feeding was a risk factor for
bleeding (OR = 3.8, p < 0.001) is of interest because
previous retrospective studies in adults have found
various effects of enteral feedings on pH and the fre-
quency of bleeding.72-75 These differences may be due to
differences in location of the enteral feeding tubes. For
example, feedings placed into the stomach may alkalin-
ize stomach contents, and jejunal feedings may stimu-
late gastric acid secretion. The fact that patients are able
to tolerate tube feedings may mean they are less ill than
patients who cannot tolerate such feedings, and this
may determine the differences noted. Other factors
may be specific to certain types of injury, such as the
development of GI edema after thermal injury.
Conflicting associations with total parenteral nutri-
tion (TPN) and bleeding have been noted. Ben-Men-
achem et al.59 found that the frequency of bleeding was
not related to the use of TPN. Ruiz-Santana et al.52

concluded that TPN was protective, but their sample
size was small, and their findings require confirmation
in larger randomized trials.
The most recently published large-sample retrospec-
tive study of risk factors in ICU trauma patients involved
2574 patients.76 The only patients receiving prophylaxis
(antacids) were those with a history of gastroduodenal
ulcerations. The published abstract does not reveal how
many of the 2574 patients received antacids. Clinically
important bleeding was not analyzed separately from GI
bleeding. GI bleeding was noted in 60 (2.3%) of the
patients. The risk factors associated with a higher risk of
bleeding included male sex, spinal cord injury, respirato-
ry failure, acute renal failure, and severe sepsis.
Of the other trials in which risk factors were studied,
a majority of those conducted in adults showed a
higher risk of bleeding as the number of risk factors
increased.37-39,42,45-47,54,55,58 The results of most trials are
consistent with those of the 1994 study by Cook et al.61
in that mechanical ventilation (as a measure for respira-
tory failure)36,41,59 and coagulopathy36,41,53 are the prima-
ry risk factors for bleeding. Other risk factors associated
with bleeding in adult patients in some studies include
sepsis,35 length of ICU stay greater than one week,41
presence of occult bleeding for at least six days,53 and
administration of high doses of corticosteroids (>250
mg/day of hydrocortisone or equivalent).54,59 However,
the studies by Cook et al. did not find use of corticoster-
oids, heparin, warfarin, or NSAIDs to be independent
risk factors for bleeding when respiratory failure and
coagulopathy were considered.53,61
Prophylaxis does not necessarily prevent bleeding in
patients with documented risk factors, and the effec-
tiveness of prophylaxis varies in different popula-
tions.59 Some potential risk factors for bleeding have
not been adequately studied, and it is unclear whether
they are independent predictors of bleeding. A majority
of investigations excluded patients with a history of GI
disease, particularly ulcers and bleeding. It is unknown
whether a history of ulceration or bleeding increases
the risk of acute, stress-induced bleeding. Similarly,
ulcerogenic medications with well-documented associ-
ations with bleeding problems, such as long-term use of
NSAIDs, have not been adequately studied as risk fac-
tors for stress-induced bleeding. Typically, patients re-
ceiving such medications either were not discussed in
the methods section of study reports or were prohibited
from enrolling in the studies.
In pediatric patients (birth to 19 years of age), coag-
ulopathy,48,57 shock,56 surgery lasting for longer than
three hours,56 trauma,56,57 and pneumonia57 were associ-
ated with an increased risk of bleeding, while the use of
enteral nutrition reduced the risk of bleeding.57 The
results were not stratified by age. One study in pediatric
patients (median age, 34.9 months) found that a Pedi-
atric Risk of Mortality Score greater than 10 was associ-
ated with a greater risk of bleeding.57 Another study in
Stress ulcer prophylaxis ASHP Report
mechanically ventilated preterm and full-term infants
found that 20 (80%) of 25 patients had stress-induced
lesions as determined by endoscopic evaluation when
no prophylaxis was administered.63 That study and
others demonstrated that gastric lesions due to stress
may occur in the very young despite their possible
physiological differences from adults.29,63
The rate of progression of these lesions to clinically
important bleeding is not known. In a study in 881
pediatric ICU patients (1006 admissions), 16 (1.6%)
clinically important bleeding episodes occurred.66 Be-
cause this was an observational investigation, physi-
cians were not hindered from prescribing medications
for stress ulcer prophylaxis. Among the 110 patients
who received prophylaxis, there were 10 clinically im-
portant bleeding episodes. The authors noted that the
three strongest independent risk factors for clinically
important bleeding were respiratory failure (OR = 10.2),
coagulopathy (OR = 9.3), and a Pediatric Risk of Mortal-
ity Score of 10 (OR = 4.0). Of the 16 patients with
clinically significant bleeding, 9 (56%) had all three risk
factors and 14 (88%) had at least two.
Summary. The reported frequency of stress-in-
duced bleeding has varied substantially since approxi-
mately 1978 and depends on the number and type of
risk factors. Data from large prospective, observational
investigations in children and adults have found that
general medical and surgical ICU patients who have
either coagulopathy or respiratory failure requiring me-
chanical ventilation have a substantially higher risk of
clinically important bleeding. The studies often exclud-
ed neurosurgery, burn, and transplant patients. Anoth-
er risk factor for children is a Pediatric Risk of Mortality
Score of 10. A number of other risk factors have been
associated with overt bleeding in isolated studies (pro-
longed ICU stay or occult bleeding and administration
of high-dose corticosteroids in adults; prolonged shock
or surgery and trauma in children), but it is unknown
whether these are independent predictors of clinically
important bleeding, except in the case of coagulopathy
or respiratory failure. Several studies that included both
medical and surgical ICU patients suggest that, as the
number of risk factors increases, the frequency of clin-
ically important bleeding increases. It has been pro-
posed that adult medical ICU patients may not neces-
sarily need stress ulcer prophylaxis, even if they have
respiratory failure or coagulopathy. However, there are
concerns related to inadequate sample sizes in the
studies that resulted in this conclusion. Overall, accord-
ing to RCTs, about 6% (range, 0.139%) of adult medi-
cal and surgical patients at risk for stress ulcers who do
not receive prophylaxis have clinically important
bleeding.64 Observational studies involving large num-
bers of pediatric or adult patients suggest that the risk
may be substantially lower.61,66
Recommendation (adults): Risk factors for ICU patients have
been delineated in trials comparing prophylaxis with no
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 355
ASHP Report Stress ulcer prophylaxis

prophylaxis by using clinically important bleeding as an Table 3.

endpoint. Prophylaxis is recommended in patients with Strength of Evidence for Prophylaxis for Adult ICU
coagulopathy or patients requiring mechanical ventilation Patients According to Risk Factora
for more than 48 hours. (Strength of evidence = C) Prophy-
Risk Factor Strength of Evidence
laxis is also recommended in patients with a history of GI
ulceration or bleeding within one year before admission and General (medical, surgical, A (for H2-RAs, antacids),
respiratory) ICU populationsb B (for sucralfate)
in patients with at least two of the following risk factors:
Head injury with Glasgow B (for H2-RAs), D (for
sepsis, ICU stay of more than one week, occult bleeding Coma Score of 10 or antacids, sucralfate)
lasting six days or more, and use of high-dose corticosteroids inability to obey simple
(>250 mg per day of hydrocortisone or the equivalent). commands
(Strength of evidence = D) (Table 3) Recommendations for Thermal injury involving B (for antacids), D (for
specific prophylactic medications can be found in the Medi- >35% of body surface area H2-RAs, sucralfate)
cations used for prophylaxis section. Partial hepatectomy C (for H2-RAs), D (for
antacids, sucralfate)
Recommendation (pediatrics): Although various risk factors Hepatic or renal transplantation D (for H2-RAs, antacids,
have been associated with bleeding in pediatric patients, sucralfate)
published RCTs have either not used clinically important Multiple trauma with Injury D (for H2-RAs, antacids,
bleeding as an outcome or had insufficient power to enable a Severity Score of 16 sucralfate)
definitive conclusion that prophylaxis provides protection. Spinal cord injury D (for H2-RAs, antacids,
Risk factors that have been associated with clinically impor- sucralfate)
tant bleeding include respiratory failure, coagulopathy, and Hepatic failure D (for H2-RAs, antacids,
a Pediatric Risk of Mortality Score of 10. (Strength of sucralfate)
History of gastric ulceration or D (for H2-RAs, antacids,
evidence = C)
bleeding during year before sucralfate)
admission
Frequency of bleeding, efficacy Presence of at least two of the D (for H2-RAs, antacids,
of prophylaxis, and risk factors for bleeding following: sepsis, ICU stay of sucralfate)
in special populations (single-system >1 wk, occult or overt
bleeding for 6 days,
injuries, thermal injuries, transplantation, corticosteroid therapy
miscellaneous) (>250 mg of hydrocortisone
Patients with head or spinal cord injuries or patients or equivalent daily)
a
undergoing surgical exploration for suspected disease H2-RAs = histamine H2-receptor antagonists, INR = International Nor-
malized Ratio, PTT = partial thromboplastin time. Refer to the text for
have usually been studied as defined groups rather than discussion of the risk factors and the economic analysis behind the
as part of general ICU populations.77-84 A majority of recommendation.
b
There is evidence to suggest that patients in general ICU populations
these studies in special populations were conducted in who have respiratory failure or coagulopathies (as defined in the text) are
adults, although two studies included younger patients at higher risk for clinically important bleeding.
(mean age, 28 years, range, 274; mean age, 35 years,
range 1376) who were not discussed separately when
the results were reported.77,79 Five of the trials were preoperative Glasgow Coma Score was <15 (impaired
RCTs.78,81-84 Three of these trials found significantly consciousness) or when the syndrome of inappropriate
lower rates of clinically important bleeding with H2- antidiuretic hormone secretion was present.80
receptor antagonist prophylaxis than with no prophy- Patients with thermal injuries represent another
laxis.78,83,84 However, in the RCT with the largest num- population that has usually been studied separately
ber of patients (n = 167), the number of patients with with regard to stress ulcer prophylaxis and bleeding.85-91
clinically important bleeding was not reported.82 Only In the only trial that appeared to be randomized (48
two of the studies looked at a possible association patients), the frequency of clinically important bleed-
between the number of risk factors and the frequency of ing was 29.2% in patients who received no prophylaxis
bleeding. In both studies, the frequency of bleeding and 4.2% in patients given antacids (p < 0.02).90 Only
increased with the number of risk factors.82,84 patients with thermal injury to >35% of their body
In general, the studies demonstrate an increasing surface area (BSA) were included in this trial. In other
frequency of bleeding as the severity of injury increases. published investigations, the number and types of risk
Two RCTs demonstrated substantial increases in clinical- factors (other than the thermal injury that may have
ly important bleeding (27.845.8%) with severe head contributed to bleeding) were not studied, except for a
injury (inability to obey simple commands in one trial possible association between sepsis and ulceration. The
and Glasgow Coma Score of 10 in the other), irrespec- retrospective study by Solem et al.91 was one of the first
tive of corticosteroid administration.78,84 In another RCT to suggest that enteral feedings might be effective pro-
involving patients with head injuries, no association was phylaxis for stress-induced bleeding, but the feedings
found among 12 specific risk factors and bleeding, al- were administered only if ulcers were unlikely to devel-
though bleeding rates were significantly higher when op, a situation that was not defined. In addition, some
more than five risk factors were present.82 In patients patients received both antacids and enteral feedings.
undergoing surgery for nontraumatic cerebral disease, While many of the thermal injury studies included
cimetidine prophylaxis was more likely to fail when the injuries in children (35 days to 13 years of age), only

356 Am J Health-Syst Pharm Vol 56 Feb 15 1999


one study investigated the effect of no prophylaxis in
pediatric patients only.88 All 477 children had thermal
injuries involving 13% or more of their BSA. Thirty-six
(7.5%) of the children had clinically important bleed-
ing when no prophylaxis was given (or at least was not
mentioned). Some 32 of the 36 children (89%) with
clinically important bleeding required blood transfu-
sions, and 5 patients (14%) required surgery; 1 death
(2.8%) was associated with GI bleeding.
Another defined population studied for stress ulcer
prophylaxis includes patients (at least 14 years of age
in published studies) undergoing renal or hepatic
transplantation or hepatic surgery.92-97 Cimetidine or
antacids were used for prophylaxis in all the trials
except one investigation that used ranitidine.97 Of the
studies evaluated, one was randomized. In all the
investigations, both randomized and nonrandomized,
overt and clinically important bleeding were com-
bined. The frequency of bleeding was lower with ci-
metidine prophylaxis in one study involving renal
transplant patients but not in the other.93,94
Prophylaxis with ranitidine was associated with a
significantly lower frequency of endoscopically con-
firmed stress ulceration in the one available study of
hepatic transplant patients, but the frequency of clini-
cally important bleeding was not delineated.97 One RCT
involved patients with hepatic failure,95 and one pro-
spective trial enrolled patients undergoing partial hepa-
tectomy.96 The frequency of bleeding was lower with
prophylaxis in both studies, but only the hepatectomy
study contained adequate information about clinically
important bleeding to be able to conclude that it was
significantly lower with prophylaxis. None of the stud-
ies looking at renal or hepatic surgery or disease inves-
tigated the number or type of other risk factors poten-
tially associated with bleeding. Thus, direct evidence
that concomitant organ disease or surgery increases the
risk of clinically important bleeding is lacking.
Several studies have included defined patient popu-
lations other than those previously mentioned.98-102
Only one of these investigations was randomized.
That study involved patients with tetanus who had
tracheostomies, a majority of whom were not mechan-
ically ventilated.100 The frequency of overt bleeding
was similar between the patients who did and did not
receive prophylaxis, and there were no episodes of
clinically important bleeding. The frequency of bleed-
ing and risk factors associated with bleeding were
evaluated in one retrospective study of 33,637 trauma
patients, most of them adults.101 It is unknown how
many of these patients received prophylaxis, and overt
and clinically important bleeding episodes were com-
bined (18 of 33,367 patients bled). Risk factors associ-
ated with bleeding included an Injury Severity Score of
16, a Glasgow Coma Score of <8, and spinal cord
injury. Elderly patients and patients with infections
and organ failure were also more likely to bleed.
Stress ulcer prophylaxis ASHP Report
The frequency of, and risk factors for, clinically
important bleeding in patients with single-system inju-
ries such as head trauma, spinal cord injury, and ther-
mal injuries; patients undergoing transplantation; and
patients with multiple trauma have not been well stud-
ied. These populations were usually excluded from
studies in which patients might be randomly assigned
to receive no prophylaxis. It is not known whether
respiratory failure or coagulopathy would serve as inde-
pendent predictors of bleeding in these populations.
Recommendation (adults): Prophylaxis is recommended for
ICU patients with a Glasgow Coma Score of 10 (or the
inability to obey simple commands) or thermal injuries to
>35% of their BSA. (Strength of evidence = B) ICU patients
with partial hepatectomy may also benefit from prophylaxis.
(Strength of evidence = C) Prophylaxis may also be indicated
in ICU patients with multiple trauma (e.g., Injury Severity
Score of 16), transplantation patients in the ICU perioper-
atively, ICU patients with hepatic failure, and ICU patients
with spinal cord injuries. (Strength of evidence = D) (Table 3)
Recommendation (pediatrics): For pediatric patients (one
month of age or older) with thermal injuries, prophylaxis is
recommended, but there is insufficient evidence to recom-
mend prophylaxis based on any given percentage of BSA.
(Strength of evidence = D) For other pediatric surgery or
trauma patients, insufficient evidence is available to allow
recommendations about prophylaxis to be made.
Medications used for prophylaxis
In general, medications used for preventing stress-
induced bleeding exert their pharmacologic effect
through one of the following mechanisms: inhibition
of gastric acid secretion, neutralization of gastric acid
secretions, and protective mechanisms unrelated to
acid secretion or neutralization.103 The H2-receptor an-
tagonists, prostaglandin analogues, and proton-pump
inhibitors act primarily as antisecretory agents by in-
hibiting gastric acid secretion. But, other explanations
for the beneficial actions of these agents have been
proposed. For example, H2-receptor antagonists have
immunomodulatory actions at the cellular and media-
tor levels.104 However, mediation of cytokine concen-
trations is a complex process, and the cytokine concen-
trations fluctuate widely in critically ill patients, often
not correlating with more global physiological de-
rangements.105 Similarly, the prostaglandin analogue
misoprostol prevents gastric mucosal damage by irri-
tants that do not appear to depend on acid or acid
secretion and is sometimes referred to as a cytoprotec-
tive agent.106 There is no convincing evidence to estab-
lish that cytoprotection with misoprostol plays an
important role in preventing stress-induced lesions.107
Although alternative explanations for the effectiveness
of antacids in preventing stress-induced bleeding have
been proposed (e.g., stimulation of prostaglandin re-
lease), neutralization of gastric acid is the primary
mechanism of action.108 In contrast, sucralfate has mul-
tiple actions on the GI tract besides providing a direct
protective barrier, including modulation of pepsin and
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 357
ASHP Report Stress ulcer prophylaxis
mucus activity, arachidonic acid metabolism, bicarbon-
ate secretion, and tissue growth or repair.109 Which, if
any, of these mechanisms is of primary importance for
stress ulcer prophylaxis is not clear.
The H2-receptor antagonists that are available com-
mercially in the United States are cimetidine, famoti-
dine, nizatidine, and ranitidine. Only cimetidine ad-
ministered as a continuous intravenous infusion has
FDA-approved labeling for the prevention of bleeding
in critically ill patients, although there is no reason to
suspect any substantial difference in prophylactic effi-
cacy when other H2-receptor antagonists are given in
equipotent doses.110 However, other reasons may pre-
clude their use, such as the lack of an i.v. dosage form
(as with nizatidine). No RCTs of adequate sample size
have compared dosage regimens (e.g., intermittent ver-
sus continuous i.v. administration) or routes (e.g., i.v.
versus oral) of H2-receptor antagonists by using clinical-
ly important bleeding as a study endpoint.
One concern with using oral H2-receptor antagonists
and proton-pump inhibitors in critically ill patients is
the potential for malabsorption. Because these agents
must be absorbed to exert their effects, the patient must
have a functioning GI tract. A functioning GI tract is
usually presumed when tube feedings are tolerated
without nausea, vomiting, abdominal distention, or
diarrhea. In patients with nasogastric tubes, the clini-
cian may monitor the gastric residual volume when
feeding formulas are administered into the stomach.
Residuals refer to the feedings and gastric secretions
that accumulate with GI dysfunction. A volume of
more than 200 mL or an amount greater than the
volume infused over a two-hour period is usually indic-
ative of dysfunction.111
Although widely used for stress ulcer prophylaxis,
sucralfate is not labeled for this indication. Because su-
cralfate appears to exert its predominant effects locally, it
must be administered either orally or by a nasogastric,
orogastric, or gastrostomy tube. Sucralfate should not be
administered with nasogastric tube feedings (see Adverse
effects of prophylactic agents). Neither should it be ad-
ministered by feeding duodenal or jejunostomy tubes
because the medication will miss the site of action.
Similar to sucralfate, antacids have local actions and
must be administered directly into the stomach. A
number of antacid products have been routinely used
for stress ulcer prophylaxis. Several formulations carry
FDA-approved labeling for this indication.
Misoprostol is available in tablet form, while proton-
pump inhibitors such as omeprazole and lansoprazole
are available in delayed-release capsules. These medica-
tions have not been well studied for stress ulcer prophy-
laxis and are not labeled for this indication. The de-
layed-release dosage forms of the proton-pump inhibi-
tors create administration problems when oral intake is
not possible, although some interesting compounding
techniques for omeprazole have been reported.112-115 In
358 Am J Health-Syst Pharm Vol 56 Feb 15 1999
addition, lansoprazole has FDA-approved labeling for
administration by nasogastric tube with some fruit
juices.116 One open-label study involving 75 mechani-
cally ventilated surgery patients found a compounded
omeprazole suspension effective in preventing stress-
induced bleeding.114 Larger comparative studies are
needed to determine efficacy and assess the potential
for adverse effects such as pneumonia (from increased
gastric pH, as postulated for the H2-receptor antago-
nists) and other unanticipated problems.
Although medications may have different mecha-
nisms for their protective effects, there is no evidence
that combination therapy is more effective than a
single agent for initial prophylaxis, but the potential
risk of adverse effects would increase with combination
therapy. Therefore, combination therapy for initial
prophylaxis cannot be recommended. Combination
therapy for the prevention of recurrent bleeding is
discussed further in this document (see Prevention of
recurrent bleeding).
Efficacy of prophylactic agents: Prevention
of bleeding
A substantial number of clinical trials, a majority of
which were randomized, have involved comparisons of
medications used for stress ulcer prophylaxis.117-174 In
general, no significant differences between medica-
tions used for the prophylaxis of clinically important
bleeding have been found. However, in a majority of
studies, the sample size needed to detect a difference
between treatment groups in clinically important
bleeding was not calculated. Therefore, the number of
patients enrolled in any given study was often insuffi-
cient to preclude a Type II statistical error. Other studies
have found substantial differences in bleeding between
groups, but the frequency of bleeding was unexpectedly
high for one of the groups. For example, Phillips et al.175
reported clinically important bleeding (the definition
of clinically important was different than the definition
used in these guidelines) in 4 (16%) of 25 patients
receiving ranitidine by continuous i.v. infusion and 1
(3%) of 33 patients receiving omeprazole suspension.
Compared with the results of other studies, 16% is a
high rate of bleeding with ranitidine.64,176
In the largest RCT published to date, 1200 patients
who required mechanical ventilation for at least 48
hours were assigned to receive either nasogastric sucral-
fate slurry (1 g every 6 hours) and i.v. placebo or i.v.
ranitidine (50 mg every 8 hours) and nasogastric place-
bo.176 The patients in this multicenter study were ad-
mitted to medical and surgical services (approximately
60% and 40%, respectively). There were relatively few
patients from special populations: CNS surgery, 49
patients; trauma, 158; burns, 12; and transplantation,
19. These special populations were not discussed sepa-
rately. Although the estimated sample size was based
on the power to detect differences in rates of pneumo-

nia (power, or 1 = 75%), the rates of clinically impor-
tant bleeding and mortality were additional study ob-
jectives, and the trials power to detect a difference in
bleeding rate was 90%. A significant difference in favor
of the H2-receptor antagonist (ranitidine) compared
with sucralfate was noted. Ten (1.7%) of the 596 pa-
tients in the ranitidine group and 23 (3.8%) of 604
patients in the sucralfate group had clinically impor-
tant bleeding (relative risk, 0.44; 95% CI, 0.210.92; p =
0.02). Endoscopic confirmation of an upper GI source
of bleeding was obtained for 3 patients in the ranitidine
group and 10 in the sucralfate group. An additional
patient in the ranitidine group had an upper GI source
of bleeding confirmed by angiography and red blood
cell scanning. Because invasive diagnostic testing was
left to the discretion of participating physicians, the
source of bleeding was not found for 19 patients. In
addition, no differences were noted in the overall
length of stay or mortality. Therefore, the largest RCT
conducted to date has not definitively determined the
agent of choice for the prevention of clinically impor-
tant GI bleeding.
Five meta-analyses have been conducted to resolve
some of the discrepancies noted between RCTs, includ-
ing the issue of inadequate sample size.5,68-71 None of
these meta-analyses included the recently published
RCT by Cook et al. (1998) and the Canadian Critical
Care Trials Group (Table 2).176 The other major limita-
tions of these analyses have been discussed previously.
In general, the meta-analyses found H2-receptor antag-
onists and antacids to be more effective than no pro-
phylaxis, but in some cases the 95% CIs were wide,
indicating substantial variation in the data. Only one
trial compared sucralfate with no prophylaxis, and this
trial was included in the 1996 meta-analysis by Cook et
al.5 The results of these meta-analyses were conflicting
when medications were compared. In the meta-analy-
ses by Lacroix et al.68 and Tryba,69 H2-receptor antago-
nists were compared with antacids, but the 95% CIs
included 1, indicating that the two regimens did not
differ significantly. In the 1991 meta-analysis by Cook
et al.,70 H2-receptor antagonists were significantly more
effective than antacids for preventing overt bleeding,
but the therapies were similar in preventing clinically
important bleeding.
Tryba71 found sucralfate to be significantly more
effective than H2-receptor antagonists and similar in
efficacy to antacids (OR = 0.532; 95% CI, 0.3030.933).
Cook et al.70 (1991) found sucralfate to be similar to H2-
receptor antagonists or antacids for preventing overt
and clinically important bleeding.
Given the disparities noted in the previous meta-
analyses, Cook et al.5 (1996) conducted a meta-analysis
to resolve the apparent discrepancies. This meta-analy-
sis included studies that were not available when the
initial meta-analyses were completed. In addition to
being significantly more effective than no prophylaxis,
Stress ulcer prophylaxis ASHP Report
H2-receptor antagonists were found to be significantly
more effective than antacids in preventing overt bleed-
ing but not clinically important bleeding. Sucralfate
was similar to antacids or H2-receptor antagonists for
prophylaxis of both overt bleeding and clinically im-
portant bleeding.
While useful, this meta-analysis raises some impor-
tant questions.5 For example, the definitions for overt
and clinically important bleeding are very explicit,
which contrasts to the definitions used in many of the
randomized investigations that were analyzed. It is not
possible to derive rates of clinically important bleeding
from many of the trials, particularly if a rigid definition
is used. The meta-analysis also included RCTs from a
variety of populations that have usually been studied as
distinct populations (e.g., patients with head and ther-
mal injuries). Even if one assumes that the pathogenesis
of bleeding is similar, there may be differences in the
frequencies of bleeding compared with populations
studied more frequently (e.g., general medical and sur-
gical ICU patients). If the frequency of bleeding has
decreased over time as a result of improvements in the
care of the ICU patient (which is difficult to verify
because many recent studies have not included a no-
treatment group), this could have also influenced the
results of the meta-analysis. Finally, the results of this
meta-analysis are somewhat inconsistent with the find-
ings of the large RCT recently published by the same
lead authors with regard to possible differences in med-
ication efficacy.176
Recommendation (adults): Given the conflicting results of
several meta-analyses and a recent RCT (both with strengths
of evidence = A), the choice among antacids, H2-receptor
antagonists, and sucralfate for use as prophylactic agents to
prevent clinically important bleeding associated with stress
in adult patients admitted to general medical and surgical
ICUs should be made on an institution-specific basis. This
choice should take into account concerns regarding adminis-
tration (e.g., functioning GI tract), adverse-effect profile, and
total costs. (Strength of evidence = D) Insufficient data on
misoprostol or the proton-pump inhibitors are available to
allow any recommendation about these agents to be made.
Recommendation (pediatrics and special populations): The
lack of comparative trials of these agents in pediatric and
special populations (e.g., patients with burns, trauma pa-
tients, patients undergoing neurosurgical procedures or with
neurologic disorders, and transplantation patients) precludes
definitive recommendations as to the agent of choice in these
situations. The choice of agent should be made on an institu-
tion-specific basis and should take into account concerns
about administration (e.g., functioning GI tract), adverse-
effect profile, and total costs.
Efficacy of prophylactic agents: Mortality
Many of the available studies did not include mortal-
ity outcomes, and still fewer specifically associated
mortality with bleeding. In the largest RCT to date,
there was not a significant difference in mortality be-
tween ranitidine recipients and sucralfate recipients
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 359
ASHP Report Stress ulcer prophylaxis

despite the finding of a lower frequency of clinically Table 4.

important bleeding with ranitidine.176 This may be Meta-analyses Investigating the Risk of Mortality
partially explained by the relatively low frequency of with and without Stress Ulcer Prophylaxis
bleeding in both groups. Any attempt to attribute dif- No.
ferences in mortality to any single intervention in ICU Reference Comparisona Trials Resultsb
patients must be interpreted with caution given the 69 H2-RAs or 11 CI included 1
antacids
problems with controlling multiple confounding vari- (combined
ables. Furthermore, the limitations associated with the group) versus
extraction and interpretation of this information from control
Sucralfate versus 9 OR and CI < 1 (lower
the original trials must be appreciated during consider-
H2-RAs or rate of mortality
ation of the results of published meta-analyses that antacids with sucralfate)
have investigated the mortality associated with various (combined
forms of prophylaxis. group)
70 Antacids versus 6 OR = 1.06,
In a meta-analysis by Tryba69 in 1991, sucralfate was control CI = 0.671.66
associated with a lower mortality rate than use of either H2-RAs versus 9 OR = 0.80,
a H2-receptor antagonist or an antacid. No significant control CI = 0.541.18
differences in mortality were found between any of the H2-RAs versus 14 OR = 1.16,
antacids CI = 0.831.61
groups in the 1991 meta-analysis by Cook et al.70 (Table Antacids versus 8 OR = 1.22,
4). In contrast to the finding of the 1991 meta-analysis, sucralfate CI = 0.831.79
sucralfate was associated with a lower rate of mortality H2-RAs versus 3 OR = 1.25,
sucralfate CI = 0.612.58
than antacids in two other meta-analyses conducted by 177 Antacids versus 5 OR = 1.36,
Cook et al.5,177 (1994 and 1996). When medications control CI = 0.832.24
were compared with no prophylaxis, all the CIs in the H2-RAs versus 11 OR = 1.03,
published meta-analyses included 1, the threshold of control CI = 0.731.48
H2-RAs versus 15 OR = 1.06,
importance, suggesting no substantial differences in antacids CI = 0.781.46
mortality. Sucralfate versus 11 OR = 0.70,
antacids CI = 0.520.94
Adverse effects of prophylactic agents (lower rate of
mortality with
Most adverse effects attributable to antacids, H2- sucralfate)
receptor antagonists, and sucralfate are uncommon Sucralfate versus 7 OR = 0.71,
and occur in less than 1% of adult patients, particularly H2-RAs CI = 0.491.04
5 Antacids versus 3 OR = 1.42,
when given on a short-term basis (e.g., for less than two control CI = 0.822.47
weeks).178 The frequency of adverse effects may increase H2-RAs versus 15 OR = 1.15,
if certain diseases are present, such as renal failure, control CI = 0.861.53
when electrolyte accumulation secondary to antacid H2-RAs versus 14 OR = 0.89,
antacids CI = 0.661.21
administration or CNS disturbances secondary to ad- Sucralfate versus 4 OR = 1.06,
ministration of H2-receptor antagonists may occur. Su- control CI = 0.671.67
cralfate may cause substantial elevations in serum alu- Sucralfate versus 11 OR = 0.73,
antacids CI = 0.540.97
minum concentrations in adult patients with chronic (lower rate of
renal insufficiency or in the elderly,179 although this mortality with
does not appear to be a problem when the drug is used sucralfate)
for less than two weeks in critically ill patients.180,181 Sucralfate versus 11 OR = 0.83,
H2-RAs CI = 0.621.09
Elevated aluminum concentrations and resultant toxic-
a
ity are more of a concern in children with renal dys- H2-RAs = histamine H2-receptor antagonists.
b
OR = odds ratio, CI = 95% confidence interval. Exact values provided
function, particularly given that well-defined dosage when available; some values were extrapolated from figures.
guidelines have not been established.182 Although alu-
minum hydroxide-containing antacids and sucralfate
may be used to lower phosphate levels in patients with tube may have to be replaced, potentially causing pa-
uremia, they may cause unwanted hypophosphatemia tient discomfort and resulting in complications from
in patients with normal renal function.183 placement of a new tube (e.g., esophageal perforation,
Some products given by oral, nasogastric, or enteral aspiration, inappropriate placement in the trachea).185
administration may result in local adverse effects. For Although not well studied, there are potential inter-
example, constipation may occur with aluminum-con- actions between enteral feeding products and medica-
taining antacids and sucralfate and diarrhea may occur tions administered enterally for prophylaxis. Such in-
with magnesium-containing antacids at frequencies teractions could result in clogged feeding tubes or di-
higher than 1%.184 Sucralfate and antacids may occlude minished medication efficacy (e.g., by inhibiting the
feeding tubes. If the occlusion cannot be removed, the local actions of sucralfate or interfering with the ab-

360 Am J Health-Syst Pharm Vol 56 Feb 15 1999


sorption of other medications). When intermittent
feedings are used, interactions can be minimized by
giving the feedings and medications at different times.
When continuous feedings are used in conjunction
with any medications, the feedings should be tempo-
rarily stopped. The tube should be flushed with water
before the medication is administered. After the medi-
cation is administered, the tube should again be flushed
with water to ensure passage through the tube. It is
probably unnecessary to discontinue postpyloric (jeju-
nal) feedings for administration of sucralfate, because
sucralfate binds to the stomach mucosa. For more de-
tails about enteral feedingmedication interactions and
methods to prevent them, the reader is referred to
published reviews.111,186
Case reports suggest that sucralfate may contribute
to esophageal and GI bezoar formation, especially
when given in conjunction with enteral feedings in
patients with motility disorders.187-190 In addition to
technical problems related to the removal of bezoars,
complications such as intestinal obstruction and perfo-
ration have been reported in pediatric patients. For
example, intestinal obstruction and perforation were
reported with sucralfate in a low-birth-weight infant
who was given 250 mg every eight hours by nasogastric
tube.191 Also, bezoars, hypermagnesemia, and intestinal
perforation have been reported with liquid antacids
used in premature infants and newborns.192,193 There-
fore, sucralfate and antacids should be used with cau-
tion, particularly in premature infants.
The H2-receptor antagonists are associated with a
number of adverse effects that occur infrequently but
may lead to a consultation with a specialist, a diagnos-
tic test, a new medication to treat the adverse effect, or
a switch to another medication for prophylaxis. Poten-
tial adverse effects include hepatitis, cytopenia, and
cardiovascular and CNS toxicities. The exact frequency
of each of these problems is difficult to determine, but
estimates range from 0.0023% for cytopenia to 1.9% for
CNS toxicity.194-199 The low rate of these adverse effects
in adults and limitations associated with postmarketing
surveillance studies prohibit accurate comparisons of
the frequencies of such effects among medications in
this class. The lack of studies in the pediatric population
precludes an accurate assessment of the frequency of
particular adverse effects. There is a possibility that
pediatric patients may be more susceptible to some
adverse effects (e.g., thrombocytopenia associated with
cimetidine49) than adults. Similarly, the lack of infor-
mation related to pediatric dosing could result in either
underdosing with diminished efficacy or overdosing
with increased adverse effects.
H2-receptor antagonists and proton-pump inhibitors
have the potential for drugdrug, drugnutrient, and
drugtest interactions through a variety of mechanisms.
For example, some drugdrug interactions are mediated
through effects on the cytochrome P-450 systems in the
Stress ulcer prophylaxis ASHP Report
liver. Although a number of interactions with some of
these acid-suppressing agents are of potential concern
(e.g., warfarin, ketoconazole, phenytoin, theophylline),
few are clinically important when patients are adequate-
ly monitored.200 However, there may be other reasons for
avoiding particular medications. For example, cimeti-
dine may increase serum creatinine concentrations with-
out affecting the glomerular filtration rate by competi-
tion for tubular secretion in the kidneys.201 This could be
interpreted as renal dysfunction in patients receiving
nephrotoxic medications, leading to inappropriate re-
ductions in the dosage of the suspected medication.
Other interactions may occur as a result of the acid-
suppressing properties of these two classes of agents.
Sucralfate and antacids can affect the absorption of
other medications. Although most problems can be
avoided if doses of sucralfate and antacids are separated
from doses of potentially interacting substances, this
practice is often not used.202 Potentially interacting med-
ications should be administered one to two hours before
the sucralfate dose. Furthermore, medications may inter-
act with sucralfate and antacids despite separation (e.g.,
the bioavailability of quinolone antimicrobials has been
substantially reduced by sucralfate even when the two
products were separated by two or more hours).203,204
Test interference is a cause for concern with all
medications used for stress ulcer prophylaxis. This con-
cern also applies to agents that do not alter pH (e.g.,
sucralfate interferes with at least one method of occult
blood testing).205
A full discussion of all potential drugdrug interac-
tions with these agents is beyond the scope of these
guidelines; however, comprehensive reviews have been
published.206
The proton-pump inhibitors have few clinically im-
portant adverse effects. The most common concerns are
mild GI or CNS toxicities.207 The prostaglandin ana-
logue misoprostol is rarely used clinically for prophy-
laxis and is associated with substantial adverse effects
compared with placebo (nausea, abdominal pain, diar-
rhea).208
Lansoprazole (pregnancy risk category B) and ome-
prazole (FDA pregnancy risk category C) should be used
in pregnant or nursing mothers only when the poten-
tial benefits exceed the potential risks.116,209 Similar
caution is advised for the H2-receptor antagonists (preg-
nancy risk category B for cimetidine, famotidine, and
ranitidine; pregnancy risk category C for nizatidine)
and sucralfate (pregnancy risk category B).110,210-213 Mis-
oprostol is an abortifacient, may result in miscarriage
(pregnancy risk category X), and is generally contrain-
dicated in pregnant women, women of childbearing
age, and nursing mothers.214
Pneumonia. The frequency of nosocomial pneu-
monia associated with stress ulcer prophylaxis has been
widely debated. In addition to patient morbidity and
economic concerns, mortality rates associated with
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 361
ASHP Report Stress ulcer prophylaxis
pneumonia may be as high as 70%.215 There are multi-
ple mechanisms by which bacteria may enter the lungs,
including inhalation, hematogenous spread, contigu-
ous spread, direct inoculation, aspiration of secretions,
and translocation from the GI tract.216 The vast majority
of studies investigating a possible connection between
pneumonia and stress ulcer prophylaxis have been
conducted in adults. In the few studies involving pedi-
atric patients receiving stress ulcer prophylaxis, pneu-
monia was usually not studied. When pneumonia was
reported, it was typically not a primary endpoint.65
Early reports of adult patients receiving antacids and
cimetidine demonstrated that the stomach and upper
airways had similar bacterial flora, suggesting retro-
grade transmission from the stomach.217 Gastric coloni-
zation was uniformly seen in patients with alkalinized
stomach contents.218 However, a positive correlation
between increased gastric pH and colonization with
bacteria does not mean there is a linear relationship
between acid-suppressing drugs and pneumonia.
It is also important to keep in mind that the tech-
niques used to diagnose pneumonia have continued to
evolve. Bronchoscopy, which is now a widely used and
accepted diagnostic tool in research, was not performed
in older studies of medication-associated pneumonia.
Although the sensitivity and specificity of bronchosco-
py for diagnosis of infection have been improved by
newer techniques such as use of a protected-specimen
brush, morbidity and economic concerns have been
expressed about its widespread clinical use.219 Other
methods are less invasive but often have lower sensitiv-
ity and specificity, particularly when not performed
appropriately.
Agents that do not alter gastric pH, such as sucralfate,
may be less likely to result in pneumonia through retro-
grade transmission or translocation of bacteria.220,221
When protected specimens, bronchoalveolar lavage, or
both were used, one prospective randomized, double-
blind study involving 141 patients showed no differ-
ence in the effect of antacids or sucralfate on gastric
acidity or rates of bacterial colonization or ventilator-
associated pneumonia.145 Decreased gastric acidity was
observed in conjunction with greater colonization of
the stomach but not of the upper respiratory tract. In
another prospective investigation in which samples
were obtained by bronchoscopy, mechanically venti-
lated patients were randomly assigned to receive either
antacids or sucralfate and then studied for risk factors
associated with colonization and pneumonia.222 As in
the previous study, gastric colonization was not associ-
ated with the development of pneumonia, but duration
of mechanical ventilation and upper-respiratory-tract
colonization were found to be risk factors. A more
recent study on this issue had a double-blind, double-
dummy design and compared the growth of gastric
pathogens in 140 patients undergoing elective surgery
who were randomly assigned to receive either sucralfate
362 Am J Health-Syst Pharm Vol 56 Feb 15 1999
or antacids.223 Patients gastric and respiratory tract
contents were cultured for routine aerobic bacteria and
fungi before surgery and daily throughout the hospital-
ization until the patient was discharged or died. Clini-
cal endpoints included upper GI tract bleeding (grossly
bloody fluid in nasogastric aspirate that failed to clear
with saline lavage), pneumonia, wound infection, and
urinary tract infection. New gastric microorganisms
appeared in 24% of the patients receiving sucralfate and
51% of the patients receiving antacids. The rates of
gastric bleeding, pneumonia, and nosocomial infection
were not significantly different.
Other risk factors for nosocomial pneumonia have
been identified and ranked according to supporting evi-
dence.224 In addition to host factors (e.g., gastric hypoa-
cidity) and environmental factors, the use of a nasogas-
tric tube to administer medications (with the attendant
risks of aspiration and guaiac-positive stools from naso-
gastric manipulation), along with the volume and pH of
medications and feedings administered, determines the
frequency of pneumonia. However, despite these other
risk factors, a committee associated with the Centers for
Disease Control and Prevention has recommended that
non-pH-altering medications (e.g., sucralfate) be used for
prophylaxis in mechanically ventilated patients (ages
not specified).225 The recommendation was suggested
for implementation in many hospitals. While sucralfate
may not contribute to translocation or colonization of
the airways by bacteria, animal models of aspiration
pneumonia have demonstrated that the volume of fluid
administered with sucralfate and the drugs minimal
buffering activity may increase the risk of acid aspiration
and pulmonary edema.226
In the RCT by Cook et al.176 that involved 1200
patients, the determination of ventilator-associated
pneumonia was based on criteria modified from the
Centers for Disease Control and Prevention. The study
had sufficient power to detect a 25% difference in rates
of pneumonia (power = 75%). Bronchoalveolar lavage
or protected specimen brush sampling was used for
diagnostic confirmation in patients with pneumonia
suspected by clinical criteria. One potentially con-
founding variable was the use of enteral feedings by a
majority (approximately 70%) of patients in each
group. Pneumonia was diagnosed in 114 (19.1%) of 596
patients in the ranitidine group and 98 (16.3%) of 604
patients in the sucralfate group, a difference that was
not significant (relative risk, 1.18; 95% CI, 0.921.51; p
= 0.19). It is possible that a significant, albeit small,
difference in favor of sucralfate would be found if a
larger trial were conducted. There were five patients
with definite pneumonia in the ranitidine group
(0.8%) but none in the sucralfate group (95% CI, 0.1
1.6; p = 0.03).
Five meta-analyses of the frequency of nosocomial
pneumonia associated with stress ulcer prophylaxis
have also been conducted (Table 5). Two of the investi-
 Stress ulcer prophylaxis ASHP Report

Table 5. had a lower rate of pneumonia than patients who

Meta-analyses Investigating the Risk of Pneumonia received an antacid or an H2-receptor antagonist. How-
with Medications Used for Stress Ulcer Prophylaxis
ever, in the other two meta-analyses, no significant
No.
differences among any of the treatments were
Reference Comparisona Trials Resultsb
found.5,227 However, these findings should be interpret-
69 Sucralfate versus 6 OR and CI < 1 (lower
H2-RAs or rate of pneumonia
ed with caution given the methodological differences
antacids with sucralfate) (e.g., diagnostic criteria for pneumonia) among the
(combined trials being evaluated, the trials not included in the
group) meta-analyses, and the tendency to combine the results
71 Sucralfate versus 5 OR = 0.498,
H2-RAs CI = 0.3160.783 for acid-suppressive therapies together (i.e., H2-receptor
(lower rate of antagonists and antacids).228
pneumonia with Summary. Antacids, H2-receptor antagonists, and
sucralfate)
4
sucralfate have been used for many years and have well-
Sucralfate versus OR = 0.402,
antacids CI = 0.2350.687 delineated adverse-effect profiles, with the one notable
(lower rate of exception of nosocomial pneumonia associated with
pneumonia with pH-altering agents in critically ill patients. Although
sucralfate)
227 Prophylaxis 3 OR = 0.63, data from RCTs or large surveillance studies are lacking
adjusted CI = 0.241.62 for pediatric patients, all these agents have been used in
according to various age groups for multiple GI disorders with rela-
gastic pH tively few adverse effects. Experience with the proton-
versus no
adjustment pump inhibitors for stress ulcer prophylaxis is limited,
Antacids or H2- 4 OR = 0.42, but experience treating peptic ulcers suggests that these
RAs versus CI = 0.611.10 agents have a low rate of serious adverse effects in adults
placebo versus
control
when used on a short-term basis. When compared with
(combined that of other agents, the adverse-effect profile of miso-
group) prostol, as well as the fact that there are limited studies
Sucralfate versus 4 OR = 0.55, of efficacy, precludes its use for stress ulcer prophylaxis.
antacids or H2- CI = 0.281.06
RAs (combined Recommendation (adults and pediatrics): It is recommend-
group) ed that patients with a history of serious reactions to
177 Sucralfate versus 6 OR = 0.50, antacids, H2-receptor antagonists, proton-pump inhibitors,
antacids or H2- CI = 0.210.79 or sucralfate avoid future use of the offending agent. There
RAs (combined (lower rate of are no other absolute contraindications that would preclude
group) pneumonia with the short-term use of any of these medications for stress
sucralfate)
8 ulcer prophylaxis. However, unless the benefits clearly ex-
5 H2-RAs versus OR = 1.25,
control CI = 0.782.00 ceed the risks, it is recommended that sucralfate and antac-
H2-RAs versus 3 OR = 1.01, ids be avoided in neonates (particularly premature neonates)
antacids CI = 0.651.57 because of the possibility of adverse effects (e.g., bezoar
Sucralfate versus 2 OR = 2.11, formation, accumulation of aluminum and magnesium).
control CI = 0.825.44 Also, it is recommended that aluminum-containing prod-
Sucralfate versus 6 OR = 0.80, ucts such as sucralfate be avoided in children with renal
antacids CI = 0.561.15 failure because dosing information has not been well estab-
Sucralfate versus 11 OR = 0.78, lished. Whether acid-suppressing agents are associated
H2-RAs CI = 0.621.09
with a higher rate of pneumonia than sucralfate is unre-
a
H2-RAs = histamine H2-receptor antagonists. solved, although any difference between these medications
b
OR = odds ratio, CI = 95% confidence interval. Exact values provided
when available; some values were extrapolated from figures. would appear to be small. It is recommended that potential
adverse effects be considered as part of the economic anal-
ysis when an agent is chosen (see Economic analysis).
(Strength of evidence = D)
gations published in 1991 were conducted by Tryba and
included many of the studies previously mentioned. Initial dosage
One meta-analysis found a lower rate of pneumonia Some of the dosages listed in Table 6 had to be
with sucralfate use than with use of either an H2- extracted from the literature because stress ulcer pro-
receptor antagonist or an antacid.69 The second meta- phylaxis is not an FDA-approved indication for most of
analysis showed a lower rate of pneumonia with sucral- the medications used for this purpose.110,209-211,213 The
fate than with H2-receptor antagonists and for sucral- dosages included in Table 6 have been commonly used
fate than with antacids.71 The other three meta-analyses for initiating prophylaxis against stress-induced bleed-
were conducted by Cook et al. and were published in ing in adults. In some of the studies, dosages were
the 1990s. In the 1994 meta-analysis by Cook et al.177 subsequently adjusted according to gastric pH measure-
involving six investigations, sucralfate-treated patients ments. Dosages for patients with renal dysfunction

Vol 56 Feb 15 1999 Am J Health-Syst Pharm 363

ASHP Report Stress ulcer prophylaxis

Table 6. and another study involving patients from birth to 18

Initial Adult Dosage Regimens for Agents Used years of age (maximum dosage, 1000 mg/day).48,49,231
for Prophylaxis of Stress-Induced Bleedinga Pharmacokinetic or dosage studies in pediatric pa-
Normal Reduced tients have been published, but these are not necessar-
Renal Renal ily related to the prevention of stress-induced bleeding.
Medication Function Function
For example, Martyn et al.236 determined the pharmaco-
Cimetidine110,178 300 mg four If CLcr <30 mL/ kinetics of cimetidine in children with burn injuries.
times a day min: 300 mg Twenty-one children ranging in age from 0.3 to 17.5
p.o., NG, or i.v. twice a day
or 50 mg/hr by p.o., NG, or i.v. years were administered cimetidine in doses of 1015
continuous i.v. or 25 mg/hr by mg/kg. These children had higher cimetidine clearanc-
infusion continuous i.v. es and shorter elimination half-lives than healthy or
infusion
burned adults (primarily because of greater renal clear-
Famotidine178,210 20 mg twice If CLcr < 30 mL/
daily p.o., NG, min: 20 mg ance). The authors suggested that in order to maintain
or i.v. or 1.7 once daily p.o., a gastric pH of 4, continuous infusions of cimetidine
mg/hr by NG, or i.v. or would be required.
continuous i.v. 0.85 mg/hr by
infusion continuous i.v. Another study looked at the pharmacokinetics of
infusion cimetidine in 30 critically ill children age 4.5 to 15
Ranitidine178,211 150 mg twice If CLcr < 50 mL/ years.237 The patients received a mean dosage of 26 mg/
daily p.o. or min: 150 mg kg/day administered in four doses infused over 15
NG, 50 mg once or twice
every 68 hr daily p.o. or minutes. Patients receiving 20 mg/kg/day maintained
i.v., or 6.25 NG, 50 mg plasma cimetidine concentrations at 0.5 g/mL for
mg/hr by every 1224 hr longer periods. The investigators found a significant (p
continuous i.v. i.v., or 24 mg/
infusion hr by continu-
< 0.001) inverse correlation between age and total body
ous i.v. infusion clearance (r = 0.75, p < 0.001) and age and apparent
Omeprazole112-115,209 40-mg loading No adjustment volume of distribution (r = 0.76, p < 0.001). They
dose, then 20 necessary concluded that a dosage of cimetidine of 2030 mg/kg/
40 mg daily
p.o. or NG day given in six divided doses would provide more
Sucralfate178,213 1 g four times No adjustment optimal steady-state plasma cimetidine concentra-
daily p.o. or necessary tions.
NG
Ranitidine was studied in 12 children ranging in age
a
NG = by nasogastric tube, CLcr = creatinine clearance. Dosages can from 3.5 to 16 years with peptic ulcer disease.238 Each
be modified on the basis of response or adverse effects.
child received ranitidine by continuous i.v. infusion,
with the rate adjusted to achieve at least 90% inhibition
were mostly taken from published guidelines.110,209-211,213 of gastric acid secretion. The dosage and response data
No well-documented maximum dosage for each agent were used to design intermittent dosage regimens, con-
has been reported, although studies involving pH de- sisting of i.v. bolus doses given every 6 hours and then
terminations often set an arbitrary upper limit. Antac- oral doses given every 12 hours. The i.v. dose ranged
ids were not included in Table 6 because of the large from 0.13 to 0.8 mg/kg. Another study involving ranit-
number of commercially available products with differ- idine for neonates with documented gastric bleeding
ing acid-neutralizing capacities and the large number of used a loading dose of 0.6 mg/kg followed by a contin-
regimens used in the literature (many adjusted on the uous infusion of 0.15 mg/kg/hr.239 No adverse effects
basis of gastric pH determinations); the reader is en- from the ranitidine were noted.
couraged to consult available studies.36-40,42,54,90-92 The Treem and colleagues240 studied i.v. famotidine in 18
dosage guidelines in Table 6 are based on limited clini- children ranging in age from 0.16 to 5.7 years who were
cal data and may need to be adjusted according to admitted to a pediatric ICU after major elective ortho-
adverse effects or clinical response.229 pedic or cardiac surgery. Doses required to keep the
Dosages for pediatric patients can be estimated from gastric pH above 4 for at least six hours ranged from 0.4
the few studies that have been published on stress ulcer to 0.8 mg/kg. Famotidine was pharmacokinetically
prophylaxis (Table 7), extrapolated from pediatric evaluated in 14 children ranging in age from 1.25 to
handbooks that describe dosing for related conditions 15.5 years who were diagnosed with gastric or duodenal
(e.g., GI bleeding), or extrapolated from pharmacoki- ulcers.241 Although famotidine effectively treated the
netic studies.48,49,56,57,63,65,88,168,230-235 In published studies, ulcers, 0.5 mg/kg i.v. or orally twice daily failed to keep
i.v. ranitidine was given in dosages of 26 mg/kg/day the pH above 5 for the dosage interval. These two
(in three or four divided doses) to preterm newborns studies suggest that, for children, famotidine should be
and children up to 18 years of age.63,65,232,233,235 Cimeti- given every six hours or, at least, every eight hours.
dine was given i.v. in dosages of 1524 mg/kg/day (in In summary, pharmacokinetic studies suggest that
four divided doses) in two studies involving newborns children clear H2-receptor antagonists faster and have

364 Am J Health-Syst Pharm Vol 56 Feb 15 1999

 Stress ulcer prophylaxis ASHP Report

Table 7.
Studies of Stress Ulcer Prophylaxis in Pediatric Populationsa
Study Design and Population No. with Clinically
Reference (No. Patients or Admissions) Age Medication Important Bleeding
88 Retrospective; thermal injury 35 days to 13 yr; None stated 36
to 1393% (mean, 29%) mean, 4.3 yr
BSA; (477)
230 Retrospective; thermal injury 4 wk to 15 yr Milk or feeding formula plus 2
to 592% BSA (582) diazepam
48 Prospective, randomized; Birth to 18 yr; mean, Cimetidine 5 mg/kg i.v. NA
general ICU (40) 1.85 yr every 6 hr (1 g/day
maximum)
231 Prospective, randomized; 3041.5 wk Cimetidine 6 mg/kg i.v. NA
general ICU (33) every 6 hr
232 Prospective, randomized; Birth to 18 yr; mean, Ranitidine 24 mg/kg NG NA
general ICU (40) 2.64.3 yr (varied by every 12 hr or 0.751.5
group) mg/kg i.v. every 6 hr
49 Prospective, randomized; Full-term neonates Cimetidine 3.755 mg/kg NA
general ICU (100) i.v. every 6 hr
65 Prospective, randomized; Birth to 20 yr; mean, Ranitidine 1.5 mg/kg i.v. 7/35 in control group
general ICU (140) 4.6 yr every 6 hr, sucralfate 0.5 versus 6/105 in
g (<10 kg) or 1 g (>10 combined medica-
kg) every 6 hr, antacid tion groups (p <
(almagate) 0.250.5 mL/ 0.05); no significant
kg every 2 hr differences for any
single medication
versus control group
56 Prospective, observational; Mean S.D., None None
general ICU (208) 38 53.5 mo
57 Prospective, observational; Mean S.E., Various (per discretion of 2/698 with no prophy-
general ICU (984) 62.6 2.1 mo physician) laxis versus 2/286
with prophylaxis
168 Prospective, randomized; 35 days to 9.85 yr; Famotidine or pirenzepine NA
cardiac surgery (79) mean, 2.62 yr 1 mg/kg/day i.v. (3 doses
if <10 kg), 0.5 mg/kg/day
if serum creatinine > 3
mg/dL
63 Prospective, randomized; Neonates, mostly Ranitidine 1.67 mg/kg i.v. NA
general ICU (53) preterm; mean, every 8 hr
32 wk gestation
233 Prospective, observational; 2 wk to 264 mo; Ranitidine 26 mg/kg/day None
general ICU (45) median, 36 mo i.v. (mean, 3.3 mg/kg/
day) given at intervals of
6, 8, or 12 hrb
66 Prospective, observational; 3 days to 18 yr; mean, Various (per discretion of 6/990 with no prophy-
general ICU (1006) 61.5 mo physician) laxis versus 10/110
with prophylaxis
a
Only studies with at least 25 patients were included. BSA = body surface area, ICU = intensive care unit, NA = not available, NG = by nasogastric tube.
b
Administered every eight hours in 89% of patients.

larger volumes of distribution than adults and that
doses should be given either by continuous infusion or
more frequently than those recommended for adults.
Studies addressing the proper dosing of agents for stress
ulcer prophylaxis in pediatrics are needed.
In general, there is little dosing information for the
neonatal population, in particular, premature neo-
nates. Dosing in premature neonates is further compli-
cated by decreased renal function secondary to disease
or lack of maturation. Caution should be exercised
when H2-receptor antagonists are used in combination
with tolazoline. Tolazoline may still be used in some
institutions to treat pulmonary hypertension in neo-
nates and has been associated with gastric bleeding. Case
reports have implicated both cimetidine and ranitidine
with reversal of tolazolines histamine-mediated effects
on pulmonary vasculature.242 In general, the use of ant-
acids and sucralfate should be avoided in premature
infants because of the possibility of complications (see
Adverse effects of prophylactic agents).
Doses of H2-receptor antagonists are often reduced
(or the intervals extended) for patients with renal dys-
function, because all these medications have slower
clearances and longer half-lives in this population.243
These alterations in dose or interval have been based on
expected serum drug concentrations, because well-con-
trolled studies have not investigated various dosage
regimens in preventing stress-induced bleeding.
Whether doses or intervals of H2-receptor antagonists
need to be adjusted in patients with severe hepatic
dysfunction or other diseases that might affect the
pharmacokinetic properties of the agents is not known.

Vol 56 Feb 15 1999 Am J Health-Syst Pharm 365

ASHP Report Stress ulcer prophylaxis

There are no adequate dosage guidelines for children Monitoring

with renal dysfunction. Many practitioners recom-
mend estimation of renal function by established
methods for children. Most methods yield creatinine
clearances normalized to an average BSA (mL/min/1.73
m2). Adjustments are then made by using adult guide-
lines for impaired renal function. Still other practitio-
ners may not make adjustments, believing that the risks
of excessive dosing would not outweigh the risk of
underdosing in children.
Gastric pH monitoring may help in developing
dosage regimens, especially in patients with renal dys-
function or immaturity (preterm infants). On days a
patient is being dialyzed, it is advisable to administer
the medications after dialysis to avoid rapid clearance
during the dialysis procedure.
Table 6 lists dosage regimens for commonly used
agents in adult patients. Some of the oral dosage regi-
mens are equivalent to the i.v. regimens in terms of
total daily dosage (e.g., cimetidine, famotidine), al-
though an argument could be made for larger oral
dosages on the basis of bioavailability differences be-
tween the two routes of administration. Table 8 pro-
vides pediatric doses for the H2-receptor antagonists
and sucralfate. The recommendations were derived
from limited data from published studies and were
based on toxicity as well as efficacy considerations.
For agents that do not affect gastric pH, such as
sucralfate, monitoring is limited to potential adverse
events and GI bleeding. However, for agents that neutral-
ize gastric acid, particularly antacids, monitoring has
frequently included pH determinations. No large, con-
trolled studies have been published that document a
benefit to pH monitoring in association with stress ulcer
prophylaxis. The issue is further complicated by differ-
ences in the validity and reliability of methods used to
measure gastric pH. Although monitoring with pH paper
is simple and is considered by many clinicians to be a
standard of practice for agents that raise gastric pH, this
method lacks accuracy.246 One study found that 33% of
gastric pH determinations were not 4, despite pH paper
testing demonstrating evidence to the contrary.247
A number of studies have concluded from gastric pH
determinations that continuous infusions of H2-recep-
tor antagonists are more effective than intermittent
dosage schedules.248-253 Many factors must be consid-
ered in the interpretation of these studies, beginning
with the role of gastric acidity in the pathogenesis of
stress ulceration. Although gastric acidity may have a
role in stress-induced damage, gastric acid is unlikely to
be the main cause of bleeding.254 Not only do many ICU
patients have hyposecretion of gastric acid,255 but gas-
tric pH fluctuates rapidly and may not be controlled

Table 8.
Pediatric Dosage Recommendations for H2-Receptor Antagonists and Sucralfate
Dosagea
Medication Neonates Infants Children
Cimetidine48,49,231,236,237 10 (520) mg/kg/day i.v. in 2040 mg/kg/day i.v. 3040 mg/kg/day i.v.
2 or 3 divided dosesb in 3 or 4 divided doses (1200 mg/day maximum)
in 6 divided doses
Famotidine168,240,241 Inadequate information 1.2 (12) mg/kg/day i.v. 1.6 (12) mg/kg/day i.v.
available to make dosage in 2 or 3 divided doses (40 mg/day maximum)
recommendations in 3 divided doses
Ranitidine63,65,232,233,235,238,239,244,245 Continuous i.v. infusion: 4.5 (36) mg/kg/day i.v. 6 (36) mg/kg/day i.v.
0.06250.2 mg/kg/hr in 3 divided doses (200 mg/day maximum)
Intermittent i.v. doses: If full in 4 divided doses
term, 1.53 mg/kg/day in 3
divided doses; if premature,
0.5 mg/kg/day in 2 divided
doses
Sucralfate65,234 Not recommendedc 40 mg/kg/day p.o. or NG 4080 mg/kg/day p.o. or NG
in 4 divided dosesd (lower end of range for
younger children, 4000
mg/day maximum)
in 4 divided dosesd
a
Dosages are for patients with normal renal function. NG = by nasogastric tube. There is a lack of data to make definitive dosage adjustments in pediatric
patients for renal dysfunction, but decreases in the total daily dosage of cimetidine, famotidine, and ranitidine would be logical. This could be done either by
decreasing individual doses while keeping the dosage interval the same as for patients with normal renal function or by extending the dosage interval and
keeping individual doses the same as for patients with normal renal function. No adjustment in the dosage of sucralfate is required for patients with renal
dysfunction.
b
In general, half-lives were longer in neonates (23.4 hours), more than likely because of immature renal function. There is inadequate dosage information
on premature neonates with respect to stratification by birth weight or gestational age. Thus, a wide range of dosages have been reported in the literature.
Many dosage handbooks and institutions use 510 mg/kg/day divided every 12 hours in premature neonates.
c
Inadequate information is available. Not recommended because of reports of bezoar formation in neonates (particularly premature neonates). Amount of
aluminum in adult doses of sucralfate may contribute to hypophosphatemia in neonates.
d
Dosage not well established. Bezoar formation with obstruction has been reported. Caution is advised when sucralfate is administered to any pediatric
patient, especially in cases of impaired gastric motility and dehydration.

366 Am J Health-Syst Pharm Vol 56 Feb 15 1999


even if dosages of antisecretory agents are individual-
ized.256,257 Gastric pH can also be increased by the pres-
ence of blood and bile in the GI tract. Although newer
methods of pH monitoring, such as noninvasive, intra-
mucosal pH measurements, may prove useful for pre-
dicting stress-induced bleeding, such measurements
have been studied primarily as indicators of systemic
tissue oxygenation and hence of overall mortality rates
in critically ill patients.258
Checking for microscopic bleeding by occult blood
testing techniques has similar limitations. Most impor-
tant, there is no proven relationship between micro-
scopic bleeding and outcomes such as clinically impor-
tant bleeding, although the results of one prospective
study suggest that occult bleeding for at least six days
increases the risk for overt bleeding.53 Overt bleeding is
defined as the presence of blood or coffee-ground
material in nasogastric aspirates, hematemesis, hema-
tochezia, or melena. Overt bleeding that results in
hemodynamic compromise or the need for blood trans-
fusions or surgery is clinically important. Therefore,
patients at risk for stress-related complications should
be routinely followed for overt bleeding.
When overt bleeding occurs, the patient should be
closely monitored for decreases in blood pressure (e.g.,
a decrease of 20 mm Hg or more in the diastolic pressure
during a 24-hour period), hemoglobin (e.g., 3 g/dL
during a 24-hour period), and hematocrit (e.g., 9%
during a 24-hour period), all of which suggest clinically
important GI bleeding in the absence of other causes.
When overt bleeding, with or without hemodynamic
compromise, continues despite conservative therapies
such as saline lavage, endoscopy is usually indicated.
Endoscopy can be used to confirm a GI source of
bleeding.
Recommendation (adults and pediatrics): It is recommended
that all patients receiving medications for stress ulcer pro-
phylaxis be monitored for bleeding and adverse drug effects
(see Adverse effects of prophylactic agents). Paper techniques
for measuring gastric pH have questionable validity and
reliability, and there is no evidence that adjusting the dosage
of pH-altering medications (antacids, H2-receptor antago-
nists, proton-pump inhibitors) on the basis of these measure-
ments influences patient morbidity or mortality. Despite the
lack of supporting data, pH monitoring for antacids may be
appropriate (goal pH of >3.54). Such monitoring may also
be useful for H2-receptor antagonists when standard dosage
regimens might not be appropriate (e.g., in cases of renal
dysfunction, for increased dosages due to perceived failure of
therapy, in pediatric patients). (Strength of evidence = D)
Other options for prophylaxis
Similar to the principles involved in preventing
global ischemia, a primary intervention for reducing
the frequency of stress-induced bleeding should be the
prevention of GI hypoperfusion and attendant ischem-
ic complications.259,260 If ischemia is prevented during
the early stages of injury, stress ulcer prophylaxis may
be unnecessary. In fact, acid inhibitors or neutralizers
Stress ulcer prophylaxis ASHP Report
may be harmful. In the case of acid neutralizers, increas-
ing gastric pH allows for bacterial overgrowth, with
subsequent spread to other organs.261
As discussed previously, the effect of enteral feedings
on the frequency of stress-induced bleeding and pneu-
monia has not been established through controlled
trials. Although gastric acid appears to play a role in
stress-induced bleeding, and while it is clear that micro-
bial growth is inhibited at low gastric pH, it has not
been conclusively demonstrated that continuous or
intermittent enteral feedings consistently raise gastric
pH.262 The site of enteral feeding administration (stom-
ach or sites distal to the pylorus) varied in published
studies, and potential site-specific effects remain to be
elucidated. The possibility that enteral feedings offer
protection against bleeding and pneumonia through
other mechanisms (e.g., maintenance of a positive ni-
trogen balance that is important for normal reparative
functions of the gastric mucosa) should be explored.
Appropriate supportive care, such as administration
of fluids and blood products, nutritional support, ven-
tilatory support, and timely definitive surgery, may
preclude the need for stress ulcer prophylaxis in many
patients.263,264 Before the widespread use of H2-receptor
antagonists for stress ulcer prophylaxis, a number of
regimens were used to prevent acute upper GI bleeding
in burn patients, including milk and diazepam given to
children and vitamin A injection given to adults.230,264
Although corticosteroids have been studied as inciting
factors for GI bleeding, other evidence suggests that
corticosteroids may protect against bleeding in some
populations, including patients with shock.265
Combinations of allopurinol and dimethyl sulfox-
ide have been studied in two RCTs in patients with leg
or pelvic fractures who had clinical evidence of
shock.166,266 These agents were studied because of their
ability to decrease free-radical formation and, there-
fore, potentially prevent gastric mucosal injury. Both
trials showed significant (p < 0.01) decreases in endo-
scopically confirmed lesions. Both of these studies are
promising but require confirmation in different popu-
lations. Comparisons with existing agents that include
economic evaluations of the options are also needed.
Recommendation (adults and pediatrics): It is premature to
recommend the use of novel therapies (e.g., free-radical
scavengers) in place of conventional agents for stress ulcer
prophylaxis, although the limited number of studies have
had promising results. (Strength of evidence = D)
Prevention of recurrent bleeding
The efficacy of nonsurgical therapies such as antac-
ids and H2-receptor antagonists in preventing recurrent
bleeding has varied considerably from study to
study.267-269 The number of patients requiring surgery
for continued or recurring stress-induced bleeding has
steadily decreased since approximately 1978. In a num-
ber of published studies, bleeding stopped spontane-
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 367
ASHP Report Stress ulcer prophylaxis
ously without intervention. In others, the patients
bleeding often stopped and did not recur when conser-
vative measures were instituted, usually an increase in
the dosage of the current medication, a switch to a
different medication, or the addition of another agent,
plus gastric lavage. No large controlled trials have com-
pared the various medication options for preventing a
recurrence of stress-induced bleeding. However, when
combination therapy for prophylaxis is being consid-
ered in a patient who bled while receiving single-agent
prophylaxis, use of drugs with different mechanisms of
action would seem logical. Potential interactions be-
tween prophylactic agents from different classes have
not been well studied but could occur (e.g., reduced
activity of sucralfate with neutral or alkaline gastric pH,
binding of agents by sucralfate). Providing any defini-
tive recommendation regarding this issue is difficult.
The assumption is, of course, that any medication is of
benefit in preventing recurrent bleeding.
Recommendation (adults and pediatrics): The lack of avail-
able trials prohibits definitive recommendations for pre-
venting recurrent bleeding after an episode of stress-induced
GI bleeding, although consideration could be given to in-
creasing the dosage of the prophylactic agent, adding an-
other medication, or switching to a different agent. (Strength
of evidence = D)
Prophylaxis in non-ICU settings
It is possible that patients in non-ICU settings could
have coagulopathy or other conditions that have been
identified as risk factors for bleeding (e.g., transplanta-
tion). Only one RCT has addressed stress ulcer prophy-
laxis in non-ICU settings.54 The study involved 100
adults and was conducted on a general medical and
surgical hospital ward in Spain. Bleeding was signifi-
cantly (p < 0.001) less frequent with antacid prophylax-
is than with placebo. However, bleeding was defined
broadly to include patients who had a decrease in
hematocrit, regardless of whether they required trans-
fusion. Three patients required transfusion in the place-
bo group and none in the antacid group. Upon institu-
tion of antacid and H2-receptor antagonist therapy, the
bleeding stopped in the three patients in the placebo
group without subsequent complications. The frequen-
cy of all types of bleeding (e.g., overt, clinically impor-
tant) was significantly lower with prophylaxis only if
two or more risk factors for bleeding were present before
prophylaxis was initiated.
Discontinuation of prophylaxis
An increase in the number of risk factors has been
associated with a higher risk of bleeding in multiple
studies conducted in the ICU setting and one study
conducted on a hospital ward. The risk of clinically
important bleeding would probably diminish as the
number of risk factors is reduced. In most clinical trials,
prophylaxis was discontinued without evidence of clin-
368 Am J Health-Syst Pharm Vol 56 Feb 15 1999
ically important bleeding upon extubation or the pa-
tients discharge from the ICU. Thus, it is reasonable to
assume that prophylaxis can be stopped once risk fac-
tors have resolved.
Recommendation (adults): Stress ulcer prophylaxis is not
recommended for adult patients in non-ICU settings. (Strength
of evidence = B for general medical and surgical patients with
fewer than two risk factors for clinically important bleeding;
strength of evidence = D for patients with two or more risk
factors) (Table 3)
Recommendation (pediatrics): Stress ulcer prophylaxis is not
recommended for pediatric general medical and surgical
patients or special populations (e.g., transplantation) in non-
ICU settings if fewer than two risk factors for bleeding are
present. (Strength of evidence = D). Data are insufficient to
allow recommendations to be made about the use of prophy-
laxis in pediatric patients with two or more risk factors. If
prophylaxis is given, it should be discontinued once risk
factors have resolved. (Strength of evidence = D)
Economic analysis
Inappropriate stress ulcer prophylaxis can be costly,
but implementing guidelines may decrease the inap-
propriateness and the expense.270,271 Published econom-
ic analyses can be useful for developing institution-
specific guidelines for prophylaxis. Two cost-effective-
ness analyses have been completed concerning prophy-
laxis for stress-induced bleeding. In the first investiga-
tion, by Schumock et al.,272 an antacid regimen of 30 mL
given every 4 hours was compared with sucralfate 1 g
given four times daily and three H2-receptor antago-
nists (ranitidine 50 mg i.v. every 8 hours, cimetidine
300 mg i.v. every 6 hours, and famotidine 20 mg i.v.
every 12 hours), all of which were based on a seven-day
course of therapy. The study was conducted from the
viewpoint of the payer, with hospital charges measured
in 1994 dollars. The authors assumed that the frequen-
cy of bleeding would be approximately 70%, 80%, and
36% lower with the use of sucralfate, antacids, and H2-
receptor antagonists, respectively, and that it cost
$6128 to treat an episode of bleeding. The frequency of
pneumonia was assumed to be unchanged with sucral-
fate but increased by approximately 7% with antacids
and 13% with H2-receptor antagonists. The net saving
associated with prevention of one case of acute upper
GI bleeding was $7373 for sucralfate and $4321 for
antacids. In contrast, therapy with an H2-receptor an-
tagonist would cost between $6655 and $7986 to pre-
vent one episode of acute upper GI bleeding. The
difference in costs between sucralfate or antacids and
H2-receptor antagonists was related to the assumed
higher rates of bleeding and nosocomial pneumonia
with H2-receptor antagonists. One-way sensitivity anal-
ysis showed that sucralfate remained the preferred
agent regardless of the cost of prophylaxis, the cost of
treatment for pneumonia or bleeding, or the presumed
frequency of bleeding or nosocomial pneumonia.
The second cost-effectiveness study, by Ben-Men-

achem et al.,64 was based on the perspective of the
health care provider. Cimetidine (300 mg i.v. every six
hours) was compared with sucralfate (1 g every six
hours), both given for seven days. One notable differ-
ence from the previous analysis was the assumption
that it would cost $595 to treat a GI bleed. It was
presumed that both therapies would decrease the fre-
quency of bleeding by 50%; in the sensitivity analysis,
the percent reduction was varied over the range of 10
90%. Despite different assumptions from the investiga-
tion by Schumock et al., the results were similar in that
sucralfate (cost of $1144 per bleeding event averted)
was more cost-effective than cimetidine ($7538 per
bleeding event averted), even when rates of pneumonia
were presumed to be equal.
In one study involving a small number of patients,
the costs of enteral and i.v. ranitidine administration
were compared, although only enteral administration
was used.273 Ten patients were assigned to receive raniti-
dine 150 mg every 12 hours and eight patients to receive
300 mg every 12 hours; both dosages were given by
nasogastric tube. Both therapies reduced stimulated
acid secretion by at least 50%. Drug costs were calculat-
ed to be at least 48% less with the enteral administra-
tion than with i.v. administration.
A formal economic analysis from an institutional
perspective was conducted as part of the guideline
development process. The general steps of acceptable
cost-effectiveness analysis were followed: identification
of clinical choices, determination of costs and benefits,
statement of time frame, determination of cost-effective-
ness ratio, and performance of a sensitivity analysis.274
Readers are encouraged to make institution-specific deci-
sions and to use the template to construct their own
institution-specific economic analysis.
The medications were assumed to have equal pro-
phylactic efficacy on the basis of the most recent meta-
analysis.5 Although both the meta-analysis and the
recent large RCT met our criteria for a grade of A, the
meta-analysis had a level of evidence of I and the RCT
a level of evidence of I (see Table 1 for definitions).
Drug and administration costs9,64 and adverse event
costs9,185,275,276 and frequency61,64,176,194-199,277,278 were ex-
trapolated from the literature (Table 9). Ranitidine was
chosen as the representative H2-receptor antagonist;
i.v. administration was assumed. Because of the cost of
commercial sucralfate suspension, the cost analysis was
done under the assumption that nursing staff would
administer sucralfate tablets as a slurry through a naso-
gastric tube. The medication cost figures were based on
a five-day course of prophylaxis. Costs and benefits
were assumed to occur within the same period, making
discounting unnecessary. Any estimates not based on
the literature were mentioned. The cost estimates for
many of the adverse effects were small (e.g., $500),
because it was assumed that the effects would be readily
reversible or found to have a different cause. The costs
Stress ulcer prophylaxis ASHP Report
reflect laboratory or consultation estimates that would
be incurred even if the problem were eventually found
to be unrelated to the medication. One hundred pa-
tients were assumed to be in each treatment group in
our decision model because of the small probabilities of
some of the events. It was assumed that the number of
events would not vary with the number of patients.
Figure 1 is the decision tree used for the economic
analysis associated with these guidelines. The overall
results are consistent with those of other published
cost-effectiveness analyses that concluded that sucral-
fate is the most cost-effective agent for prophylaxis,
with a saving of $4913 for each episode of bleeding
averted. The cost-effectiveness ratio for ranitidine was
lower, with a cost saving of $1766. Antacids were nearly
cost neutral. The differences are particularly notable if
the pH-altering medications are assumed to cause a
higher rate of nosocomial pneumonia (0.8% for acid
suppressants and 0 for sucralfate); this is true regardless
of the route of administration for the H2-receptor antag-
onists. If it is assumed that none of the medications
cause adverse effects (including pneumonia) and that
they are similar in efficacy, sucralfate and orally admin-
istered H2-receptor antagonists would have similar
costs.
The following is a template for evaluating the cost-
effectiveness of stress ulcer prophylaxis regimens on
the basis of institution-specific data.
Step 1. Estimate the risk of clinically important bleed-
ing events without prophylaxis (baseline rate stated as a
percentage).
Step 2. Estimate the reduction in clinically important
bleeding events associated with prophylaxis.
Step 3. Estimate the cost per patient of treating GI
bleeding at the institution.
Step 4. Estimate the cost of using sucralfate prophylaxis
in 100 patients.
Step 5. Estimate the cost of adverse events per 100
patients if all 100 are given prophylaxis.
Step 6. Estimate the cost of treating bleeding per 100
Table 9.
Cost Assumptions 9,64,185,275,276
Cost Assumptions per
Episode or Course
Variable of Therapy ($)a
Pneumonia 10,062
Bleeding 7,000
Hepatitis 500
CNS toxicity 500
Cytopenia 500
Cardiovascular toxicity 500
Clogged tubes 160
Antacids every two hours 78.00
Histamine H2-receptor antagonist
three times dailyb 61.50
Sucralfate four times daily 33.80
a
A course of therapy was assumed to be five days. Drug acquisition
costs are average wholesale costs.
b
Ranitidine used as the example.
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 369
ASHP Report Stress ulcer prophylaxis

Figure 1. Decision tree for stress ulcer prophylaxis. H2-RAs = histamine H2-receptor antagonists, CV = cardiovascular.

Cost per 100

patients ($)
No adverse drug reactions 97.3%
5,804

Pneumonia 0.8% $10,062 per episode 7,856

No bleeding
Adverse
97% drug Hepatitis 0.6% $500 per episode 327
reactions CNS toxicity 1.8% $500 per episode 980
Cytopenia 0.0023% $500 per episode 1 TOTAL
H2-RAs
CV toxicity 0.6% (H2-RAs)
n = 100 $500 per episode 327 $37,000 per
$61.50 per 100 patients
course of No adverse drug reactions 97.3%
20,613
Yes therapy
n = 300 Pneumonia 0.8% $10,062 per episode 411
Bleeding
Adverse
3% drug Hepatitis 0.6% $500 per episode 136
$7000 per reactions CNS toxicity 1.8% $500 per episode 408
episode
Cytopenia 0.0023% $500 per episode 1
CV toxicity 0.6% $500 per episode 136

No adverse drug reactions 82%

2,688 TOTAL
No bleeding (sucralfate)
Stress ulcer 97% Adverse drug reactions, clogged tubes 18% $160 per episode $27,260 per
3,384
prophylaxis Sucralfate 100 patients
n = 400 n = 100 No adverse drug reactions 82%
patients at $33.80 per 17,303
Bleeding
risk course of
3% Adverse drug reactions, clogged tubes 18% $160 per episode
therapy 3,885
$7000 per
episode
No adverse drug reactions 81.2%
6,144
No bleeding Adverse
Pneumonia 0.8% $10,062 per episode
97% drug 7,869
reactions

Antacids Clogged tubes 18% $160 per episode

4,156
n = 100 TOTAL
$78 per No adverse drug reactions 81.2%
17,242 (antacids)
course of $39,731 per
Bleeding Adverse
therapy Pneumonia 0.8% $10,062 per episode 100 patients
3% drug 411
$7000 per reactions
episode Clogged tubes 18% $160 per episode
3,909

No bleeding 94%
0 TOTAL
No (no prophylaxis)
n = 100 Bleeding 6% $7000 per episode $42,000 per 100
42,000 patients

patients treated [(risk of bleeding without prophylaxis)
(estimated cost of treating GI bleed per patient)].
Step 7. Estimate the savings with stress ulcer prophy-
laxis per 100 patients treated {[(risk of bleeding without
prophylaxis) (risk reduction with prophylaxis expressed
as a decimal)] (cost of treating GI bleed per patient)}.
Step 8. Determine the marginal cost of prophylaxis per
100 patients treated {[(cost of medication per 100 pa-
tients) + (cost of adverse drug events per 100 patients)]
(savings with stress ulcer prophylaxis in 100 patients)}.
Note that positive numbers represent a cost liability,
negative numbers a cost saving.
Step 9. Determine the cost-effectiveness ratio [(margin-
al cost of prophylaxis in 100 patients)/(risk of
bleeding)(risk reduction with prophylaxis expressed as a
decimal)]. A negative value indicates a saving.
Table 10 provides an example of how the cost-
effectiveness calculation for sucralfate was performed.
The cost-effectiveness ratios for the various therapies
can be compared in order to choose the appropriate
agent. As with any guidelines, patient-specific informa-
tion should always be used for determining prophylaxis
for the individual patient. To perform a sensitivity

370 Am J Health-Syst Pharm Vol 56 Feb 15 1999

 Stress ulcer prophylaxis ASHP Report

analysis for various rates of bleeding and reductions in data. The strength of the evidence for prophylaxis varies
bleeding associated with prophylaxis, simply vary the substantially from one risk factor to the next (Table 3).
values in step 9. Table 11 shows the results of the ICU patients with a history of recent GI pathology are
sensitivity analysis for sucralfate. deemed appropriate candidates for prophylaxis, but the
Figure 2 is an algorithm for stress ulcer prophylaxis recommendation must be graded D because patients
in adult patients that is based on the recommendations with recent histories of GI pathology were often excluded
contained in this document. The lack of pediatric RCTs from the published investigations, and thus it is un-
involving medications and the age stratification in known whether these patients are at increased risk for
those studies that did include pediatric patients pre- clinically important bleeding. The recommendation for
clude development of a separate pediatric algorithm. use of oral H2-receptor antagonists in patients with func-
Because the number (2) and type (coagulopathy, respi- tioning GI tracts (Figure 2) is based on presumptive
ratory failure, and Pediatric Risk of Mortality Score of efficacy, because no RCTs are available that have com-
10) of risk factors for clinically important bleeding pared i.v. with oral H2-receptor antagonists administra-
have been elucidated,66 the reader is referred to the tion for preventing clinically important bleeding.
discussion in the section titled Adverse effects of pro- Recommendation (adults): Given some of the unresolved
phylactic agents for help in deciding which medica- issues regarding stress ulcer prophylaxis, it is recommended
tion, if any, should be used for prophylaxis. that institution-specific guidelines be developed on the
The adult algorithm is intended to serve as a template basis of economic models such as the one included in this
that can be modified according to institution-specific document. For institutions willing to accept the assumption
that H2-receptor antagonists and sucralfate have equal
efficacy, the accompanying economic analysis found su-
cralfate to be the most cost-effective agent. Exceptions to
Table 10. the use of sucralfate include lack of oral or other gastric
Cost-effectiveness Calculations for Sucralfate access for administration and, potentially, documented
Variable Value failure of prophylaxis with sucralfate. If ranitidine is as-
Risk of bleeding without
sumed to be more effective than sucralfate without increas-
6.0 (0.139)61,64
prophylaxis (%) ing the risk of pneumonia, ranitidine (and presumably
Risk reduction with 50 (1090)64 other H2-receptor antagonists) would be the drug of choice
prophylaxis (%) and would also result in a cost saving, although less than
Cost of treating episode of GI 7000 that achieved with sucralfate.
bleeding per patient ($) Recommendation (pediatrics): There are also unresolved
Cost of sucralfate per 100 3380
patients ($)
issues for pediatric patients. Institution-specific guidelines
Cost of adverse drug events 2880
can be developed by using the economic models included in
per 100 patients treated ($) this document, but the percentages and costs need to be
Cost of treating GI bleeding in 42,000 tailored to this population on the basis of institution-
100 patients ($) specific data. There is supporting evidence in the literature
[(Six episodes of bleeding) that the risk of stress-induced bleeding is greater in pediatric
($7000 cost of treatment)] patients with respiratory failure, coagulopathy, a Pediatric
Savings with stress ulcer 21,000 Risk of Mortality Score of 10, and thermal injuries. Whether
prophylaxis in 100 patients ($) prophylaxis will reduce the risk of bleeding is yet to be
[(Three episodes of
bleeding) ($7000 cost of
proven in this population, so there is no clear agent of choice
treatment)] at this time.
Marginal cost of prophylaxis 14,740
in 100 patients ($) Conclusion
[($3380 + $2880) ($21,000)]
Cost-effectiveness ratio 4913 for each Although medications such as antacids have been
bleeding episode used for at least two decades to prevent stress-induced
averted bleeding, many issues remain unresolved. While pro-

Table 11.
Cost-effectiveness Ratio for Sucralfate Prophylaxis: Results of Sensitivity Analysisa

% Reduction in Risk Risk of Bleeding (%)

with Prophylaxis 0.1 1 2 4 6 10 20 39
10 619,000 55,600 24,300 8,650 3,433 (740) (3,870) (5,395)
30 201,667 13,867 3,433 (1,783) (3,522) (4,913) (5,957) (6,465)
50 118,200 5,520 (740) (3,870) (4,913) (5,748) (6,374) (6,679)
70 82,429 1,943 (2,528) (4,764) (5,509) (6,106) (6,553) (6,771)
90 62,556 (44) (3,522) (5,261) (5,841) (6,304) (6,652) (6,822)
a
Assumptions about the risk of bleeding and the effectiveness of prophylaxis were varied from 0.1% to 39% and from 10% to 90%, respectively. The
values represent the cost or saving (in parentheses) for each bleeding episode averted. Costs and benefits were presumed to occur within a similar period,
making discounting unnecessary.

Vol 56 Feb 15 1999 Am J Health-Syst Pharm 371

ASHP Report Stress ulcer prophylaxis

Figure 2. Algorithm for stress ulcer prophylaxis in adult patients.

Is stress ulcer prophylaxis needed?

(Prophylaxis is appropriate for patients
admitted to the ICU with one or more
of the risk factors listed in Table 3.)

Yes No

Continue periodic assessment

Does patient have gastric access via oral route,
nasogastric tube, or gastrostomy?

Yes No

Sucralfate (if Does patient have

continuous enteral access
nasogastric suction, (via nasoenteral tube
stop suction for or ostomy)
two hours after and adequate
giving sucralfate) GI function
(i.e., absorption of
feedings)?

Yes No

Enteral H2- I.V. H2-

blocker blocker

Continue periodic assessments

phylactic agents have demonstrated efficacy in pre- References

venting clinically important bleeding in randomized,
controlled trials (and meta-analyses), the frequency of
stress-induced bleeding has varied substantially from
study to study since approximately 1978. This has led
some experts to suggest that prophylactic agents are
very effective if used appropriately; other experts con-
clude that the frequency of clinically important stress-
induced bleeding has been decreasing as a result of
advances in technology and patient care, not medica-
tion prophylaxis. The collection of institution-specific
data should help clinicians to resolve this issue, at least
for their particular patient populations.
When institution-specific rates of stress-induced
bleeding are not available, the recommendations con-
tained in these guidelines can serve as a model for
adaptation by the institution. Although the recom-
mendations were made on the basis of data published
up to the final guideline review process, changes may
be needed as information evolves. The reader is encour-
aged to consider such changes as they occur rather than
wait for revised guidelines.
1. Anderberg B, Sjodahl R. Prophylaxis and management of
stress ulcers. Scand J Gastroenterol. 1985; 20(suppl 110):101-4.
2. Shuman RB, Schuster DP, Zuckerman GR. Prophylactic ther-
apy for stress ulcer bleeding: a reappraisal. Ann Intern Med.
1987; 106:562-7.
3. Halpern NA, Bettes L, Greenstein R. Federal and nationwide
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4. Dasta JF. Drug prescribing issues in the intensive care unit:
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5. Cook DJ, Reeve BK, Guyatt GH et al. Stress ulcer prophylaxis
in critically ill patients: resolving discordant meta-analyses.
JAMA. 1996; 275:308-14.
6. Peura DA. Prophylactic therapy of stress-related mucosal
damage: why, which, who, and so what? Am J Gastroenterol.
1990; 85:935-7.
7. Tryba M. Stress ulcer prophylaxisquo vadis? Intensive Care
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8. Berger JT, Rosner F. The ethics of practice guidelines. Arch
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tions using levels of evidence for antithrombotic agents.

372 Am J Health-Syst Pharm Vol 56 Feb 15 1999

 Recommendations
Indications for prophylaxis
For adults: Risk factors for ICU patients have been delineated in
trials comparing prophylaxis with no prophylaxis by using
clinically important bleeding as an endpoint. Prophylaxis is
recommended in patients with coagulopathy or patients re-
quiring mechanical ventilation for more than 48 hours.
(Strength of evidence = C) Prophylaxis is also recommended in
patients with a history of GI ulceration or bleeding within one
year before admission and in patients with at least two of the
following risk factors: sepsis, ICU stay of more than one week,
occult bleeding lasting six days or more, and use of high-dose
corticosteroids (>250 mg per day of hydrocortisone or the
equivalent). (Strength of evidence = D) (Table 3) Recommenda-
tions for specific prophylactic medications can be found in the
Medications used for prophylaxis section.
For pediatrics: Although various risk factors have been associat-
ed with bleeding in pediatric patients, published randomized,
controlled trials (RCTs) have either not used clinically impor-
tant bleeding as an outcome or had insufficient power to en-
able a definitive conclusion that prophylaxis provides
protection. Risk factors that have been associated with clinical-
ly important bleeding include respiratory failure, coagulopa-
thy, and a Pediatric Risk of Mortality Score of 10. (Strength of
evidence = C)
Indications in special populations
For adults: Prophylaxis is recommended for ICU patients with a
Glasgow Coma Score of 10 (or the inability to obey simple
commands) or thermal injuries to >35% of their body surface
area (BSA). (Strength of evidence = B) ICU patients with partial
hepatectomy may also benefit from prophylaxis. (Strength of
evidence = C) Prophylaxis may also be indicated in ICU pa-
tients with multiple trauma (e.g., Injury Severity Score of 16),
transplantation patients in the ICU perioperatively, ICU pa-
tients with hepatic failure, and ICU patients with spinal cord
injuries. (Strength of evidence = D) (Table 3)
For pediatrics: For pediatric patients (one month of age or older)
with thermal injuries, prophylaxis is recommended, but there
is insufficient evidence to recommend prophylaxis based on
any given percentage of BSA. (Strength of evidence = D) For
other pediatric surgery or trauma patients, insufficient evi-
dence is available to allow recommendations about prophylaxis
to be made.
Agent of choice
For adults: Given the conflicting results of several meta-analyses
and a recent RCT (both with strengths of evidence = A), the
choice among antacids, H2-receptor antagonists, and sucralfate
for use as prophylactic agents to prevent clinically important
bleeding associated with stress in adult patients admitted to
general medical and surgical ICUs should be made on an insti-
tution-specific basis. This choice should take into account con-
cerns regarding administration (e.g., functioning GI tract),
adverse-effect profile, and total costs. (Strength of evidence = D)
Insufficient data on misoprostol or the proton-pump inhibitors
are available to allow any recommendation about these agents
to be made.
For pediatrics and special populations: The lack of comparative
trials of these agents in pediatric and special populations (e.g.,
patients with burns, trauma patients, patients undergoing neu-
rosurgical procedures or with neurologic disorders, and trans-
plantation patients) precludes definitive recommendations as
to the agent of choice in these situations. The choice of agent
should be made on an institution-specific basis and should take
into account concerns about administration (e.g., functioning
GI tract), adverse-effect profile, and total costs.
Adverse effects
For adults and pediatrics: It is recommended that patients with a
history of serious reactions to antacids, H2-receptor antagonists,
proton-pump inhibitors, or sucralfate avoid future use of the
offending agent. There are no other absolute contraindications
that would preclude the short-term use of any of these medica-
tions for stress ulcer prophylaxis. However, unless the benefits
clearly exceed the risks, it is recommended that sucralfate and
antacids be avoided in neonates (particularly premature neo-
nates) because of the possibility of adverse effects (e.g., bezoar
Stress ulcer prophylaxis ASHP Report
formation, accumulation of aluminum and magnesium). Also, it is
recommended that aluminum-containing products such as sucralfate
be avoided in children with renal failure because dosing information
has not been well established. Whether acid-suppressing agents are
associated with a higher rate of pneumonia than sucralfate is unre-
solved, although any difference between these medications would
appear to be small. It is recommended that potential adverse effects
be considered as part of the economic analysis when an agent is
chosen (see Economic analysis). (Strength of evidence = D)
Monitoring
For adults and pediatrics: It is recommended that all patients receiving
medications for stress ulcer prophylaxis be monitored for bleeding
and adverse drug effects (see Adverse effects of prophylactic agents).
Paper techniques for measuring gastric pH have questionable validity
and reliability, and there is no evidence that adjusting the dosage of
pH-altering medications (antacids, H2-receptor antagonists, proton-
pump inhibitors) on the basis of these measurements influences
patient morbidity or mortality. Despite the lack of supporting data,
pH monitoring for antacids may be appropriate (goal pH of >3.54).
Such monitoring may also be useful for H2-receptor antagonists when
standard dosage regimens might not be appropriate (e.g., in cases of
renal dysfunction, for increased dosages due to perceived failure of
therapy, in pediatric patients). (Strength of evidence = D)
Other options
For adults and pediatrics: It is premature to recommend the use of
novel therapies (e.g., free-radical scavengers) in place of conventional
agents for stress ulcer prophylaxis, although the limited number of
studies have had promising results. (Strength of evidence = D)
Prevention of recurrent bleeding
For adults and pediatrics: The lack of available trials prohibits definitive
recommendations for preventing recurrent bleeding after an episode
of stress-induced GI bleeding, although consideration could be given
to increasing the dosage of the prophylactic agent, adding another
medication, or switching to a different agent. (Strength of evidence =
D)
Non-ICU patients
For adults: Stress ulcer prophylaxis is not recommended for adult
patients in non-ICU settings. (Strength of evidence = B for general
medical and surgical patients with fewer than two risk factors for
clinically important bleeding; strength of evidence = D for patients
with two or more risk factors) (Table 3)
For pediatrics: Stress ulcer prophylaxis is not recommended for
pediatric general medical and surgical patients or special popula-
tions (e.g., transplantation) in non-ICU settings if fewer than two
risk factors for bleeding are present. (Strength of evidence = D)
Data are insufficient to allow recommendations to be made about
the use of prophylaxis in pediatric patients with two or more risk
factors. If prophylaxis is given, it should be discontinued once risk
factors have resolved. (Strength of evidence = D)
Institution-specific guidelines
For adults: Given some of the unresolved issues regarding stress
ulcer prophylaxis, it is recommended that institution-specific
guidelines be developed on the basis of economic models such as
the one included in this document. For institutions willing to
accept the assumption that H2-receptor antagonists and sucralfate
have equal efficacy, the accompanying economic analysis found
sucralfate to be the most cost-effective agent. Exceptions to the use
of sucralfate include lack of oral or other gastric access for adminis-
tration and, potentially, documented failure of prophylaxis with
sucralfate. If ranitidine is assumed to be more effective than sucral-
fate without increasing the risk of pneumonia, ranitidine (and
presumably other H2-receptor antagonists) would be the drug of
choice and would also result in a cost saving, although less than
that achieved with sucralfate.
For pediatrics: There are also unresolved issues for pediatric pa-
tients. Institution-specific guidelines can be developed by using
the economic models included in this document, but the percent-
ages and costs need to be tailored to this population on the basis of
institution-specific data. There is supporting evidence in the litera-
ture that the risk of stress-induced bleeding is greater in pediatric
patients with respiratory failure, coagulopathy, a Pediatric Risk of
Mortality Score of 10, and thermal injuries. Whether prophylaxis
will reduce the risk of bleeding is yet to be proven in this popula-
tion, so there is no clear agent of choice at this time.
Vol 56 Feb 15 1999 Am J Health-Syst Pharm 373
ASHP Report Stress ulcer prophylaxis
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