Journal of Critical Care (2005) 20, 35 – 45

Pathophysiology and prophylaxis of stress ulcer in

intensive care unit patients
Neil Stollman MDa,*, David C. Metz MDb
a
Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco,
CA 94110, USA
b
Division of Gastroenterology, Department of Medicine, University of Pennsylvania Health System, Philadelphia,
PA 19104, USA

Received 12 May 2004; revised 24 August 2004; accepted 12 October 2004

Keywords:
Abstract Gastrointestinal complications frequently occur in patients admitted to the intensive care unit.
Pathophysiology;
Of these, ulceration and bleeding related to stress-related mucosal disease (SRMD) can lengthen
Prophylaxis;
hospitalization and increase mortality. The purpose of this review is to discuss the many risk factors and
Ulcer
underlying illnesses that have a role in the pathophysiology of SRMD and evaluate the evidence
pertaining to SRMD prophylaxis in the intensive care unit population. Suppressing acid production is
fundamental to preventing stress-related mucosal ulceration and clinically important gastrointestinal
bleeding. Traditional prophylactic options for SRMD in critically ill patients include antacids, sucralfate,
histamine2-receptor antagonists (H2RAs), and proton pump inhibitors. Many clinicians prescribe
intermittent infusions of H2RAs for stress ulcer prophylaxis, a practice that has not been approved for
this indication and may not provide the necessary degree or duration of acid suppression required to
prevent stress ulcer–related bleeding. New data suggest that proton pump inhibitors suppress acid
production more completely in critically ill patients, but more studies are required to assess their clinical
effectiveness and safety for this indication. The prophylactic regimen chosen to prevent stress ulcer
bleeding should take into account the risk factors and underlying disease state of individual patients to
provide the best therapy to those most likely to benefit.
D 2005 Elsevier Inc. All rights reserved.

1. Introduction function as well as stress-related mucosal disease [SRMD])

An estimated 4.4 million patients are admitted to
intensive care units (ICUs) each year. Of these, about
12%, or 500 000 patients, die in the ICU [1]. Gastrointestinal
(GI) complications (eg, gastric and intestinal motor dys-
T Corresponding author. East Bay Center for Digestive Health,
Oakland, CA 94609, USA. Tel.: +1 510 444 3297; fax: +1 510 444 6421.
E-mail address: nstollman@medsfgh.ucsf.edu (N. Stollman).
frequently occur in these patients and adversely affect patient
outcomes. Gastrointestinal motor dysfunction may predis-
pose patients to impaired enteral nutrition and pulmonary
aspiration of gastric contents [2]. Stress-related mucosal
damage— an acute erosive gastritis — occurs in many criti-
cally ill patients in ICUs and may develop within 24 hours of
admission [3]. The incidence of clinically important GI
bleeding, defined as overt bleeding complicated by hemo-
dynamic instability, decrease in hemoglobin, and/or need for

0883-9441/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcrc.2004.10.003
36
blood transfusion, from SRMD in the ICU population was
1.5% in a prospective study of 2252 patients [4]. In addition,
the morbidity associated with this type of severe ulceration
and bleeding can increase the length of stay in the ICU by up
to 8 days, and mortality is as much as 4-fold higher than it is
in ICU patients without this complication [5].
2. Pathophysiology and pathogenesis of SRMD
Several factors have a role in the pathogenesis of SRMD,
including gastric acid secretion, mucosal ischemia (as a result
of splanchnic hypoperfusion), and reflux of upper intestinal
contents into the stomach (Fig. 1) [6,7]. Gastric hypoperfu-
sion leads to an imbalance between oxygen supply and
demand that may induce mucosal damage. Moreover,
reperfusion after prolonged hypoperfusion may itself result
in nonocclusive mesenteric ischemia and mucosal damage.
As a result of ischemia, there is also a reduced ability to
neutralize hydrogen ions, which can contribute to cell death
and ulceration. Protective processes such as mucous produc-
tion may also be impaired, further promoting SRMD [6,8]. In
animal studies, Ritchie [6] showed that elevated gastric acid
levels, bile salts, and ischemia must all be present for gastric
lesions to form, whereas none of these factors alone or in
combination with each other led to ulceration.
In stress ulceration, homeostasis of the gastric mucosa is
disrupted as are the cellular defense mechanisms that
normally protect against a highly acidic gastric milieu.
Cellular defense is primarily mediated by gastric prosta-
glandins, which, in animal models, have been shown to
prevent ulcer formation and accelerate the healing process.
This seems to occur partly because prostaglandins reduce
acid secretion. More importantly, they have been shown to
exert a direct cytoprotective effect against agents that kill
Fig. 1 Pathophysiology of stress ulcers. Adapted from Chest 2001;119:1222; Hosp Pract 1980;15:93.
N. Stollman, D.C. Metz
mucosal cells on contact [9]. Thus, prevention of acid injury
and stress ulceration might be achieved by therapies that
reduce acid secretion or enhance protective mechanisms.
The endoscopic signs of SRMD include multiple sub-
epithelial petechiae progressing to superficial erosions, and
in some cases, discrete ulceration, particularly in the gastric
fundus [8]. Microscopically, these lesions are characterized
by focal loss of the superficial epithelium, coagulation
necrosis of the mucosa, and hemorrhage [10]. These lesions
do not usually perforate and tend to bleed from superficial
mucosal capillaries [11]. Because of the diffused nature of
the lesions, stress ulcers are not generally amenable to
endoscopic therapy.
2.1. Splanchnic hypoperfusion
Critical illness that warrants admission to an ICU (eg,
trauma, severe shock, burns, sepsis) can contribute to
splanchnic hypoperfusion, which has a major role in the
pathogenesis of SRMD. Significant decreases in visceral
blood flow can occur even when systemic circulation is
maintained, and conventional measures of systemic tissue
oxygenation may not accurately reflect regional GI oxy-
genation [12,13]. Intramucosal pH, which can be measured
using gastric tonometry, is a marker of the adequacy of
oxygenation in the upper GI tract and is used in
experimental settings to assess the magnitude of splanchnic
ischemia [12].
2.2. Underlying illness
Critical illness is often characterized by hypotension and
hypovolemia, which can directly contribute to gastric
hypoperfusion. In addition, critically ill patients often
exhibit inflammatory responses involving the release of
cytokines that can also result in hypoperfusion [8].
Stress ulcer prophylaxis
2.3. Mechanical ventilation
Mechanical ventilation can influence systemic hemody-
namics, especially with potentially injurious ventilator
strategies such as high tidal volumes or high positive end-
expiratory pressure (PEEP). High PEEP decreases venous
return and reduces preload, which in turn may reduce cardiac
output (CO) [14] and result in splanchnic hypoperfusion.
PEEP promotes plasma-renin-angiotensin-aldosterone
activity, as well as catecholamine release, which may also
contribute to splanchnic hypoperfusion [8,15,16].
Mesenteric blood flow and CO were found to signifi-
cantly decrease with increasing levels of PEEP in rats
randomized to PEEP vs control [15]. An inverse relationship
between increasing plasma catecholamine levels and
decreases in CO was observed in dogs treated with graded
doses of PEEP [14]. Effects on the sympathetic nervous
system have also been validated in human beings. In a study
of 10 healthy males receiving continuous positive-pressure
breathing, muscle sympathetic nerve activity rapidly
increased, as did measurements of vasopressin and plasma
renin activity as compared to control [17]. In addition,
mechanical ventilation with large tidal volumes and high
end-expiratory pressures have been shown in animals to
promote release of pulmonary cytokines, which can enter the
systemic circulation from the lungs, potentially causing
splanchnic hypoperfusion [8,18,19].
Despite these data showing that PEEP can negatively
influence blood flow, the effect of PEEP on GI bleeding in
the ICU setting remains unknown.
2.4. Medications used in the ICU
Medications administered to patients in the ICU can have
deleterious effects on GI function, especially when com-
pounded with the effects of mechanical ventilation. Opiates
and sedatives, such as benzodiazepines, can decrease gut
motility and impair venous return [20]. Other agents that
may contribute to GI complications include vasopressors
and antibiotics [2,8,21]. Theoretically, any drug resulting in
hypotension, decreased heart rate, or CO can in turn reduce
mesenteric blood flow and put a critically ill patient at risk
of developing SRMD [15].
2.4.1. Helicobacter pylori
Helicobacter pylori has been implicated as the causative
agent in the pathogenesis of chronic gastritis and peptic
ulcer. Its relationship to stress ulceration and GI bleeding,
however, is not well documented. The relatively few studies
exploring this association yielded conflicting results. A
prospective epidemiologic survey of critically ill patients in
an ICU found a significantly higher rate of seropositivity for
H pylori in the ICU group than in the control group (67% vs
39%, P b .001) [3]. The relationship between H pylori status
and GI bleeding was not significant, but there was a trend
toward increasing seropositivity with increasing bleeding
severity—from 50% seropositivity among patients with
37
occult bleeding to 100% seropositivity among those with
clinically significant bleeding [3]. In a prospective cohort
analysis, 50 consecutive patients admitted to the ICU
requiring mechanical ventilation were screened for H pylori
infection using the laser-assisted ratio analyzer urea breath
test and underwent endoscopy to assess mucosal injury. Of
the 29 patients who developed minor mucosal disease,
34.5% were infected with H pylori. On the contrary, of the
15 patients that presented with major mucosal disease, 80%
were infected, supporting the theory that the severity of
mucosal injury is correlated with H pylori infection [22].
Yamamoto et al [23] inoculated a group of test animals
with H pylori. After these, control animals were subjected to
stress treatment; ulcer formation and bleeding occurred
regardless of whether the animals were or were not infected
with H pylori. However, after 30 minutes of treatment, the
bleeding rate and index were significantly higher in the
infected group than in the uninfected group ( P = .036 and
P = .038, respectively). The ulcer index was also higher in
the infected group. It was determined that H pylori infection
lowers the threshold for gastric mucosal injuries in the early
phase of stress exposure, but suppresses the formation of
mucosal lesions in the late phase [23].
In contrast, another study found no association between
H pylori infection and GI bleeding. This study was
conducted prospectively over 1 year in patients with and
without evidence of GI bleeding admitted to the ICU after
cardiac surgery. All patients received stress ulcer prophy-
laxis with ranitidine. Results showed that H pylori infection
was not significantly more prevalent in patients with upper
GI bleeding than in those without bleeding [24]. Only a
limited association was found in another study. Among 874
critically ill patients admitted to an ICU and followed for 6
weeks, 76 (8.7%) developed stress gastritis [25]. Anti–H
pylori immunoglobulin A was found to be an independent
risk factor for stress gastritis, but not anti–H pylori
immunoglobulin G, possibly suggesting that only a subset
of individuals with chronic H pylori infection is at risk for
stress gastritis [25].
3. Complications associated with SRMD
Mortality rates increase proportionately with the inci-
dence and severity of SRMD. In 2 prospective multicenter
studies, Cook et al [4,5] found significant differences in
mortality between clinically important GI bleeding and
nonbleeding patients (Fig. 2). In these studies, patients who
bled as a result of SRMD had mortality rates of 49% and
46%. In contrast, mortality rates for nonbleeding patients
were 9% and 21% ( P b .001 and P b .0001, respectively)
[4,5]. These findings are consistent with those of a study
that evaluated the effectiveness of cimetidine in prevention
and treatment of stress-induced GI lesions. In this study,
mortality was significantly correlated with severity of GI
mucosal injury: mortality rates were 57% in patients with
38
Fig. 2 Differences in mortality between bleeding (n = 33) and
nonbleeding (n = 2219) patients. Asterisk indicates P b .001.
Adapted from N Engl J Med 1994;330:377.
endoscopically evident ulcers and/or bleeding and 24% in
patients with nonhemorrhagic erosions or normal mucosa
( P b .03) [26]. Because it is possible to identify patients
who are at the greatest risk for bleeding, strategies should
logically focus on the prevention of SRMD and bleeding,
rather than on its treatment after the fact. Such an approach
may minimize complications associated with SRMD and,
ideally, improve outcomes.
3.1. Impact of GI bleeding on ICU patients
Clinically important GI bleeding may cause hemody-
namic instability or require red blood cell transfusions. The
attendant risks of transfusion include infection and potential
for immunosuppression, as well as possible blood-related
incompatibilities [27]. As noted earlier, there is a potential
for an increased length of stay in the ICU among patients
with significant bleeding compared to nonbleeders, as well
as a statistically significant increase in mortality.
4. Risk factors for stress
ulcer–related bleeding
As noted, critically ill patients admitted to ICUs are at
risk for developing stress ulceration and subsequent
bleeding as a result of both underlying disease and
therapeutic interventions. Prophylaxis against stress ulcers
can significantly minimize bleeding, but such therapy may
be costly and can have adverse effects. Therefore, it is
important to identify risk factors that would substantiate the
need for prophylaxis and target interventions to those at
highest risk. A study involving more that 2200 patients
admitted to ICUs (primarily postcardiovascular surgery)
evaluated potential risk factors for stress ulcer–related
bleeding [4]. Prophylactic therapy was withheld in all
N. Stollman, D.C. Metz
except 674 patients; these patients had received drugs that
increased their risk of bleeding, had a history of peptic ulcer
or gastritis, were undergoing high-risk surgery, or required
prophylaxis for other reasons (eg, head injury, trauma) [4].
The only independent risk factors for clinically important
stress ulcer bleeding determined by the study were
respiratory failure requiring more than 48 hours of
mechanical ventilation (odds ratio, 15.6) and coagulopathy
(odds ratio, 4.3) [4]. Among 847 patients who had one or
both of these risk factors, 31 (3.7%) developed clinically
important bleeding, whereas among 1405 patients who had
neither risk factors, only 2 (0.1%) developed significant
bleeding [4].
Hastings et al [28] randomly assigned 100 patients at risk
of developing stress ulcers and bleeding to receive antacid
prophylaxis or no prophylaxis. An analysis of the patients
reported 6 risk factors for acute GI bleeding: respiratory
failure, extraabdominal sepsis, peritonitis, jaundice, renal
failure, and hypotension. Notably, the frequency of bleeding
increased with the number of risk factors present in both
treated and untreated groups (Fig. 3) [28]. Results of this
study demonstrated that there is a distinct association
between acute GI ulceration and bleeding, and presence of
risk factors [28].
The predictive value of risk factors for GI bleeding was
also validated in another study of patients with illnesses or
conditions requiring admission to an ICU [29]. In this study,
the risk factors considered included surgery, burns, major
trauma, established liver or renal disease, respiratory failure
requiring mechanical ventilation, sepsis, and hypotension
Fig. 3 The incidence of bleeding by number of risk factors in
patients receiving and not receiving antacid prophylaxis. Asterisk
indicates P b .01; dagger, P b .025; double dagger, P b .005.
Adapted from N Engl J Med 1978;298:1041.
Stress ulcer prophylaxis
[29]. The authors demonstrated that the probability for
massive GI bleeding from stress ulceration increased as the
number of risk factors rose and as the intramucosal pH fell,
implying mucosal hypoperfusion. Gastrointestinal bleeding
was, in fact, seen only in patients whose intramucosal pH
had fallen below the lower limit of normality (7.24). Thus,
the combination of risk factors and intramucosal pH were the
best predictors of bleeding [29]. It is important to note that
none of the risk factors discussed have been conclusively
demonstrated to be the direct cause of stress ulcer–related
bleeding; rather, they may be surrogate markers for severity
of illness. All of the studies described strongly suggest that
identifying risk factors can provide a valid predictive tool for
GI bleeding that will allow clinicians to prescribe prophy-
lactic treatment to the patients most likely to benefit [4, 29].
The risk factors associated with increased risk of stress
ulcer–related bleeding are summarized in Table 1.
5. Stress ulcer prophylaxis options
Prevention of stress-related bleeding is clearly the most
effective strategy for patients at risk for SRMD in the ICU.
This can be accomplished by preventing gastric ischemia or
acid injury. Although high acid concentrations are not the
only factor that contributes to SRMD, controlling acid
production in at-risk patients seems to be protective against
bleeding episodes [9]. A metaanalysis of clinical trials by
Cook et al [30] reported that various prophylactic therapies
such as antacids, sucralfate, and histamine2 receptor
antagonists (H2RAs) reduced the incidence of overt or
clinically important bleeding compared to no prophylaxis.
Thus, agents that protect gastric mucosa from acid, either by
minimizing injury from produced acid or by inhibiting acid
secretion, have an important role in the prevention of
bleeding due to SRMD.
5.1. Antacids
Antacids work by directly buffering or neutralizing the
acidic contents of the stomach. In the study already referred
to above, Hastings et al [28] found that in critically ill
Table 1 Risk factors for SRMD
Risk factor
Respiratory failure
Coagulopathy
Hypotension
Sepsis
Hepatic failure
Renal failure
Surgery
Burns
Major trauma
Adapted from Gastroenterology 1983;85:613; N Engl J Med 1978;
298:1041; N Engl J Med 1994;330:377.
39
patients at risk for GI ulceration and bleeding, the frequency
of bleeding was significantly reduced when antacid therapy
was titrated to keep the pH above 3.5. Results showed that
2 patients (4%) in the antacid group bled compared with
12 patients (25%) in the group receiving no prophylaxis
( P b .005). However, the fact that these agents need to be
given every 1 or 2 hours to achieve adequate acid neutral-
ization makes their use cumbersome. Moreover, adminis-
tration of high doses of antacids may increase the risks of
aspiration pneumonia and toxicity related to cation accu-
mulation (particularly in patients with renal dysfunction).
5.2. Sucralfate
Sucralfate protects the gastric mucosa from acid by
adhering to epithelial cells and forming a protective barrier,
but has no acid-neutralizing activity. Used in prevention of
SRMD, it has been shown to be more effective than no
prophylaxis in decreasing overt bleeding, but no more
effective than placebo, antacids, and H2RAs in reducing
clinically important bleeding rates [27,30]. The interest in
sucralfate increased after a clinical trial, and a metaanalysis
reported a trend toward a lower incidence of pneumonia
with sucralfate than with agents that suppress acid [30,31].
However, a large randomized study of 1200 ICU patients
reported no difference in the incidence of nosocomial
pneumonia between patients receiving intravenous raniti-
dine 50 mg every 8 hours and those receiving sucralfate
suspension 1 g via nasogastric tube every 6 hours. In the
ranitidine group, 114 (19%) of 596 patients had ventilator-
associated pneumonia compared with 98 (16%) of 604
patients in the sucralfate group. More importantly, clinically
important GI bleeding was higher in the sucralfate group
than in the ranitidine group, 3.8% and 1.7%, respectively
( P = .02) [32].
5.3. H2-receptor blockade
H2RAs inhibit histamine-stimulated acid secretion by
blocking H2-receptor sites of the parietal cell in a highly
selective manner; they have little or no effect on histamine
receptors not involved with gastric secretion [9]. H2RAs
have been found to be significantly better than placebo,
antacids, and sucralfate in reducing the incidence of
clinically significant bleeding (Fig. 4) [32].
5.3.1. Continuous infusion vs bolus injection
Maintaining the pH between 3.5 and 4.5 is a surrogate
endpoint accepted by many and should be the minimum
goal of prophylactic therapy [11]. Effective prophylaxis
requires selection of not only the proper drug and dose, but
the appropriate method of administration. A continuous
intravenous infusion of cimetidine (50-100 mg/h) was
evaluated in a double-blind placebo-controlled study to
determine its effectiveness in preventing upper GI hemor-
rhage [33]. Results showed that intragastric pH (N4.0 in both
groups at baseline) declined over time in the placebo group
40
Fig. 4 The results of a metaanalysis on the efficacy of H2RAs in
stress ulcer prophylaxis. Asterisk indicates overt bleeding accom-
panied by hemodynamic changes or a decrease in hemoglobin of
2 g/dL requiring transfusion of 2 units of blood within 24 hours or
requiring surgery. Adapted from JAMA 1996;275:308.
but not in the cimetidine group, and significantly less upper
GI bleeding occurred in the cimetidine group ( P = .009)
[33]. This study clearly indicated that prophylaxis with
continuously infused cimetidine is a valuable approach for
preventing GI hemorrhage in patients with risk factors (eg,
major surgery, trauma, burns, hypotension, sepsis, or organ
failure) for stress-related mucosal bleeding [33].
Although cimetidine given by continuous intravenous
infusion is currently the only regimen approved by the US
Food and Drug Administration for prevention of stress-
related mucosal bleeding, various H2-receptor antagonists
are often given by intermittent infusion for this indication in
clinical practice [34]. However, the ability of these agents,
when given intermittently, to maintain the intragastric pH
above 4.0 is questionable, given their relatively short half-
lives [35]. One study compared bolus doses and continuous
infusions of cimetidine in the maintenance of intragastric
pH above 4.0 in critically ill patients with at least one major
organ system failure or multiple traumas. Patients were
randomized to receive cimetidine either in bolus doses
(up to 300 mg IV every 6 hours) or by continuous intra-
venous infusion (up to 50 mg/h for 24 hours) [36]. Most
patients (87%) receiving continuous infusions maintained
their intragastric pH above 4.0. There was a strong (92.9%
positive) correlation between serum levels of cimetidine
and intragastric pH above 4.0. Thus, cimetidine given by
continuous infusion proved to be effective in maintaining
pH above 4.0, thereby potentially preventing stress ulcer-
ation (Fig. 5) [36]. It is important to note that although
H2RAs dosed as a continuous infusion are more effective in
raising gastric pH than H2RAs dosed intermittently, there
are no comparative trials evaluating these dosing regimens
on clinical outcomes. One can only surmise that more
complete acid suppression leads to enhanced GI protection.
5.3.2. Risk of nosocomial pneumonia
In regard to the association of increased pH—as a
consequence of H2RA administration for SRMD prophy-
N. Stollman, D.C. Metz
laxis—with potential for nosocomial pneumonia, Navab and
Steingrub [37] reported that the results of several studies
were conflicting. They concluded that other factors such as
intragastric volume, severity of illness, bile reflux, and
infection contributed to the development of pneumonia and
that the pathogenesis of pneumonia is multifactorial [37]. As
noted earlier, a large, well-controlled, randomized trial failed
to find a difference in the rate of nosocomial pneumonia
when ranitidine was compared to sucralfate in critically
ill patients [32].
5.3.3. Limitations of H2RAs
A significant limitation of H2RAs is the tendency for
tolerance to occur within a relatively short interval after
initiation of therapy. Two studies in healthy subjects
demonstrated that the H2RA ranitidine rapidly lost anti-
secretory effect after the first day of administration [38,39].
One study reported the development of tolerance despite
dose escalations on days 2 and 3 [38]. The other study found
that continuous infusions of ranitidine were superior to
intermittent injections only on day 1 of treatment [39]. The
latter observation may seem to contradict results of the
previously cited study comparing continuously infused and
bolus doses of cimetidine. However, that study did not
extend beyond a 12-hour observation period; thus, the
impact of tolerance was not detected [36].
Some H2RAs interfere with cytochrome P450 metabo-
lizing enzymes, potentially leading to drug interactions.
Cimetidine and, to a lesser extent, ranitidine inhibit P450
enzymes, which may facilitate accumulation and possibly
toxicity of coadministered drugs. In addition, H2RAs require
dosing adjustments in the setting of renal dysfunction [40].
Another clinical concern is thrombocytopenia that may be
induced by H2RAs, but it remains a rare occurrence in the
absence of another independent risk factor [41].
5.4. Proton pump inhibitors
Gastric acid is produced and regulated by mechanisms
within the parietal cell [42]. Transport of H + by the
proton pump, H +,K+-ATPase, is the underlying mediator
and final step in the regulation of acid secretion [43].
Proton pump inhibitors (PPIs) inactivate this enzyme and
inhibit gastric acid secretion by specific inhibition of
H +,K+-ATPase at the secretory surface of the parietal cell
[43], regardless of whether the cell is stimulated by
histamine, gastrin, or acetylcholine.
The efficacy and utility of PPIs have been established for
several acid-related GI disorders, but they have not, as yet,
been approved as prophylaxis for GI bleeding associated
with stress ulceration. Small open-label trials have examined
the use of oral PPIs administered as extemporaneously
compounded suspensions in patients at risk for stress ulcer.
No clinically significant bleeding was reported in these
trials, but drawing conclusions regarding efficacy is difficult
because of several methodological limitations of these
studies, such as the lack of a comparator arm and the small
Stress ulcer prophylaxis
Fig. 5 The effect of intermittent and continuous infusion
cimetidine on gastric pH. Asterisk indicates effect on representa-
tive patient. Adapted with permission from Gastroenterology
1985;89:532.
number of patients. In the first open-label study by Lasky et
al [44], 60 mechanically ventilated trauma patients with an
additional risk factor for stress ulcer development received
omeprazole suspension 40 mg given twice on the first day,
approximately 6 hours apart, followed by 20 mg/d. Baseline
pH (a secondary outcome in this study) was 3.3 for patients
enrolled in this study, with a mean gastric pH increase to 6.7
after administration of omeprazole [44]. The second
prospective open-label study by Phillips et al [45] included
patients admitted to a surgical ICU and to a burn unit
requiring mechanical ventilation and with at least one
additional risk factor for stress ulcer disease. Seventy-five
eligible patients received omeprazole suspension 40 mg,
followed by a second 40-mg dose 6 to 8 hours later, and
thereafter 20 mg daily. Four hours postomeprazole admin-
istration, the gastric pH increased to 7.1. The mean pH was
6.8 after starting therapy, up from an initial mean baseline
pH of 3.5 ( P b .001) [45]. No bleeding was reported in
either of these trials, but the number of patients enrolled is
likely insufficient to adequately assess an outcome of such
low incidence [44,45].
Few clinical studies have compared a PPI with an H2RA
for prophylaxis of GI bleeding in patients at risk for stress
ulceration. Levy et al [46] compared omeprazole with
ranitidine in patients with risk factors for stress ulcer–related
bleeding. Sixty-seven patients were randomized to receive
either ranitidine (n = 32), as a 50-mg bolus followed by a
50-mg IV infusion every 8 hours, or omeprazole (n = 32), as
41
a 40-mg capsule administered orally or nasogastrically once
a day [46]. Results showed significantly more clinically
significant bleeding in the ranitidine group than in the
omeprazole group (31% vs 6%, P b .05). In addition, fewer
patients receiving omeprazole developed nosocomial pneu-
monia (3% vs 14%), although the difference between groups
was not significant [46]. It should be noted, however, that
despite randomization, the ranitidine-treated patients had
more risk factors present at baseline than the omeprazole
group (2.7 vs 1.9, P b .05) [46]. The fact that PPIs are more
potent pump inhibitors raises theoretical concerns that their
more potent acid suppression may actually confer increased
risk of ventilator-associated pneumonia, which is a more
frequent and serious problem than stress ulcer bleeding.
Additional randomized trials in stress ulcer patients have
been published in abstract form only. One study compared
omeprazole suspension administered nasogastrically with
continuously infused ranitidine (150 or 200 mg/d) in
58 patients with at least 2 risk factors for stress ulcer–related
bleeding. Omeprazole was shown to be superior to ranitidine
in efficacy, safety, and cost. Clinically significant GI
bleeding occurred in 3% of patients receiving omeprazole
(n = 33) vs 16% of those receiving ranitidine (n = 25; P b.05)
[47]. Another trial compared the efficacy of ranitidine
150 mg/d via continuous infusion, sucralfate 1 g every
6 hours via nasogastric tube, and omeprazole 40 mg IV every
12 hours as prophylaxis for stress ulcers in 108 patients with
at least one risk factor for stress-related GI bleeding.
Gastrointestinal bleeding occurred in 10.5% of patients in
the ranitidine group (n = 38), 9.3% of those in the sucralfate
group (n = 32), and none of those in the omeprazole group
(n = 38) [48]. These studies suggest the superiority of
omeprazole for the prophylaxis of GI bleeding in high-risk
patients, but await the scrutiny of full-text publication.
Unlike H2RAs, PPIs do not seem to develop tolerance
with sustained therapy. Two studies comparing omeprazole
with ranitidine found that omeprazole maintained a pH
greater than 4.0 over 72-hour treatment periods [38,39]. In
one of the studies, the dose of omeprazole required to
maintain this degree of acid suppression actually decreased
by 43% from the first to the third day of treatment [38].
These results seem to be supported by those of a pilot study
by Morris [49]. This study included 202 critically ill patients
at high risk for GI bleeding who were randomized to receive
1 of 5 different dosing regimens of intravenous pantopra-
zole administered intermittently or a standard regimen of
cimetidine administered as a continuous infusion, with each
regimen given at least 48 hours and up to 7 days. The time to
achieve pH 4.0 or more was 4.3 hours for the pantoprazole
groups compared to 4.5 hours for the cimetidine group. In
all pantoprazole groups, the percentage of time that pH
remained at or above 4.0 increased on day 2 compared with
day 1 (Fig. 6). In contrast, this percentage actually decreased
on day 2 in the cimetidine group, despite administration of
continuous infusions. These data suggest that intermittent
dosing with intravenous pantoprazole can rapidly achieve
42
Fig. 6 The effect of intravenous pantoprazole and continuous infusion cimetidine on intragastric pH (n = 202). Adapted from Crit Care
Med 2002;30(suppl):A34.
and maintain a pH of 4.0 or more in critically ill patients,
implicating a rapid onset of action in the presence of a
requisite number of activated parietal cells to provide
efficacy comparable to cimetidine in the absence of
tolerance [49].
5.4.1. Administration issues
Proton pump inhibitors are inactivated by gastric acid
and thus must be given as enteric-coated granules in gelatin
capsules or enteric-coated tablets [50]. This requirement
poses an obstacle to PPI therapy in patients who cannot
swallow capsules. Attempts have been made to deliver the
granules orally with orange juice, with applesauce, or in an
aqueous solution with bicarbonate as a suspending agent
[50]. However, these extemporaneous formulations, primar-
ily evaluated in healthy subjects, have the potential to clog
enteral feeding tubes [51], have variable bioavailability [52],
and require that patients have adequate absorptive capacity,
which is often altered during critical illness [2,53]. The
availability of an intravenous PPI formulation offers a
potentially attractive alternative to oral PPI administration,
but there is a need for published outcome data regarding the
role of this route of administration. Overall, data on the use
of PPIs for the prevention of stress-related bleeding in
critically ill patients are limited; hence, further studies are
required to clearly establish their efficacy and safety for
this indication.
5.5. Enteral nutrition
Enteral nutrition offers many benefits to critically ill
patients. It may provide protection from postoperative
sepsis by supporting mucosal immunity and modulate
progression from gut ischemia to the systemic inflammatory
N. Stollman, D.C. Metz
response syndrome. Studies of animals subjected to brief
periods of mesenteric ischemia and reperfusion have found
that enteral feeding, as compared to total parenteral
nutrition, reduced mortality rate, abnormal gastric motility,
and organ permeability [54,55]. With regards to stress ulcer
prophylaxis, however, the efficacy of enteral nutrition is
controversial. A review of studies evaluating enteral
nutrition as stress ulcer prophylaxis found that the effects
of intragastric or postpyloric enteral nutrition on gastric pH
were variable, but that intramucosal pH was generally
lowered—a condition that predisposes to GI hemorrhage
[56]. In animals subjected to intestinal hypoperfusion, it
was found that aggressive delivery of enteral nutrition soon
after trauma increased oxidative demands and exacerbated
intestinal hypoxia, with the potential of leading to intestinal
ischemia [57].
Trials that evaluated enteral nutrition for reducing risk of
GI bleeding produced conflicting results and were limited
by design, size, varying definitions of bleeding, and
inconsistencies surrounding enteral nutrition [58-60]. It
seems that although early enteral nutrition offers benefits
to critically ill patients and is generally desirable, it should
not be used as the sole method of prophylaxis against stress
ulcer–related bleeding. Enteral nutrition should probably not
be started until hemodynamic perturbations have been
corrected in the ICU.
An additional issue to consider is the potential impact
of enteral nutrition on the efficacy of the stress ulcer pro-
phylaxis regimen a patient is receiving. Recent data pre-
sented in abstract form suggest that a continuous infusion of
intravenous cimetidine (300 mg bolus followed by 50 mg/h)
may be less effective at maintaining pH 4 or more in ICU
patients that are enterally fed compared to intravenous
Stress ulcer prophylaxis
Fig. 7 The impact of guidelines on use in reducing cost for stress ulcer prophylaxis. Adapted from Crit Care Med 1997;25:1678.
pantoprazole. Cimetidine increased intragastric pH 4 or
more for 76% of the time in patients in the fasting state, but
only for 49% of the time once the patients were enterally
fed. The opposite held true in the patients receiving
pantoprazole (doses ranging from 40 mg QD to 80 mg
TID) with an average pH of 4 or more for 69% and 89% of
the time during the nothing by mouth period and fed period,
respectively. Regardless of the dose infused, pantoprazole
was more effective during the period for which the patients
were fed [61].
6. Cost of prophylaxis
When evaluating the cost of regimens used for preven-
tion of stress ulcer–related bleeding, it is important to
recognize that acquisition cost is only one of several factors
that need to be considered. Other factors include cost of
preparing and administering the agent, as well as the
potential for overuse, adverse effects, and risk of bleeding.
Evidence strongly suggests that stress ulcer prophylaxis
should be limited to patients with established risk factors for
clinically significant GI bleeding. Several institutions have
developed guidelines for stress ulcer prophylaxis in an effort
to improve quality and cost of patient care. Two medical
centers that instituted such guidelines evaluated their impact
on drug costs and frequency of major GI bleeding. One
study found that limiting stress ulcer prophylaxis to patients
with established risk factors resulted in significantly fewer
patients receiving prophylaxis and a significant reduction
(80% decrease) in drug costs, without altering frequency of
GI bleeding [62]. The other study implemented the guide-
lines in 2 phases—a 2-month preintervention surveillance
and a 2-month postintervention drug use evaluation. The
investigators found that mean duration of prophylaxis and
mean medication costs were both reduced from phase 1 to
43
phase 2 (8.69 F 8.04 days and $36.19 F 38.29 vs 6.31 F
6.65 days and $24.92 F 27.36, respectively), resulting in an
overall decrease in the cost of hospitalization (Fig. 7). They
also noted that when clinically significant bleeding did
occur, it resulted in extended hospital stays and a
concomitant increase in overall costs [63].
7. Conclusions
The etiology of SRMD is multifactorial, but 2 conditions
that seem to be necessary are intraluminal acid and gastric
mucosal ischemia. Therefore, prophylaxis and treatment
require maintenance of perfusion and protection against acid
damage through elevation of gastric pH. Underlying disease
and risk factors including surgery, burns, trauma, respiratory
failure requiring mechanical ventilation, and coagulopathy
predispose patients to SRMD. Gastrointestinal bleeding
exacerbates the underlying illness and results in an increase
in morbidity and mortality. Therefore, in high-risk patients,
the emphasis should be on prevention of SRMD rather than
on treatment of complications.
Several approaches can be taken to prevent SRMD. First,
it is extremely important to restore hemodynamic stability to
maximize mesenteric perfusion and avoid ischemia. Second,
suppressing acid production pharmacologically is funda-
mental to preventing stress-related ulceration and potential
GI bleeding. If intraluminal pH is kept at or above 3.5,
bleeding from stress ulcers can be minimized. Because pH
titration is not common in clinical practice, it is important to
be knowledgeable about the medical literature, which can
assist us in choosing the appropriate pharmacologic agent.
Although H2RAs have demonstrated superiority over
placebo, antacids, and sucralfate in preventing clinically
significant stress-related GI hemorrhage, their effectiveness
at raising intragastric pH may be limited as tolerance
44
quickly develops. Proton pump inhibitors have been shown
to suppress acid production more effectively than H2RAs,
but data on their role in SRMD prophylaxis are limited, and
they have not, as yet, received approval for this indication.
They do possess theoretical advantages over H2RAs. In
contrast to H2RAs, PPIs lack tolerance, and thus are
effective for longer periods in critically ill patients. Further,
they are clearly more potent antisecretory agents. The
largest disadvantage at the present time is the fact that there
are currently limited published data assessing the role of
PPIs in the prevention of stress-related bleeding. Enteral
nutrition improves splanchnic blood flow, but trials have
been inconsistent with regard to its use in stress ulcer
prophylaxis and yielded conflicting results on its ability to
reduce GI bleeding. It should therefore not be used as sole
therapy for stress-ulcer prophylaxis.
Choosing an appropriate prophylactic regimen to prevent
complications associated with stress ulcers requires that the
clinician carefully evaluate the available data. Studies
performed so far that seek to determine the best means of
prevention have been characterized by conflicting outcomes
and have several limitations that need to be considered.
Acid suppression is an established preventive measure;
thus, it should begin as soon as major risk factors are
identified. A thorough review of the available evidence, a
clear understanding of the pathophysiology involved in this
type of GI injury, and a careful assessment of the individual
patient’s underlying disease status and risk factors are
necessary to ensure the provision of appropriate and cost-
effective care to critically ill patients at risk for stress ulcer–
related complications.
Acknowledgment
This work is supported by Wyeth Pharmaceuticals,
Philadelphia, PA, with editorial support provided by Accel
Medical Education, New York, NY.
References
[1] Young MP, Birkmeyer JD. Potential reduction in mortality rates using
an intensivist model to manage intensive care units. Eff Clin Pract
2000;3:284 - 9.
[2] Ritz MA, Fraser R, Tam W, Dent J. Impacts and patterns of disturbed
gastrointestinal function in critically ill patients. Am J Gastroenterol
2000;95:3044 - 52.
[3] Robertson MS, Cade JF, Clancy RL. Helicobacter pylori infection in
intensive care: increased prevalence and a new nosocomial infection.
Crit Care Med 1999;27:1276 - 80.
[4] Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal
bleeding in critically ill patients. Canadian Critical Care Trials Group.
N Engl J Med 1994;330:377 - 81.
[5] Cook DJ, Griffith LE, Walter SD, et al. The attributable mortality and
length of intensive care unit stay of clinically important gastrointes-
tinal bleeding in critically ill patients. Crit Care 2001;5:368 - 75.
[6] Ritchie Jr WP. Acute gastric mucosal damage induced by bile salts,
acid, and ischemia. Gastroenterology 1975;68:699 - 707.
N. Stollman, D.C. Metz
[7] Kivilaakso E, Silen W. Pathogenesis of experimental gastric-mucosal
injury. N Engl J Med 1979;301:364 - 9.
[8] Mutlu GM, Mutlu EA, Factor P. GI complications in patients
receiving mechanical ventilation. Chest 2001;119:1222 - 41.
[9] Silen W. The prevention and management of stress ulcers. Hosp Pract
1980;15:93 - 100.
[10] Lev R, Molot MD, McNamara J, Stremple JF. bStressQ ulcers
following war wounds in Vietnam. A morphologic and histochemical
study. Lab Invest 1971;25:491 - 502.
[11] Vorder Bruegge WF, Peura DA. Stress-related mucosal damage:
review of drug therapy. J Clin Gastroenterol 1990;12(Suppl 2):
S35-S40.
[12] Maynard N, Bihari D, Beale R, et al. Assessment of splanchnic
oxygenation by gastric tonometry in patients with acute circulatory
failure. JAMA 1993;270:1203 - 10.
[13] Maynard ND, Bihari DJ, Dalton RN, Smithies MN, Mason RC.
Increasing splanchnic blood flow in the critically ill. Chest 1995;108:
1648 - 54.
[14] Welsh DA, Summer W, deBoisblanc B, Thomas D. Hemody-
namic consequences of medical ventilation. Clin Pulm Med 1999;
6:52 - 65.
[15] Chernow B, Soldano S, Cook D, et al. Positive end-expiratory
pressure increases plasma catecholamine levels in non-volume loaded
dogs. Anaesth Intensive Care 1986;14:421 - 5.
[16] Love R, Choe E, Lippton H, Flint L, Steinberg S. Positive end-
expiratory pressure decreases mesenteric blood flow despite normal-
ization of cardiac output. J Trauma 1995;39:195 - 9.
[17] Tanaka S, Sagawa S, Miki K, Claybaugh JR, Shiraki K. Changes in
muscle sympathetic nerve activity and renal function during positive-
pressure breathing in humans. Am J Physiol 1994;266:R1220 - 8.
[18] Tremblay L, Valenza F, Ribeiro SP, Li J, Slutsky AS. Injurious
ventilatory strategies increase cytokines and c-fos m-RNA expression
in an isolated rat lung model. J Clin Invest 1997;99:944 - 52.
[19] von Bethmann AN, Brasch F, Nusing R, et al. Hyperventilation
induces release of cytokines from perfused mouse lung. Am J Respir
Crit Care Med 1998;157:263 - 72.
[20] Thoren T, Tanghoj H, Mattwil M, Jarnerot G. Epidural morphine
delays gastric emptying and small intestinal transit in volunteers. Acta
Anaesthesiol Scand 1989;33:174 - 80.
[21] Levein NG, Thorn SE, Lindberg G, Wattwill M. Dopamine reduces
gastric tone in a dose-related manner. Acta Anaesthesiol Scand
1999;43:722 - 5.
[22] van der Voort PH, van der Hulst RW, Zandstra DF, et al. Prevalence of
Helicobacter pylori infection in stress-induced gastric mucosal injury.
Intensive Care Med 2001;27:68 - 73.
[23] Yamamoto N, Sakagami T, Fukuda Y, et al. Influence of Helicobacter
pylori infection on development of stress-induced gastric mucosal
injury. J Gastroenterol 2000;35:332 - 40.
[24] Halm U, Halm F, Thein D, Mohr FW, Mossner J. Helicobacter pylori
infection: a risk factor for upper gastrointestinal bleeding after cardiac
surgery? Crit Care Med 2000;28:110 - 3.
[25] Riester KA, Peduzzi P, Holford TR, Ellison III RT, Donta ST.
Statistical evaluation of the role of Helicobacter pylori in stress
gastritis: applications of splines and bootstrapping to the logistic
model. J Clin Epidemiol 1997;50:1273 - 9.
[26] Peura DA, Johnson LF. Cimetidine for prevention and treatment of
gastroduodenal mucosal lesions in patients in an intensive care unit.
Ann Intern Med 1985;103:173 - 7.
[27] Spiess BD. Hemorrhage, coagulation, and transfusion: a risk-benefit
analysis. J Cardiothorac Vasc Anesth 1994;8:19 - 22.
[28] Hastings PR, Skillman JJ, Bushnell LS, Silen W. Antacid titration in
the prevention of acute gastrointestinal bleeding: a controlled,
randomized trial in 100 critically ill patients. N Engl J Med 1978;
298:1041 - 5.
[29] Fiddian-Green RG, McGough E, Pittenger G, Rothman E. Predictive
value of intramural pH and other risk factors for massive bleeding
from stress ulceration. Gastroenterology 1983;85:613 - 20.
Stress ulcer prophylaxis
[30] Cook DJ, Reeve BK, Guyatt GH, et al. Stress ulcer prophylaxis in
critically ill patients: resolving discordant meta-analyses. JAMA
1996;275:308 - 14.
[31] Driks MR, Craven DE, Celli BR, et al. Nosocomial pneumonia in
intubated patients given sucralfate as compared with antacids or
histamine type 2 blockers. The role of gastric colonization. N Engl J
Med 1987;317:1376 - 82.
[32] Cook D, Guyatt G, Marshall J, et al. A comparison of sucralfate and
ranitidine for the prevention of upper gastrointestinal bleeding in
patients requiring mechanical ventilation. Canadian Critical Care
Trials Group. N Engl J Med 1998;338:791 - 7.
[33] Martin LF, Booth FV, Karlstadt RG, et al. Continuous intrave-
nous cimetidine decreases stress-related upper gastrointestinal hem-
orrhage without promoting pneumonia. Crit Care Med 1993;21:
19 - 30.
[34] Erstad BL, Barletta JF, Jacobi J, et al. Survey of stress ulcer
prophylaxis. Crit Care (London) 1999;3:145 - 9.
[35] Feldman M, Burton ME. Histamine2-receptor antagonists. Standard
therapy for acid-peptic diseases. N Engl J Med 1990;323:1672 - 80.
[36] Ostro MJ, Russell JA, Soldin SJ, Mahon WA, Jeejeebhoy KN.
Control of gastric pH with cimetidine: boluses versus primed
infusions. Gastroenterology 1985;89:532 - 7.
[37] Navab F, Steingrub J. Stress ulcer: is routine prophylaxis necessary?
Am J Gastroenterol 1995;90:708 - 12.
[38] Merki HS, Wilder-Smith CH. Do continuous infusions of omeprazole
and ranitidine retain their effect with prolonged dosing? Gastroenter-
ology 1994;106:60 - 4.
[39] Netzer P, Gaia C, Sandoz M, et al. Effect of repeated injection and
continuous infusion of omeprazole and ranitidine on intragastric pH
over 72 hours. Am J Gastroenterol 1999;94:351 - 7.
[40] Wolfe MM, Sachs G. Acid suppression: optimizing therapy for
gastroduodenal ulcer healing, gastroesophageal reflux disease, and
stress-related erosive syndrome. Gastroenterology 2000;118:S9 - 31.
[41] Wade EE, Rebuck JA, Healey MA, Rogers FB. H(2) Antagonist-
induced thrombocytopenia: is this a real phenomenon? Intensive Care
Med 2002;28:459 - 65.
[42] Modlin IM, Sachs G. The parietal cell. In: Modlin IM, Sachs G,
editors. Acid Related Diseases: Biology and Treatment. Konstanz
(Germany)7 Schnetztor-Verlag GmbH D-Konstanz; 1998. p. 92 - 109.
[43] Modlin IM, Sachs G. Inhibition of the gastric acid pump. Acid Related
Diseases: Biology and Treatment. Konstanz (Germany)7 Schnetztor-
Verlag GmbH D-Konstanz; 1998. p. 126 - 45.
[44] Lasky MR, Metzler MH, Phillips JO. A prospective study of
omeprazole suspension to prevent clinically significant gastrointesti-
nal bleeding from stress ulcers in mechanically ventilated trauma
patients. J Trauma 1998;44:527 - 33.
[45] Phillips JO, Metzler MH, Palmieri TL, Huckfeldt RE, Dahl NG. A
prospective study of simplified omeprazole suspension for the
prophylaxis of stress-related mucosal damage. Crit Care Med 1996;
24:1793 - 800.
[46] Levy MJ, Seelig CB, Robinson NJ, Ranney JE. Comparison of
omeprazole and ranitidine for stress ulcer prophylaxis. Dig Dis Sci
1997;42:1255 - 9.
45
[47] Phillips JO, Metzler MH, Huckfeldt RE, Olsen K. A multicenter,
prospective, randomized clinical trial of continuous infusion I.V.
ranitidine vs omeprazole suspension in the prophylaxis of stress
ulcers. Crit Care Med 1998;26:A101.
[48] Azevedo JR, Soares MG, Silva G, Palacio G. Prevention of stress
ulcer bleeding in high risk patients: comparison of three drugs. Crit
Care Med 1999;27:A41.
[49] Morris JA. Intermittent intravenous pantoprazole rapidly achieves and
maintains gastric pH N 4 compared with continuous infusion H2-
receptor antagonist in intensive care unit (ICU) patients. Crit Care
Med 2002;30.
[50] Berardi RR, Welage LS. Proton-pump inhibitors in acid-related
diseases. Am J Health Syst Pharm 1998;55:2289 - 98.
[51] Chun AH, Eason CJ, Shi HH, Cavanaugh JH. Lansoprazole: an
alternative method of administration of a capsule dosage formulation.
Clin Ther 1995;17:441 - 7.
[52] Dunn A, White CM, Reddy P, Quercia RA, Chow MS. Delivery of
omeprazole and lansoprazole granules through a nasogastric tube in
vitro. Am J Health Syst Pharm 1999;56:2327 - 30.
[53] Heyland D, Cook DJ, Winder B, et al. Enteral nutrition in the critically
ill patient: a prospective survey. Crit Care Med 1995;23:1055 - 60.
[54] Ephgrave KS, Brasel KJ, Cullen JJ, Broadhurst KA. Gastric mucosal
protection from enteral nutrients: role of motility. J Am Coll Surg
1998;186:434 - 40.
[55] Fukatsu K, Zarzaur BL, Johnson CD, et al. Enteral nutrition prevents
remote organ injury and death after a gut ischemic insult. Ann Surg
2001;233:660 - 8.
[56] MacLaren R, Jarvis CL, Fish DN. Use of enteral nutrition for stress
ulcer prophylaxis. Ann Pharmacother 2001;35:1614 - 23.
[57] Kles KA, Wallig MA, Tappenden KA. Luminal nutrients exacerbate
intestinal hypoxia in the hypoperfused jejunum. JPEN J Parenter
Enteral Nutr 2001;25:246 - 53.
[58] Pingleton SK, Hadzima SK. Enteral alimentation and gastrointestinal
bleeding in mechanically ventilated patients. Crit Care Med 1983;
11:13 - 6.
[59] Gurman G, Samri M, Sarov B, Bearman JE, Heilig I. The rate of
gastrointestinal bleeding in a general ICU population: a retrospective
study. Intensive Care Med 1990;16:44 - 9.
[60] Raff T, Germann G, Hartmann B. The value of early enteral nutrition
in the prophylaxis of stress ulceration in the severely burned patient.
Burns 1997;23:313 - 8.
[61] Smith JS, Karlstadt R, Blatcher B, Field B. Gastric pH improvement
from NPO to enteral-fed period with intermittent intravenous (IV)
pantoprazole (P) vs. continuously infused cimetidine (C). Presented at
the American College of Gastroenterology 67th Annual Scientific
Meeting; October 21-23, 2002; Seattle. WA [abstract 143]. Am J
Gastroenterol 2002;97:S47.
[62] Devlin JW, Claire KS, Dulchavsky SA, Tyburski JG. Impact of trauma
stress ulcer prophylaxis guidelines on drug cost and frequency of
major gastrointestinal bleeding. Pharmacotherapy 1999;19:452 - 60.
[63] Erstad BL, Camamo JM, Miller MJ, Webber AM, Fortune J.
Impacting cost and appropriateness of stress ulcer prophylaxis at a
university medical center. Crit Care Med 1997;25:1678 - 84.