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Creator: University of Florida College of Pharmacy
Publisher: College of Pharmacy, University of Florida
Publication Date: October 2007
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A REVIEW OF ACUTE STRESS
ULCER PROPHYLAXIS IN THE
INTENSIVE CARE UNIT

Stephen Tan, Pharm.D. Candidate


It is a well known fact that patients in inten-
sive care unit (ICU) settings are prone to ulcers. Ul-
cers are generally defined as upper gastrointestinal
(GI) in nature and are often secondary to a traumatic
event, such as surgery, burns, or a head injury that is
critical in nature.1 These types of ulcers are known as
acute stress ulcers. There are other types of ulcers
that can be secondary to NSAID use or to a Helico-
bacter pylori infection. Stress ulcers can form very
quickly following a traumatic event, sometimes
within hours. Recent studies reveal that evidence of
acute mucosal damage can be seen within 72 hours
of a traumatic event.2 It must also be noted that only
a small percentage of these ulcers will progress to
symptoms of acute blood loss.3
Although an ulcer is present, many times
there are no obvious signs of clinically important
bleeding. Signs of clinically important bleeding in-
clude hematemesis, hematochezia, or melena compli-
cated by hemodynamic changes. Endoscopy can de-
tect GI bleeds, but many remain undetectable. If
clinically important bleeding is present, the patient
may present with tachycardia, hypotension, or a de-
crease in hemoglobin greater than 2 g/dL from base-
line. With a large decrease in hemoglobin, a blood
transfusion maybe necessary.1
Patients may be at higher risk for developing
acute stress ulcers depending on several risk factors.


The first of which is admission etiology to the inten-
sive care unit. Patients admitted for moderate to se-
vere traumatic events, spinal cord injuries, head in-
jury, thermal bums, organ transplantation or hepatic
failure are at an increased risk. Mechanical ventila-
tion greater than 48 hours, platelet count less than
50,000 mm3, or baseline prothrombin time > 16 sec-
onds, are three additional independent risk factors.1

Pathophysiology
Ulcers that form within the first few days
generally will form at the more distal region of the
gastrointestinal tract. These ulcers are more severe in
nature. Both early and late ulcerations form by the
same mechanism, and is believed to be due to an im-
balance of mucosal protective mechanisms and a hy-
persecretion of gastric acid. Hypersecretion is caused
by over-stimulation of parietal cells by gastrin.3 This
phenomenon is primarily seen in patients suffering
from head trauma. The stomach is also protected by
a layer of mucus which forms a barrier against hy-
drogen ion diffusion and is also useful in trapping
bicarbonate. This allows acid neutralization in the
area nearest to the stomach wall. In patients who suf-
fer a traumatic event, this glycoprotein mucus layer
is compromised due to a higher output of bile salts
and uremic toxins. Ischemia or poor perfusion also



INSIDE THIS ISSUE:
A REVIEW OF ACUTE STRESS ULCER PROPHYLAXIS
IN THE INTENSIVE CARE UNIT

INDEX FOR VOLUME 22 (OCT. 2006-SEP. 2007)


* l *


mm
PharmaNote Volume 23, Issue 1 October 2007


SPharmaNote


VOLUME 23, ISSUE 1 OCTOBER 2007


Volume 23, Issue 1 October 2007


PharmaNote






Figure 1. Pathophysiology of acute stress ulcers

Critical Illness

Hypovolemia
Increased
catecholamines
---cate min- Cardiac output Proinflammatory
increased vasoconstriction cytokine release

Splanchnic hypoperfusion


Reduced
HCO3
secretion
t


Reduced
mucosal
blood flow
t


Decreased
GI motility
t


ute stress u
Acute stress ulcer


Adapted from Stollman N, et al.1


plays a role because it will decrease the body's abil-
ity to secrete this glycoprotein mucus. This in turn
leads to ulceration of the mucosal layer.3
H. pylori infections may also play a role in
stress ulcer development, although supporting data is
limited. In one multi-center case-controlled study,
patients infected with H. pylori and admitted to an
intensive care unit, were more likely to suffer from
an acute upper GI bleed than those not infected (36%
vs. 16%; p=0.04).4

Pharmacology
Proton Pump Inhibitors (PPIs)
Proton pump inhibitors [omeprazole
(Prilosec), lansoprazole (Prevacid), rabeprazole
(AcipHex), pantoprazole (Protonix), and esome-
prazole (Nexium)] have the ability to create an en-
vironment in the gastrointestinal tract that is favor-
able for healing. By increasing the pH of the stomach
to a level between 4 and 6, PPIs may also decrease
the risk of rebleeding. Proton pump inhibitors also
have reduced tolerance, especially when compared to
H2 receptor antagonists (H2RAs). Tolerance of
H2RAs may occur within 24 to 72 hours of use.
H2RAs are not able to maintain a higher pH. At peak
effect, H2RAs may achieve a pH of 5, but will de-
cline to baseline over a few days of treatment.1
PPIs are prodrugs; therefore, they must be
converted to an active form in order to provide bene-


fit. PPIs are converted to their active form by an
acidic environment. Once activated, the molecule
will bind to cysteine residues and inactivate H+, K+-
ATPase, otherwise known as the proton pump. This
will systematically stop the function of the proton
pump. This mechanism is irreversible and will pre-
vent any hydrogen ions from being transported for
the life of the proton pump. The average lifespan of a
proton pump is approximately 96 hours. New proton
pumps must be created for the secretion of acid to
resume.
Proton pump inhibitors have many different
dosage forms. (Table 1) In the United States, PPIs
can be administered in the ICU by IV infusion, sus-
pension, or even encapsulated granules. Tablets and
capsules are available for patients able to tolerate an
oral diet.
Proton pump inhibitors have many adverse
drug reactions, some more serious than others. The
incidence of these adverse reactions is quite low,
ranging from 1-4%. Some of the more common and
less serious adverse effects of PPIs are: abdominal
pain, nausea, diarrhea, flatulence, rash, eructation,
insomnia, hyperglycemia, and headaches.5 Drug in-
teractions may also occur with the use of PPIs. Spe-
cific interactions may occur with drugs that are me-
tabolized through CYP2C19 and 3A4 and drugs that
need an acidic environment for absorption (i.e. azole
antifungals and some protease inhibitors).10


PharmaNote Volume 23, Issue 1 October 2007


Acid back
diffusion

t


Volume 23, Issue I October 2007


PharmaNote







Table 1. Proton pump inhibitor dosage forms and strengths


Proton Pump Inhibitor (generic)


AcipHex" (rabeprazole)

Nexium (esomeprazole)



Prevacid (lansoprazole)


Protonix (pantoprazole)

Prilosec (omeprazole)


Dosage forms


Delayed release tablet
Delayed release tablet
Delayed release suspension
IV powder for injection
Delayed release capsule
Granules for suspension
IV powder for injection
Solutab (orally disintegrating)
Delayed release tablet
IV powder for injection
Delayed release capsule


H2 receptor antagonists
H2 receptor antagonists [Cimetidine
(Tagamet'), Ranitidine (Zantac), Famotidine
(Pepcid), Nizatadine (Axid)] are often used to con-
trol peptic ulcer disease, and for the treatment of gas-
tro-esophageal reflux disease (GERD) and dyspep-
sia. H2RAs are also used to reduce the incidence of
stress ulceration. By blocking H2 receptors on parie-
tal cells, H2RAs will inhibit the stimulatory effects
and decrease acid secretion.3 There have been several
studies showing the effectiveness of H2RAs in the
setting of stress ulcer prophylaxis. H2RAs can be
given either as an IV bolus or continuous infusion.
The use of continuous infusion was shown to main-
tain higher levels of gastric pH, without decreased
rates of bleeding.2 HRAs are also effective when
given orally or through a nasogastric tube.7
H2 receptor antagonists are well tolerated and
well absorbed. Peak serum concentrations are gener-
ally reached 1-3 hours after ingestion. Absorption
may be inhibited by approximately 20% if taken with
an antacid, but food has no effect. H2RAs do cross
the blood brain barrier and so may have an effect on
the central nervous system. These can range from
common effects such as headache, to vertigo and
lethargy which occur much less frequently.3
In randomized clinical trials, H2RAs adverse
effects were not significantly different than placebo.8
Some rare adverse effects included gynecomastia,
impotence, myelosuppression, thrombocytopenia,
neutropenia, anemia, pancytopenia, polymyositis,
interstitial nephritis, restlessness, somnolence, agita-
tion, headaches, and dizziness.

Antacids
Antacids [Rolaids, Tums, Maalox, and


Mylanta] contain aluminum hydroxide, magnesium
hydroxide, or calcium carbonate, and may have
combinations of the aforementioned ingredients.
Antacids work simply by neutralizing stomach acid.
Studies have reported that the use of antacids is ef-
fective in preventing stress ulcers, and are roughly
equivalent in effectiveness to H2 receptor antagon-
sits.9
Most antacids are inexpensive and readily
available. Administration of antacids becomes prob-
lematic due to the high frequency needed for effec-
tiveness. Most antacids need to be administered
every 2 hours at a dose of 30 60 ml. This can be
administered orally or through a nasogastric tube.
Many argue that the increased cost of nursing care
far outweighs cost saving of antacids.
Common adverse effects of antacids include,
hypophosphatemia, hypermagnesemia, constipation,
diarrhea, and increased risk of nosocomial pneumo-
nia are some of the adverse reactions seen with ant-
acid use.10

Sucralfate
Complex polyaluminum hydroxide salts
[sucralfate (Carafate)] may also be used for ulcer
prophylaxis. By coating the gastric mucosa, sucral-
fate protects the mucosa from overproduction of
acid. In the acidic environment of the stomach, su-
cralfate becomes highly polar where it preferentially
binds to exposed ulcer beds; thus, protecting them
from further damage from gastric secretions.6
The effectiveness of sucralfate is controver-
sial. The most rigorous study found that in 1200 pa-
tients being mechanically ventilated, sucralfate in-
creased the risk of GI bleed greater than those pa-
tients being treated with an H2RA, specifically raniti-


PharmaNote Volume 23, Issue 1 October 2007


Strength


20mg
20mg, 40mg
20mg, 40mg
20mg, 40mg
15mg, 30mg
15mg, 30mg
30mg
15mg, 30mg
20mg, 40mg
40mg
10mg, 20mg


Volume 23, Issue I October 2007


PharmaNote







dine.11 There was one meta-analysis that found that
sucralfate reduced mortality (though with higher in-
cidences of GI bleed) versus H2RAs.12 It is a possi-
bility that this result may be due to a lower incidence
of nosocomial pneumonia in the sucralfate popula-
tion.
Sucralfate is well tolerated and there is little
evidence of increased levels of plasma serum alumi-
num. This result was consistent in patients with renal
impairment. Another consideration is the reduced
cost of sucralfate compared to PPIs and H2RAs.6

Prostaglandin Analogs
A lesser known option for prophylaxis of
stress ulcers are the prostaglandin analogs. Pros-
taglandin E and I are specifically known to reduce
cAMP in parietal cells, effectively inhibiting acid
secretion. One of the better known prostaglandin El
analogs is misoprostol [Cytotec]. Misoprostol has
also been approved by the FDA for the prevention of
NSAID-induced ulcers.6' 10
It is believed that prostaglandin analogs have
antisecretory and cytoprotective effects on the gas-
trointestinal tract. The cytoprotection afforded by
this class of drugs may be due to its ability to reduce
acid secretion from the parietal cell, increase bicar-
bonate and mucus production, and cause vasodilata-
tion in capillary beds, thus decreasing the chance for
local ischemia.10
There have been several small trials compar-
ing the efficacy of these drugs against H2RAs and
antacids. Most of these trials have shown comparable
efficacy, but adverse effects, most notably severe


diarrhea, prevent the use of misoprostol in most set-
tings.13, 14 Misoprostol is contraindicated in women
of child bearing age who are not on contraception
due to its ability to cause uterine contractions and
miscarriage.

Clinical Trials
Although there are clinical trials comparing
the efficacy of different prophylactic agents for acute
stress ulcers, recent data has suggested that the most
effective prophylactic class of drugs are proton pump
inhibitors and H2 receptor antagonists. As such clini-
cal trials comparing the efficacy of proton pump in-
hibitors and H2 receptor antagonists will be re-
viewed.

Omeprazole versus IV cimetidine
This was a non-inferiority analysis designed
to show the effectiveness of immediate-release ome-
prazole in preventing upper gastrointestinal bleeding
in critically ill patients.15 A total of 359 patients in 47
intensive care units were included in the study. These
patients were mechanically ventilated for greater
than 48 hours, had Acute Physiology and Chronic
Health Evaluation score of greater than 11 at base-
line. They also had an intact stomach and either a
nasogastric or orogastric feeding tube in place. Pa-
tients included in the study also had at least one addi-
tional risk factor for upper gastrointestinal bleed.
These patients were randomized to either 40 mg of
omeprazole suspension via either the nasogastric or
orogastric tube or IV cimetidine (300 mg bolus, then
50 mg/hr maintenance) for up to 14 days. The pri-


Table 2. Comparison of omeprazole oral suspension to intravenous (IV) cimetidine


Confidence interval
Omeprazole oral sus- IV cimetidineene
for the difference in
pension (n= 178) (n= 181) (
rates (%)

Clinically significant bleeding, n (%) 7 (3.9) 10 (5.5) -100 to 2.8"

Any overt bleeding, n (%) 34(19.1) 58(32) -21.9 to -4b

Inadequate pH control, n (%) 32 (18) 105 (58) -49.2 to -30.9c

Both end point and non-end point bleeding was included in the definition of any overt bleeding. Inadequate pH control was considered to be two
consecutive gastric pH readings of < 4 at least 1 hour apart on any given day of treatment; tabulated patients experienced inadequate pH control on
at least one occasion during the trial. The difference in rates was calculated as omeprazole-cimetidine.
"Non-inferiority analysis, one-sided 97.5% confidence interval
btwo-sided 95% confidence interval, p= 0.005
'two-sided 95% confidence interval, p< 0.001
Pharm~oteVolue 23 Issu 1 Otobe1200


Volume 23, Issue I October 2007


PharmaNote







Figure 2. Oral omeprazole suspension vs. IV cimetidine on median gastric pH
10
*-- Omeprazole Oral Suspension (N=178)
9 Intravenous Cimetidine (N=181)


Number of patients
*166 170 143 124 109 89 73 60 53 43 40 35 31 27
*174 175 157 122 103 88 78 70 59 51 46 39 33 28

1 2 3 4 5 6 7 8 9 10 11 12 13 14


Trial Day

Adapted from Conrad SA, et al."


mary endpoint was clinically significant upper gas-
trointestinal bleeding. This was characterized as
bright red blood not clearing after 5-10 minutes of
lavage or persistent occult-positive coffee ground
material for 8 hours on days 1-2 for 2-4 hours on
days 3-14 and not clearing with > 100 ml of lavage.
The omeprazole suspension treated population
showed a 3.9 % rate of clinically significant bleeding


versus a 5.5 % rate of clinically significant bleeding
in the IV cimetidine group (Table 2).
Omeprazole suspension was able to achieve a
gastric pH > 6 on all trial days. In the IV cimetidine
group, gastric pH > 6 was achieved on only 50% of
the trial days. (Figure 2) In addition, more patients
in the cimetidine group had pH levels below 4.
(Table 3) This study was able to demonstrate that
immediate-release omeprazole suspension is effec-


Table 3. Percentage and number of patients with median gastric pH < 4"
Trial Day Omeprazole oral suspension % Intravenous Cimetidine, % p value
1 2.4 (4/166) 11.5 (20/174) < 0.1
2 0.6 (1/170) 10.3 (18/175) < 0.1
3 2.8 (4/143) 17.8 (28/157) < 0.1
4 4 (5/124) 13.1 (16/122) 0.01
5 2.8 (3/109) 15.5 (16/103) < 0.1
6 2.2 (2/89) 20.5 (18/88) < 0.1
7 1.4(1/73) 17.9(14/78) < 0.1
8 5(3/60) 24.3 (17/70) < 0.1
9 3.8(2/53) 32.2 (19/59) < 0.1
10 4.7 (2/43) 33.3 (17/51) < 0.1
11 5(2/40) 30.4 (14/46) < 0.1
12 0(0/35) 25.6 (10/39) < 0.1
13 0(0/31) 27.3 (9/33) < 0.1
14 3.7 (1/27) 28.6 (8/28) 0.02

PharmaNote Volume 23, Issue 1 October 2007






Table 4. Ranitidine vs. omeprazole in percentage of patients with bleed and pneumonia16
Ranitidine Omeprazole P
Stress ulcer bleed 11(31%) 2(6%) <0.05
Nosocomial Pneumonia 5(14%) 1 (3%) NS


tive in preventing upper gastrointestinal bleeding and
superior to IV cimetidine's ability to maintain a gas-
tric pH > 4 in critically ill patients.15

Comparison of Omeprazole and Ranitidine for Stress
Ulcer Prophylaxis
This was a prospective, randomized clinical
trial designed to compare the efficacy of omeprazole
and ranitidine for stress ulcer prophylaxis.16 The
study enrolled 67 high risk patients that were ran-
domized to either receive ranitidine 150 mg (n=35)
intravenously daily, or omeprazole 40 mg (n=32)
orally or via nasogastric tube daily. These patients
were then monitored for clinically important bleed-
ing. Differences in the characteristics of those en-
rolled, such as gender, race, sex, or age was not sta-
tistically significant. The patients were also com-
pared in regard to the severity of their illness based
on APACHE II scores, the duration of their ICU
stay, duration of ventilator dependency, and mortal-
ity rate. There was a significant difference in regards
to the number of risk factors for each patient. The
ranitidine group had a greater number of risk factors
compared to the omeprazole group (2.7 vs. 1.9, p <
0.05). In the ranitidine group 11 patients developed
clinically significant bleeding versus only two pa-
tients in the omeprazole group (31% vs. 6%, p <
0.05). In addition, five patients in the ranitidine
group developed nosocomial pneumonia versus only
one patient in the omeprazole group. (Table 4) This
secondary outcome was not statistically significant.
The authors concluded that omeprazole is clinically
safe and effective for the indication of stress ulcer
prophylaxis.16

Summary
Acute stress ulcers are a common event for
patients who have undergone a traumatic event and
are admitted to an ICU. They can develop very
quickly and may not show any signs of clinically sig-
nificant bleeding. Patients at high risk, such as those
on mechanical ventilation > 48 hrs should be prophy-
lactically treated for acute stress ulcers. There are
several pharmacological choices available for treat-


ment. These include antacids, prostaglandin analogs,
sucralfate, H2 receptor antagonists, and proton pump
inhibitors. The most commonly studied agents to
date have been H2 receptor antagonists and proton
pump inhibitors. While both of these agents have
been shown to be effective in recent studies, individ-
ual hospital formulary and clinician preference may
guide therapy decisions.

References
1. Zeigler A. The role of proton pump inhibitors in
acute stress ulcer prophylaxis in mechanically
ventilated patients. Dimensions of Critical Care
Nursing 2005; 24: 109-14
2. Baghaie AA, Mojtahedzadeh M, Levine RL, et
al. Comparison of the effect of intermittent admi-
nistration and continuous infusion of famotidine
on gastric pH in critically ill patients: Results of a
prospective randomized, crossover study. Crit
Care Med 1995; 23: 687
3. Weinhouse GL, Manaker S. Stress ulcer prophy-
laxis in the intensive care unit,
www.uptodate.com Accessed 7/10/2007
4. Maury E, Tankovic J, Ebel A, Offenstadt G. An
observational study of upper gastrointestinal
bleeding in intensive care units: Is Helicobacter
pylori the culprit? Crit Care Med 2005; 33:1513-
8
5. Neudeck BL, Martindale RG. Acid suppression
in the ICU: the constant dilemma. Pharm Pract
News 2003; Oct: 48-54
6. Martindale RG, Friedman BC. Point-
counterpoint: key controversies in critical care.
Gut-related issues in the ICU setting. A Day-
break Panel discussion at the Society of Critical
Care Medicine's 33rd Critical Care Congress;
February 24, 2004; Orlando, Fla.
7. Pemberton LB, Schaefer N, Goehring L, et al.
Oral ranitidine as prophylaxis for gastric stress
ulcers in intensive care unit patients: Serum
concentrations and cost comparisons. Crit Care
Med 1992; 21: 339
8. Reynolds JC. The clinical importance of drug
interactions with antiulcer therapy. J Clin Gastro-


PharmaNote Volume 23, Issue 1 October 2007


Volume 23, Issue I October 2007


PharmaNote







enterol 1990; 12: S54
9. Shuman RB, Schuster DP, Zuckerman GR. Pro-
phylactic therapy for stress ulcer bleeding: A re-
appraisal. Ann Intern Med 1987; 106: 562
10. Soll AH. Pharmacology of antiulcer medications,
www.uptodate.com Accessed 7/10/2007
11. Cook D, Guyatt G, Marshall J, et al. A compari-
son of sucralfate and ranitidine for the prevention
of upper gastrointestinal bleeding in patients re-
quiring mechanical ventilation. N Engl J Med
1998; 338:791
12. Cook DJ, Reeve BK, Guyatt GH, et al. Stress ul-
cer prophylaxis in critically ill patients. Resolv-
ing discordant meta-analyses. JAMA 1996; 275:
308
13. DePriest JL. Stress ulcer prophylaxis: Do criti-
cally ill patients need it? Postgrad Med 1995; 98:
159
14. Martin LF, Booth FVM, Reines D, et al. Stress
ulcers and organ failure in intubated patients in
surgical intensive care units. Ann Surg 1992;
215:332
15. Conrad SA, Gabrielli A, Margolis B. Random-
ized, double-blind comparison of immediate re-
lease omeprazole oral suspension versus intrave-
nous cimetidine for the prevention of upper gas-
trointestinal bleeding in critically ill patients. Crit
Care Med 2005; 33: 760
16. Levey MJ, Seelig CB, Robinson NJ, et al. Com-
parison of Omeprazole and Ranitidine for Stress
Ulcer Prophylaxis. Dig Dis Sci; 1997; 42: 1255-
9.
17. Stollman N, Metz DC. Pathophysiology and pro-
phylaxis of stress ulcer in intensive care unit pa-
tients. Journal of Critical Care 2005; 20: 35-45

Index for Volume 22 (Oct 2006 Sep 2007)

Topic Issue (Page)


Acute cough
Aliskiren
Alli
Amitiza

B-C-D
Cervarix
Darifenacin


E-F-G-H-I-J
Enablex
Etonogestrel implant


Oct 2006 (01)
Mar 2007 (01)
Sep 2007 (05)
Sep 2007 (01)


Dec 2006 (01)
Nov 2006 (01)


Nov 2006 (01)
Dec 2006 (05)


Fibric acid derivatives for primary
and secondary CHD prevention
Gardasil
HPV vaccines
Implanon
Januvia

K-L-M-N
Lubiprostone
Migraine prophylaxis
No\aIfll'

O-P-Q-R
Orlistat
Phenylephrine for pseudoephedrine
in OTC cold medicines
Posaconazole
The Role of Digoxin in Treating
Systolic Heart Failure
RotaTeq
Rotavirus vaccine

S-T-U-V
Sitagliptin
Tektuma
Tolvaptan
Traditional vs. low-dose
oral contraceptives
Triptans in the management of
acute migraine


Aug 2007 (01)

Dec 2006 (01)
Dec 2006 (01)
Dec 2006 (05)
Nov 2006 (01)


Sep 2007 (01)
Jan 2007 (01)
May 2007 (01)


Sep 2007 (05)
Apr 2007 (01)

May 2007 (01)
Feb 2007 (01)

Jun 2007 (01)
Jun 2007 (01)


Nov 2006 (06)
Mar 2007 (01)
Jul 2007 (01)
Feb 2007 (08)

Apr 2007 (5)


W-X-Y-Z


The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacy Practice
University of Florida



John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

Shawn Anderson Assistant Editor
Pharm.D.


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