Stress Ulcer Prophylaxis Introduction
The development of “stress” ulceration in the
upper gastrointestinal (GI) tract has been part
of critical care folklore since the beginning. In
1842 Curling described a series of severe
duodenal ulceration associated with burns; in
1832 Cushing reported ulcer disease
associated with surgery and trauma. In the
early years of intensive care, a strong
association between severity of illness and the
incidence of GI bleeds was established.
Patients who had major bleeds had a high
mortality rate, and, consequently, prophylaxis
against this complication has become a central
issue in ICU care. The objective of this tutorial
is to give you an idea of the incidence, causes
and risks associated with stress ulceration. We
will also address the potential complications
associated with prophylaxis.
To learn about the causes of stress
To evaluate the incidence and cost
effectiveness of prophylaxis,
To explore the literature, addressing
which agent is most effective at
To determine the complications
associated with ulcer prophylaxis,
Stress Ulcer Proph
Stress Ulceration What is it? Why is it
Stress ulceration is a gastrointestinal
mucosal injury related to critical illness.
There is a relationship between GI bleeding
and severity of disease.
Likewise there is a strong relationship
between bleeding and mortality
Stress ulceration is a gastrointestinal mucosal
injury related to critical illness. The ulceration
may vary from diffuse superficial injuries to
deep hemorrhaging ulcerations. There is a
relationship between severity of disease and
incidence of ulceration (1) The development of
stress ulceration is not related to a history of
peptic ulcer disease or Helicobacter infection.
The cause, as we will see below, is
multifactorial, and related to hypoperfusion and
loss of host defenses. The development of
clinically significant gastrointestinal ulceration
can be devastating to the critically ill patient,
representing, as it does, loss of physiological
reserve and causing acute hypovolemia and
end organ injury. The mortality rate associated
with such bleeds is astonishingly high: varying
between 48.5% (2) and 87.5% (3).
Like all complications of critical illness, poor
patient outcome following gastrointestinal
bleeding may reflect underlying severity of
illness, rather than importance of the disease
process itself. A GI bleed may be a marker of
the patient’s condition, rather like a low serum
albumin. As the mortality rate for patients
admitted to intensive care units is diminishing,
so too is the incidence of life threatening
Stress Ulceration What causes it?
Ulceration is caused by ischemic injury to the gastric mucosa, loss of cytoprotectants
and assault by gastric acid.
The mucosa is injured and cannot repair itself sufficiently well to ward off aggressive factors
present in the gut lumen: these aggressors include gastric acid, bile and digestive enzymes.
Mucosal blood flow is diminished, and there is an imbalance of demand for and supply of
oxygen. The result is reduced production of cytoprotectant factors, such as prostaglandins,
mucosal atrophy and increased permealility, loss of reparative capacity and loss of ability to
neutralize acid (hydrogen ions).
The mucosa is compromised by ischemia and attacked (mostly) by acid. It is injured, and, due
to the presence of acid, cannot repair itself (hostile environment). The use of external agents to
neutralize acid resolves this problem.
Stress Ulceration Risk Factors
The major risk factors are respiratory failure,
coagulopathy, sepsis, hypotension and
hepatic and renal failure.
This has been extensively studied: based on the
two studies by Cooke’s group (2;4) , we know
that patients with respiratory failure and with
coagulopathy have significantly higher
incidences of bleeding than other patients. The
other major risk factors were sepsis, liver failure,
hypotension and renal failure.
Overall, we know that there is a good
relationship between severity of illness (as
determined by, for example, Apache II scores)
and incidence of ulceration. Moreover, the
longer a patient is in ICU, the more likely they
are to have a GI bleed (5). Patients who are
likely to have a number of these risk factors –
burns patients for example (ventilated,
hypotensive, coagulopathic), are more likely to
have ulceration and bleeding.
Stress Ulceration What is the Incidence?
The incidence of stress ulceration is
diminishing, probably reflecting better
care before and during intensive care
In the 1970s and 80s, meta analyses have
put the incidence of overt bleeding to be
approximately 15% (6). The prevalence
appears to be diminishing. Work by Cooke
and colleagues ascribed the risk of overt
bleeding to be 4.4% and clinically significant
bleeding to be 1.5% (2)The incidence of
clinically significant bleeding appears to be
dependent on severity of illness and the type
of patient population studied. For example, in
Perioperative cardiac surgery patients the risk
is approximately 0.4% (7). In stroke patients
(who were not mechanically ventilated) the
risk is 0.1% (8). There is a strong relationship
between duration of mechanical ventilation,
duration of intensive care stay, and incidence
of ulceration: patients without coagulopathy
and mechanical ventilation had an incidence
of bleeding of 0.1% in the earlier Cooke study
(2). Again, duration of care and mechanical
ventilation represent markers of severity of
illness rather than direct causes of ulceration.
Stress Ulceration Treatment
Ranitidine and sucralfate are the most effective
agents. Ranitidine is associated with a lower
incidence of clinically significant bleeding,
sucralfate with a lower incidence of
The prevention of stress ulceration has focused on
reducing the quantity of luminal acid, using H2
receptor antagonists or antacids. The overall
objective of such therapy is to increase the pH of
the stomach above 3.5. Multiple studies have
compared H2 antagonists to sucralfate, a
cytoprotectant agent, given as a gel which turns
into a foam and coats the stomach on contact with
acid. A large randomized controlled trial by Cooke
and colleagues (4), remains the best source of
data available. In this study, which compared the
H2 antagonist ranitidine to sucralfate, the
incidence of clinically important GI bleeding was
1.7% in the ranitidine group, compared with 3.8%
in the sucralfate group (p=0.02). In absolute terms
this represented 10 bleeds in 596 patients
receiving ranitidine, and 23 bleeds in 604 patients
receiving sucralfate; a very low overall incidence
of bleeding. Interesting, a series of meta-analyses
by Messori (9)failed to demonstrate a difference
between both ranitidine and sucralfate as
compared with placebo. There is little data
available with regard to other anti-acid therapy,
such as proton pump inhibitors, in the intensive
Stress Ulceration Treatment Strategy
Patients who do not have one of the six major
risk factors do not require treatment.
Patients in shock, sepsis, respiratory, hepatic or
renal failure, or who have a coagulopathy, who
are admitted to intensive care, should all be
given stress ulcer prophylaxis. The agent of
choice currently is probably ranitidine, based on
best current evidence (although sucralfate
remains a useful alternative). Patients involved in
trauma probably also require prophylaxis, due to
their propensity to develop the above problems.
There is no evidence that prophylaxis of other
patients, particularly chronic (non pulmonary)
medical and perioperative surgical patients
warrant the expense of prophylaxis.
Stress Ulceration Treatment Complications
Nosocomial pneumonia is the main
complication of ulcer prophylaxis treatment.
Nosocomial pneumonia is common in critically ill
patients, and remains the leading cause of death.
It has been established that the use of anti-acid
therapy promotes gastric colonization with
pathogenic bacteria, and that aspiration of these
bacteria may cause nosocomial pneumonia (10).
The use, therefore, of ranitidine or proton pump
inhibitors would be expected to be associated
with a higher incidence of GI bleeds, and
sucralfate would not. In the Cooke paper (4) there
was a 19.1% incidence of nosocomial pneumonia
in the ranitidine group compared with 16.2% in
the sucralfate group – this was not statistically
significant. In the Messori meta analysis (9),
ranitidine significantly increased the rate of
nosocomial pneumonia over sucralfate.
Conversely, neither agent increased the
nosocomial infection rate in meta analyses
The other side effects of these agents should not
be forgotten: ranitidine can cause all kinds of
mental status changes, particularly in elderly
patients, and has been reported to cause
arthralgia and other musculoskeletal pain.
There is some evidence that giving H2
antagonists as a continuous infusion has greater
efficacy (in terms of keeping gastric pH >3.5) than
as intermittent boluses (11). Interestingly, in the
Cooke study (4), randitidine was given as a bolus
- 50mg every eight hours and gastric pH was not
measured (as this would have unblinded the
There have been no quality cost effectiveness
analyses on stress ulcer prophylaxis to date.
Stress Ulceration Key Points &
1. Stress ulceration is a gastrointestinal
mucosal injury related to critical illness.
2. There is a relationship between GI
bleeding and severity of disease.
3. Likewise there is a strong relationship
between bleeding and mortality.
4. Ulceration is caused by ischemic injury to
the gastric mucosa, loss of
cytoprotectants and assault by gastric
5. The major risk factors are respiratory
failure, coagulopathy, sepsis, hypotension
and hepatic and renal failure.
6. The incidence of stress ulceration is
diminishing, probably reflecting better care
before and during intensive care
7. Ranitidine and sucralfate are the most
effective agents. Ranitidine is associated
with a lower incidence of clinically
significant bleeding, sucralfate with a
lower incidence of pneumonia.
8. Nosocomial pneumonia is the main
complication of ulcer prophylaxis
9. Patients who do not have one of the six
major risk factors do not require treatment.
(1) Pruitt BA, Jr., Foley FD, Moncrief JA.
Curling's ulcer: a clinical-pathology study of
323 cases. Ann Surg 1970; 172(4):523-539.
(2) Cook DJ, Fuller HD, Guyatt GH, Marshall
JC, Leasa D, Hall R et al. Risk factors for
gastrointestinal bleeding in critically ill
patients. Canadian Critical Care Trials
Group. N Engl J Med 1994; 330(6):377-381.
(3) Skillman JJ, Bushnell LS, Goldman H,
Silen W. Respiratory failure, hypotension,
sepsis, and jaundice. A clinical syndrome
associated with lethal hemorrhage from
acute stress ulceration of the stomach. Am
J Surg 1969; 117(4):523-530.
(4) Cook D, Guyatt G, Marshall J, Leasa D,
Fuller H, Hall R 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
(5) Schuster DP, Rowley H, Feinstein S,
McGue MK, Zuckerman GR. Prospective
evaluation of the risk of upper
gastrointestinal bleeding after admission to
a medical intensive care unit. Am J Med
(6) Shuman RB, Schuster DP, Zuckerman
GR. Prophylactic therapy for stress ulcer
bleeding: a reappraisal. Ann Intern Med
(7) Rosen HR, Vlahakes GJ, Rattner DW.
Fulminant peptic ulcer disease in cardiac
surgical patients: pathogenesis, prevention,
and management. Crit Care Med 1992;
(8) Wijdicks EF, Fulgham JR, Batts KP.
Gastrointestinal bleeding in stroke. Stroke
(9) Messori A, Trippoli S, Vaiani M, Gorini M,
Corrado A. Bleeding and pneumonia in
intensive care patients given ranitidine and
sucralfate for prevention of stress ulcer:
meta-analysis of randomised controlled
trials. BMJ 2000; 321(7269):1103-1106.
(10) Cook DJ, Walter SD, Cook RJ, Griffith LE,
Guyatt GH, Leasa D et al. Incidence of and
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pneumonia in critically ill patients. Ann
Intern Med 1998; 129(6):433-440.
(11) Heiselman DE, Hulisz DT, Fricker R,
Bredle DL, Black LD. Randomized
comparison of gastric pH control with
intermittent and continuous intravenous
infusion of famotidine in ICU patients. Am J
Gastroenterol 1995; 90(2):277-279.