2. STRESS-RELATED MUCOSAL INJURY
Stress-related mucosal injury is a term used to
describe erosions in the gastric mucosa that
occur in almost all patients with acute, life-
threatening illness .
3. Stress ulcers are diffuse in nature and
are not amenable to endoscopic
therapy; they generally heal over time,
without intervention, as the patient’s
clinical status improves.
4. These erosions can be superficial and confined
to the mucosa, or they can bore deeper and
extend into the submucosa.
The deeper lesions are called stress ulcers,
and are more likely to cause troublesome
bleeding.
The term “stress ulcer” will indicate both
types of gastric erosions.
5. Stress Ulcers Peptic Ulcers
Multiple
superficial
lesions at the
proximal
stomach bulb;
involves
superficial
capillaries
Few deep
lesions in the
duodenum;
typically
involves a
single vessel
6. Pathogenesis
The gastric mucosa must protect itself against injury
from the acid environment in the stomach, and
gastric mucosal blood flow is considered to play
an important part in this protection (by supplying
nutrients to maintain the functional integrity of
the mucosa).
The importance of mucosal blood flow is
demonstrated by the fact that 70 to 90% of the
blood supply to the stomach is delivered to the
gastric mucosa .
7. Splanchnic vasoconstriction and hypoperfusion
is common in critically ill patients, and the
resultant decrease in gastric mucosal blood
flow is considered the principal cause of
gastric erosions .
Once the gastric mucosa is disrupted, the
acidity in the gastric lumen can aggravate
the surface lesions.
8. Clinical Consequences
Erosions are visible on luminal surface of the
stomach in 75% to 100% of patients within
24 hours of admission to the ICU .
These lesions often ooze blood from eroding into
superficial capillaries, but clinically significant
bleeding (i.e., results in a significant drop in
blood pressure or a drop in hemoglobin >2 g/dL) is
observed in less than 5% of ICU patients .
9.
10.
11. Risk Factors
The independent risk factors (i.e., require no
other risk factors to promote bleeding)
include mechanical ventilation for longer than
48 hours, and a significant coagulopathy
(i.e., platelets <50,000, INR>1.5, or activated
PTT>twice control) .
However, all of the conditions are indications
for prophylaxis to prevent stress ulcer
bleeding.
12. Preventive Measures
The goal of prophylaxis for stress ulcers is not
to prevent their appearance (since they
appear almost immediately after ICU
admission), but to prevent clinically
significant bleeding from these lesions.
13. Surveys indicate that about 90% of ICU
patients receive some form of prophylaxis for
stress ulcer bleeding , but this is excessive.
Prophylaxis is primarily indicated for the
conditions listed in Table , and is especially
important for patients who are ventilator-
dependent for longer than 48 hours, or have
a significant coagulopathy.
14. Methods of Prophylaxis
The principal method of prophylaxis for stress ulcer
bleeding is to block the production of gastric
acid using histamine type-2 receptor antagonists
or proton pump inhibitors, and maintain a pH≥4
in gastric aspirates.
The other method of prophylaxis involves the use of a
cytoprotective agent (sucralfate) that protects
damaged areas of the gastric mucosa without
altering gastric acidity .
15. Antacids
a. Dose-dependent neutralization of gastric
acid .
b. Not recommended for routine use because
of frequency of administration
(up to every hour).
Adverse effects (diarrhea, constipation,
electrolyte abnormalities), and interactions
(interferes with the absorption of some
drugs)
16.
17. Histamine H2- Receptor Antagonists
Inhibition of gastric acid secretion with histamine
H2-receptor antagonists (H2 blockers) is the
most popular method of stress ulcer
prophylaxis.
The drugs most frequently used for this purpose
are ranitidine and famotidine; both drugs
are typically given as an intravenous bolus .
Ranitidine is the most studied gastric
acid–suppressing drug for stress ulcer
prophylaxis..
18. A single 50 mg dose of ranitidine given as an IV
bolus will reduce gastric acidity (pH>4) for 6–8
hrs, so the typical ranitidine dosing regimen is
.
Famotidine has a longer duration of action;
i.e., a single 20 mg dose of famotidine given as an
IV bolus will reduce gastric acidity (pH>4) for
10–15 hours , so the typical famotidine dose
50 mg IV every 8
hours
20 mg IV every 12
hours
19. DOSE ADJUSTMENTS:
Intravenous doses of famotidine and
ranitidine are largely excreted unchanged in
the urine, and accumulation of these drugs in
renal failure can produce a neurotoxic
condition characterized by confusion,
agitation and even seizures.
Reduced dosing is therefore advised in patients
with renal insufficiency.
20.
21. BENEFITS AND RISKS:
H2 blockers are effective in reducing the
incidence of clinically important bleeding from
stress ulcers, but the benefit occurs primarily in
patients with one or more of the risk factors.
Prolonged use of H2 blockers is accompanied by a
decrease in their ability to maintain a pH ≥4 in
gastric aspirates, but this does not influence
their ability to prevent stress ulcer-related
bleeding .
22. The principal risks associated with H2 blockers
are related to reduced gastric acidity , these
risks include an increased in-cidence of
infectious
These risks, however, may be greater with PPI .
gastroenteriti
s
pneumonia
Clostridium difficile
enterocolitis
from aspiration of
infectious gastric
secretions into the
airways
23. Proton Pump Inhibitors (PPIs)
Proton pump inhibitors (PPIs) are potent acid-
suppressing drugs that reduce gastric acidity
by binding to the membrane pump responsible
for hydrogen ion secretion by gastric parietal
cells .
24. These drugs are actually prodrugs, and must
be converted to the active form within
gastric parietal cells.
Once activated, these drugs bind irreversibly
to the membrane pump and produce complete
inhibition of gastric acid secretion.
25. PHARMACOLOGICAL
ADVANTAGES
PPIs have several advantages over H2 blockers.
First, they produce a greater reduction in
gastric acidity and have a longer duration
of action, often requiring only a single daily
dose.
26. Secondly, the responsiveness to PPIs
does not diminish with continued
usage .
Finally, PPIs are metabolized in the liver,
and do not require a dose adjustment in
renal failure.
As a result of these advantages, PPIs are
gradually replacing H2 blockers for stress
ulcer prophylaxis in hospitalized patients .
27.
28. COMPARATIVE BENEFITS AND RISKS:
Despite their enhanced potency, PPIs have not
shown any advantage over H2 blockers for
prophylaxis of stress ulcer bleeding .
Furthermore, the enhanced gastric acid
suppression with PPIs may create a greater
risk of infection than with H2 blockers.
PPIs may also have immunosuppressive
effects through the inhibition of
neutrophils.
29. This is supported by studies showing a higher
incidence of hospital-acquired pneumonia
with PPIs compared to H2 blockers , and a
higher incidence of Clostridium difficile
enterocolitis in outpatients treated with PPIs
instead of H2 blockers .
The overall risk-benefit accounting for PPIs is
in favor of avoiding these drugs for the
prophylaxis of stress ulcer bleeding.
30. PPIS AND CLOPIDOGREL
The popular antiplatelet agent, clopidogrel, is
a prodrug that is converted to its active form by
the same (cytochrome P-450 2C19) pathway
in the liver that metabolizes PPIs.
Therefore, PPIs can impede clopidogrel
activation in the liver(by competitive
inhibition) and reduce its antiplatelet activity .
31. This effect is evident with in vitro tests of
platelet aggregation, but the clinical
significance of this interaction is unclear.
Nevertheless,the Food and Drug
Administration advises avoiding PPIs, if
possible, in patients taking clopidogrel.
32.
33. Sucralfate
Sucralfate is an aluminum salt of sucrose
sulfate that adheres primarily to damaged
areas of the gastric mucosa (via electrostatic
bonds with exposed proteins) and forms a
viscous covering that shields the denuded
surface from luminal acids and pepsin
proteolysis.
34. It is classified as a protectant or
cytoprotective agent , and has no effect on
gastric acid secretion.
Sucralfate promotes the healing of gastric and
duodenal ulcers, and reduces the incidence of
clinically important bleeding from stress ulcers .
35. Sucralfate is available as atablet (1 gram per
tablet) or a suspension (1g/10 mL), and is
most effective when given as a suspension
(tablets can be crushed and dissolved in
water, if necessary).
A single dose of sucralfate (1 g) will remain
adherent to the damaged mucosa for about 6
hours, so dosing at 6-hour intervals is
advised.
36. DRUG INTERACTIONS
Sucralfate binds the following drugs in the lumen of
the bowel: ciprofloxacin, digoxin,
ketoconazole , norfloxacin, phenytoin,
ranitidine , thyroxin , tetracycline ,
theophylline , and warfarin.
(The interactions with ciprofloxacin and norfloxacin
are considered the most significant) When these
drugs are given orally or via feeding tube,
sucralfate dosing should be separated by at least 2
hours to avoid any drug interactions.
37. ALUMINUM CONTENT:
The sucralfate molecule contains 8 aluminum
hydroxide moieties that are released when
sucralfate reacts with gastric acid.
The aluminum can bind phosphate in the
bowel, but hypophosphatemia is rare .
Nevertheless, sucralfate is not advised for
patients with persistent or severe
hypophosphatemia .
Sucralfate does not elevate plasma aluminum
levels, even with prolonged use .
38. Sulcrafate vs. Gastric Acid
Suppression
Sucralfate is appealing because it does not alter
gastric acidity, and should not create the increased
risk of infection that accompanies acid-suppressing
drugs.
Several clinical trials have compared sucralfate with
an acid-suppressing drug (ranitidine) for stress
ulcer prophylaxis, shows the combined results from
10 clinical trials involvin.
39. Clinically significant bleeding (defined earlier)
occurred less frequently with ranitidine,
while pneumonia occurred less frequently with
sucralfate.
When the incidence of bleeding and pneumonia
are combined (as shown in the center box),
there are fewer adverse events with sucralfate.
Although not shown, the mortality rate was the
same with both drugs.
40. There are two possible interpretations of the
results, based on the desired outcome.
If the desired result is fewer episodes of bleeding,
then ranitidine is superior to sucralfate.
However if the desired result is fewer adverse
events ( pneumonia), then sucralfate is
superior to ranitidine.
It seems that the goal of any preventive strategy
is fewer adverse events, in which case the
results would favor sucralfate over ranitidine
(i.e., gastric acid suppression) for prophylaxis
of stress ulcer bleeding.
41.
42. Gastric Acid Suppression and C.
difficile
One of the most compelling reasons for avoiding
gastric acid–suppressing drugs is the increased
risk of Clostridium difficile enterocolitis
associated with these drugs.
This has been reported in both outpatients and
inpatients , and is a greater risk with proton
pump inhibitors than with H2 blockers .
43. In fact, the increase in C. difficile enterocolitis
that has been observed in recent years
coincides with the increased use of proton
pump inhibitors in both outpatients and
inpatients.
It is very possible that the increasing incidence of
C. difficile enterocolitis in hospitalized patients
is not the result of increased antibiotic usage
(since antibiotics have always been overused),
but instead is a consequence of the escalating
use of gastric acid suppression for stress ulcer
prophylaxis .
44. Enteral Feeding
Enteral tube feedings exert a trophic effect on
the GI mucosa that helps to maintain the
structural and functional integrity of the
mucosal surface
Enteral feeding solutions also raise the pH in the
lumen of the stomach.
Both of these effects should protect against
stress ulcer bleeding.
45. The benefit of enteral tube feedings is revealed
in the combined results of three clinical
studies, which showed that the ability of H2
blockers to reduce stress ulcer bleeding was
lost when patients received a full regimen of
enteral tube feedings .
These results suggest that patients who receive
enteral tube feedings do not require any
further prophylactic measures for stress
ulcer bleeding.
46. I. Guideline Recommendations
1. In 1999, the first guideline from the
American Society of Health-System
Pharmacists was published (Am J Health Syst
Pharm1999;56:347-79).
The guideline recommended that institutions
decide on H2RAs , antacids, or sucralfate
according to safety profile, costs, and ease of
administration.
47. 2. In 2008, the Eastern Association
for the Surgery of Trauma published
a guideline recommending
cytoprotective agents, H2RAs, or
PPIs.
Antacids were not recommended.
3.In 2012, the Surviving Sepsis
Campaign guidelines commented on
SUP, recommending H2RAs or PPIs,
with PPIs as the preferred agent (Crit
48. 4. In 2014, the Danish Society of
Intensive Care Medicine and the
Danish Society of Anaesthesiology
and Intensive Care Medicine
published guidelines suggesting PPIs
as the preferred agent (Dan Med J
2014;61:C4811).
49. References
Steinberg KP. Stress-related mucosal disease in the critically ill patient: Risk factors
and strategies to prevent stress-related bleeding in the intensive care unit. Crit Care
Med 2002; 30(Suppl):S362–S364.
Fennerty MB. Pathophysiology of the upper gastrointestinal tract in the critically ill
patient: rationale for the therapeutic benefits of acid suppression. Crit Care Med
2002; 30(Suppl):S351–S355.
O’Brien PE. Gastric acidity: the gastric microvasculature and mucosal disease. In
Marston A, Bulkley GB, Fiddian-Green RG, Hagland UH, eds. Splanchnic Ischemia and
Multiple Organ Failure. St. Louis: C.V. Mosby, 1989:145–158.
Cook DJ, Fuller MB, Guyatt GH. Risk factors for gastrointestinal bleeding in critically
ill patients. N Engl J Med 1994; 330:377–381.
Daley RJ, Rebuck JA, Welage LS, et al. Prevention of stress ulceration: current trends in
critical care. Crit Care Med 2004; 32:2008–2013.
Ranitidine. AHFS Drug Information, 2011. Bethesda, MD: American Society of Health
System Pharmacists, 2011:2983–2990.
Famotidine. AHFS Drug Information, 2011. Bethesda, MD: American Society of
Health System Pharmacists, 2011:2977–2983.
50. Egred M. Clopidogrel and proton-pump inhibitor interaction. Br J Cardiol 2011.
Sucralfate. AHFS Drug Information, 2011. Bethesda, MD: American Society of Health
System Pharmacists, 2011:2996–2998.
Miller SJ, Simpson J. Medication–nutrient interactions: hypophosphatemia associated
with sucralfate in the intensive care unit. Nutr Clin Pract 1991; 6:199–201.
Tryba M, Kurz-Muller K, Donner B. Plasma aluminum concentrations in long-term
mechanically ventilated patients receiving stress ulcer prophylaxis with sucralfate.
Crit Care Med 1994; 22:1769–1773.
Lowe DO, Mamdani MM, Kopp A, et. al. Proton pump inhibitors and hospitalization
for Clostridium difficile-associated disease: a population-based study. Clin Infect Dis
Dial S, Alrasadi K, Manoukian C, et. al. Risk of Clostridium-difficile diarrhea among
hospitalized patients prescribed proton pump inhibitors: cohort and case-control
studies. Canad Med Assoc J 2004; 171:33–38.
Aseri M, Schroeder T, Kramer J, Kackula R. Gastric acid suppression by proton pump
inhibitors as a risk factor for Clostridium difficile-associated diarrhea in hospitalized
patients. Am J Gastroenterol 2008; 103:2308–2313.
Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new
millenium: a systematic review and meta-analysis. Crit Care Med 2010;. Maier RV, Mitchell D,
Gentiello L. Optimal therapy for stress gastritis. Ann Surg 1994;.
Rosenthal P, Thompson J, Singh M. Detection of occult blood in gastric juice. J Clin
• Gastroenterol 1984; 6:119.
