BACKGROUND

Stress-related mucosal disease (SRMD) is an acute, erosive

gastritis representing conditions ranging from stress-related injury
to stress ulcer.

Stress-related injury is superficial mucosa damage that present

primarily as erosion.

Stress ulcer are deep, focal mucosa damage penetrating the

submucosa with high risk for gastrointestinal bleeding.

Clinical important :
• Hemodynamic instability.
• Need for red blood cell transfusion.
• Increase the length of stay in the ICU.
• Increase mortality.
 EPIDEMIOLOGY
Mucosa damage to occur during within the first 24 hours after ICU
admission, approximately 75-100 %.

56-75% of general medicine patients begin acid suppression

therapy in hospital.

80% patients transferred the ICU continued to receive acid

suppression therapy.

Gastroduodenal bleeding associated with clinically impotent

complication (hemodynamic compromise, need for blood
transfusion, need for surgery), occurs in approximately 2-6%.
 EPIDEMIOLOGY

Schuster et al, found that 6 % of patient in ICU had overt bleeding

(episode of coffee-ground emesis requiring lavage, hematemesis
or melena with or without a change in hemoglobin levels or
hematocrit)

Mortality patient with evidence ulcer, bleeding or both within 18

hours of admission to a medical ICU was 57% compared with 24%
with normal mucosa, nonhemorrhagic erosion or petechial.

About 50- 70% of critically ill patient with gastrointestinal bleeding

will die
Acid-related
GI disease
 Primary regions of gastric
acid-related disease

Acid reflux
Oesophagitis
Strictures
Barrett’s
oesophagus
Oesophageal Gastritis
adenocarcinoma
Peptic ulcer
disease
(Includes NSAID-
induced ulcers)
Functional
dyspepsia
Duodenitis
Duodenal ulcer
UNDER NORMAL CONDITION
Integrity of the gastric mucosa is maintained by
several factor, including;
• Microcirculation.
• Mucus layer.
• Nourishes the mucosa.
• Eliminates hydrogen ion, oxygen radical and other
potentially toxic substance in gut lumen.
 COMPONENTS INVOLVED IN PROVIDING
GASTRODUODENAL MUCOSAL DEFENSE

Preepithelial
H+ Pepsin Lumen
• Mucus pH 1-2
• Bicarbonate
• Surface active Mucus gel
phospholipids HCO3- pH 7 HCO3-
Epithelium
Epithelial
• Cellular resistance Prostaglandin
• Restitution
• Growth factors, Microcirculation
protaglandins
•Cell proliferation

Subepithelial
• Blood flow
•Leukocyte
 Pathogenesis of NSAID-induced ulcers

PROTECTIVE
FACTORS AGGRESSIVE FACTORS
Prostaglandins

Acid + pepsin H. pylori

Mucus layer

Bicarbonate

Surface
epithelial
cells

Mucosal blood
supply

Seager & Hawkey, BMJ 2001; 323: 1236–9.

 Pathogenesis of NSAID-induced ulcers

PROTECTIVE
FACTORS AGGRESSIVE FACTORS
Prostaglandins

NSAIDs Acid + pepsin H. pylori

Mucus
layer
Bicarbonate

Surface epithelial
cells

Mucosal blood
supply

Seager & Hawkey, BMJ 2001; 323: 1236–9.

 Pathogenesis of NSAID-induced ulcers

PROTECTIVE
FACTORS AGGRESSIVE FACTORS
Prostaglandins

NSAIDs Acid + pepsin H. pylori

Mucus layer

Bicarbonate

Surface epithelial
cells

Mucosal blood
supply

Seager & Hawkey, BMJ 2001; 323: 1236–9.

 Pathogenesis of NSAID-induced ulcers

PROTECTIVE
FACTORS AGGRESSIVE FACTORS
Prostaglandins

NSAIDs Acid + pepsin H. pylori

Mucus layer

Bicarbonate

Surface epithelial
cells

Mucosal blood
supply

Seager & Hawkey, BMJ 2001; 323: 1236–9.

 Pathogenesis of NSAID-induced ulcers

PROTECTIVE
FACTORS AGGRESSIVE FACTORS
Prostaglandins

NSAIDs Acid + pepsin H. pylori

Mucus layer

Bicarbonate

Surface epithelial
cells

Mucosal blood
supply

Seager & Hawkey, BMJ 2001; 323: 1236–9.

 Pathogenesis of NSAID-induced ulcers

PROTECTIVE
FACTORS AGGRESSIVE FACTORS
Prostaglandins

NSAIDs Acid + pepsin H. pylori

Mucus layer

Bicarbonate

Surface epithelial
cells

Mucosal blood
supply

Seager & Hawkey, BMJ 2001; 323: 1236–9.

 Pathogenesis of NSAID-induced ulcers

PROTECTIVE
FACTORS AGGRESSIVE FACTORS
Prostaglandins

NSAIDs Acid + pepsin H. pylori

Mucus
layer
Bicarbonate

Surface epithelial
cells

Mucosal blood
supply

Seager & Hawkey, BMJ 2001; 323: 1236–9.

 Pathogenesis of NSAID-induced ulcers

PROTECTIVE
FACTORS AGGRESSIVE FACTORS
Prostaglandins

NSAIDs Acid + pepsin H. pylori

Mucus layer

Bicarbonate

Surface
epithelial
cells

Mucosal
blood
supply

Seager & Hawkey, BMJ 2001; 323: 1236–9.

Type of Mucosal Lesion Stress
Ulcer

1. Stress-related injury:
• Diffuse, superficial mucosa damage.

2.Discrete stress ulcer:

• Deep focal lesion that penetrate the submucosa, most often in
body and fundal parts of the stomach.

 Preceded by mucosal congestion often lead to bleeding in

focal areas and then eventually affect multiple areas of upper
gastrointestinal.
 ETIOLOGY
Multifactor.

Ischemia and reperfusion are thought to cause the mucosal

defenses to break down, resulting in mucosal injury and
ulceration.

Major factor :
• Reduced blood flow.
• Mucosal ischemia.
• Hypoperfusion.
• Reperfusion injury.
• H pylori.
 Gastric mucous layer in normal gaster and
gastritis
INFECTION CHRONIC GASTRITIS
Damaging influences : Atrophy
Helicobacter pylori Intestinal metaplasia
urease Lymphoid aggregates
toxins Neutrophil infiltrates
Gastric acidity
Peptic enzymes
H.pylori Intestinal metaplasia

Mucus
Neutrophils
Mucosa

Muscularis
mucosa

Submucosa
PATOFISIOLOGI DAN PATOGENESIS

KERUSAKAN PD PRINSIPNYA O.K. GGUAN

KESEIMBANGAN ANTARA FAKTOR DEFENSIF DAN
FAKTOR AGRESIF,UMUMNYA SBG AKIBAT
MELEMAHNYA FAKTOR DEFENSIF
TEORI LAMA’ NO ACID NO ULCER, DR SCWARTZ
(1910) TDK BENAR.
FISIOLOGI: MUKOSA LAMBUNG RESISTEN TERHADAP
PROSES OTODIGESTI DAN PUNYA MEKANISME
PERLINDUNGAN THDP PENGA RUH DR LUAR. APA
BILA FAKTOR KESEIMBANGAN TERGANGGU MAKA
DAYA TAHAN MUKOSA MENURUN TERJADILAH
GASTRITIS ATAU TUKAK PEPTIK
 FAKTOR DEFENSIF

1 RINTANGAN MUKUS ( MUCUS BARRIER)

2 BIKARBONAT: DIHASIL-SEL EPIT- LAMB-& DUOD-

3 PROSTAGLANDIN: DIHASILKAN SEL EPITEL LAMB-

4 ALIRAN DARAH MUKOSA

5 REGENERASI SEL: EPIT- MUKOSA GANTI 2-6 HARI

6 FAKTOR PERTUMBUHAN (GROWTH FAKT-)

 FAKTOR AGRESIF

1. FAKTOR KERUSAKAN MUKUS

2. PRODUKSI BIK-NAT YG MENURUN

3. ALIRAN DARAH MUKOSA YG TERGGGU

 FAKTOR AGRESIF

4. FAKTOR DARI LUAR( ASPIRIN,NSAID,

ROKOK,MINUMAN,STRESS DLL )

5 FAKTOR GENETIK.RIWAYAT KELUARGA

MEMPUNYAI RESIKO 3 X UTK TUKAK PEPTIK
DUODENUM LEBIH BESAR

6 HELIKOBAKTER PYLORI,DITEMUKAN
WARREN & MARSHAL 1983 DI AUSTRALIA
 PATHOPHYSIOLOGY

Underlying cause stress-related mucosal disease is gastric

hypoperfution:
• 1. Release of nitric oxide.
• 2. Overproduction of oxygen radical.
• 3. Reduction of prostaglandin synthesis
• 4. Infection H pylori.

• When the mucosal compromised and can no longer block the

detrimental effects hydrogen ion and oxygen radical  stress-
related mucosal disease
1. Release of Nitric Oxide :

Normal levels:
• Nitric oxide synthesis enhances gastric mucosal integrity
by maintaining blood flow and perfusion in gastric
mucosa.

Elevated nitric oxide cause :

• Reperfusion hyperemia and cell death.
• Enhanced inflammatory response.
• Gastric and small-bowel dysmotility.
2. Overproduction of Oxygen Radical :

Increased production of oxygen radicals and

reduced ability to clear them also cause:
• Inflammation.
• Cell death.
• Release of damaging cytokine.
• Mucosa repair mechanism are impaired.
Hydrogen ions
Oxygen radicals
3. Reduction of Prostaglandin Synthesis.

Prostaglandin synthesis is decreased by gastric hypoperfusion

or bicarbonate and mucus secretion.
• Diffusion of hydrogen ions and pepsin that damage the mucosa epithel
layer.

Normally :
• Buffering effect of bicarbonate and mucus layer keep pH neutral even
thought the pH in gastric lumen is often between 1,5 -2.0.
• Upper gasrointestinal motility is slowed, a situation that reduces
stomach emptying  to prolonged exposure of the poorly defended
mucosa to gastric acid, thus increased the risk of ulceration.
 4. Infection Helicobacter pylori

Several prospective studies have investigated the role of H

pylori associated with increased gastrointestinal bleeding.

H pylori was risk major mucosa damage.

H pylori maybe present in more than 50% of ICU patients that is

an independent risk factor for clinically impotent bleeding.

It produces cyto-toxins, causing

mucosal inflammation.

It stimulates acid secretion

through:
Stimulates of gastrin
secretion
Inhibition of somatostatin
secretion
 CLINICAL FEATURES FOR
GASTROINTESTINAL BLEEDING

Spontaneous decrease in systolic blood pressure of 20 mmHg

or more.

Increase in heart rate more than 20 beats per minute.

Decrease systolic blood pressure than 10 mmHg on sitting up.

Decrease in hemoglobin level more than 2 g/dL and subsequent

transfusion of blood after which hemoglobin levels do not
increase.
Patient with nasogastric tube :
• Bloody gastric aspirate or the appearance of material that
looks like coffee ground in the gastric aspirate.

Patient without nasogastric tube:

• Hematemesis or melena.
Risk factor for clinically important
bleeding:

Respiratory failure requiring mechanical ventilation for

longer 48 hours.
Coagulopathy.
Older age.
Repair of abdominal aortic aneurysm.
Severe burn.
Spinal cord injuries.
Multiple trauma.
Neurological trauma.
Multiple organ failure.
Risk factor for clinically important
bleeding:

Hepatic failure : total bilirubin >5 mg/dL, AST>150 IU/L

or ALT > 150 IU/L.
Partial hepatotectomy.
Hepatic or renal transplantation.
Head injury with Glasgow coma scale of < 10.
Sepsis or septic shock.
Intensive care unit stay > 1 week.
Occult or overt bleeding >6 days.
High-dose corticosteroid therapy ( intravenous or oral ≥
40 mg/d).
Medical Management and
Therapeutic Intervention
 Medical Management and
Therapeutic Intervention

1.Non pharmacological Prophylaxis.

2.Pharmacological Prophylaxis.
 1. Non pharmacological
Prophylaxis
Maintain hemodynamic optimation.

Assessment :
• Clinical :
– Blood pressure.
– Skin color and appearance.
– Skin warmth.
– Mental status.
• Laboratory:
– Hemoglobin.
– Hematocrit level.
– White blood cell counts.
– Electrolyte level.
 Non pharmacological Prophylaxis….

Local irritant (NSAD or aspirin).

Vasopressors can worsen ischemia of the gastrointestinal.

Early enteral nutrition should be considered in certain patients.

• Raff et al found that enteral feeding initiated within 12 hours of
trauma were as effective as histamine 2 receptor antagonist and or
antacids for reducing hemorrhage in the upper gastrointestinal.
• Cook et al found that the risk gastric bleeding was reduced in
patient receiving enteral feeding.
2. Pharmacological Prophylaxis

Guideline for stress ulcer prophylaxis of American Society of

Health System Pharmacists Commision on Therapeutic.

Recommended for adults admitted to ICU who:

• Have coagulopathy ( AT < 50.000, INR>1,5, aPTT> 2) .
• Require mechanical ventilation for more than 48 hours.
• Have a history of gastrointestinal ulceration or bleeding within 1
years before admission.
• Have at least 2 of the following risk factor :
– Sepsis.
– ICU stay longer than 1 week.
– Occult bleeding lasting 6 days or longer.
– Use of more than 250 mg hydrocortisone or equivalent.
Pharmacological Prophylaxis
Medications used for :
• Inhibiting gastric acid secretion.
• Neutralizing gastric acid.
• Protective the gastric mucosa.

Drug prevent mucosa damage :

• Histamine 2 Receptor Antagonist (H2RAs).
• Sucralfate.
• Proton Pump Inhibitors.
• Antacid.
1.Histamine 2 Receptor Agonist
(H2RAs)
Decreasing gastric acid secretion through competitive
inhibition of histamine stimulated acid secretion.
Reducing basal acid production.
To be less effective than PPIs in preventing bleeding of stress
ulcer.
Effectiveness for preventing stress ulcer 15-40 %.
Often require 3 or 4 dose a day.
Dose adjusted in patients with renal dysfunction.
Cimetidine decrease clearance of warfarin, theophylline,
phenytoin, lidocain & clarithromycin.
Ranitidine interactions, through less frequent.
 2. Sucralfate
Less widely used than H2RAs for stress ulcer prophylaxis.
Protective layer between the mucosa and gastric acid in
lumen.
Effectiveness for preventing stress ulcer 10-25 %.
Can be administered through a nasogastric tube with dosing
every 6 hours.
Decrease the absorption of ciprofloxacin, norfloxacin,
theophylline, tetraxycline, phynytoin, cimetidine, ratitidine, L-
thyroxine, ketoconazole & digoxin.
Avoid in patients with renal function due to potential
aluminium accumulation and toxicity with repeated doses and
prolong use.
3.Proton Pump Inhibitors (PPIs)

Effective preventing stress ulcer.

Inhibit the final step in acid production.
Long-lasting suppression of acid secretion.
Clinical trial ranitidine 150 mg iv (n=35) daily or omeprazole 40
mg (n= 32)daily  31% vs 6% had bleeding.
Open-label studies (n=60, n=70) no high-risk patient
experienced bleeding.
Not renally eliminated, so use in patient with renal dysfunction
are minimal.
Can be given via nasogastric tube.
Target pH value for preventing stress ulcer (≥4)
 Evidence base omeprazole

Phillips et al, open label trial evaluating of omeprazole

suspension for prophylaxis stress ulcer.
• Omeprazole suspension was as 40 mg, followed by a second 40
mg dose 6-8 hours later, then 20 mg daily 
• no clinically significant upper gastrointestinal bleeding.

Omeprazole suspension with severe trauma + mechanical

ventilation
• no clinically significant upper gastrointestinal bleeding.
 Evidence base omeprazole….

Randomized omeprazole (40 mg daily orally or NGT) vs

ranitidine ( 50 mg bolus followed by 150 mg daily by
continuous infusion or intermittent) in ICU have risk factor
stress ulcer 
• Bleeding occurred 6% vs 31% (p=0,013)
• Nosoccomial pneumonia developed 3% vs 14%.

Lasky et al, 1998 prospective study of 60 trauma patient +

mechanical ventilation
• Omeprazole suspension prevented significant gastrointestinal
bleeding, maintained excellent control of gastric pH, produced
no toxicity.
 Adverse drug reaction

< 1% when given on short term basic ( as < 2

week).
Delirium and thrombocytopenia when
receiving an H2RA.
Increase adverse drug reaction when renal
impared, elderly and malnourished.
PPI and H2RA have been associated with an
increase in risk of developing community and
hospital acquired pneumonia.
4. Other Prophylaxis Option

Antacid.
• Administered to patient every 1-2 hour.
• To maintain pH levels.
• Adverse effect :
– Diarrhea, flatulence, headache, nausea, hepatic dysfunction,
electrolyte abnormality, constipation.
• Rarely used to prevent stress ulcer.
• High dose of antacid are associated with aspiration pneumonia
and toxicity due to electrolyte accumulation.
Prostaglandin analog such asa, misoprostol are ineffective
for prophylaxis.
 CONCLUSION

Increased knowledge of risk factor and improved ICU care

have decreased the incidence of stress–related bleeding.
All critically ill patient with associated risk factor stress ulcer
and mortality.
Omeprazole appears to be effective for stress ulcer
prophylaxis.
Prolonged mechanical ventilation and coagulopathy are 2
factor associated with the risk of stress ulcer.
 Level 1
(Prospective randomized clinical trial)
Prophylaxis is recommended for all patients with:
• Mechanical ventilation.
• Coagulopathy.
• Trauma brain injury.
• Major burn injury.

Agent for stress ulcer

• There is no difference between H2 antagonist, cytoprotective and
proton pum inhibitor.
• Antacid should not be used as stress uler prophylaxis

Duration for prophylaxis

• There were no level 1 recommendation.
 Level 2
(Prospective non-comparative clinical study or
retrospective analysis)

Prophylaxis is recommended for all Intensive care Unit (ICU)

patients with:
• Multi trauma.
• Sepsis.
• Acute renal failure.

Agent for stress ulcer

• Aluminum containing compounds should not be used inpatient
on dialysis

There were no level 1 recommendation.

• During mechanical ventilation or intensive care unit stay
 Level 3
(Retrospective case series or data base review)

Prophylaxis is recommended for all ICU patients with :

• Injury Severity Score (ISS) >15.
• Requirement of high-dose steroid (>250 mg hydrocortison or
equvalent per day)

Agent for stress ulcer

• Enteral feeding alone may be insufficient stress ulcer
prophylaxis

During mechanical ventilation or intensive care unit stay

• Until able to tolerate enteral nutrition

Guillamondequi, et al, 2008.(EAST)