Upper GI Bleeding

Klaus Gottlieb, MD, FACP, FACG

A common medical condition

250,000 500,000 admissions/year US
UGI bleeding incidence 100/100,000 adults
Incidence increases 20-30 fold from third to
ninth decade of life

LGI bleeding incidence 20/100,000 adults

Overwhelmingly disease of the elderly

GI bleeding stops spontaneously in 80 %

Morbidity Data
Majority will receive blood transfusions
2 10 % require urgent surgery to arrest
bleeding
Average LOS 4 7 days
Mortality rates for UGI bleeding 2 15 %
Mortality for patients who develop bleeding
after admission to hospital for another
reason is 20 30 %

Costs
Average hospital costs exceed $ 5,000 per
admission
Most of this for hospital bed and ICU stays
rather than physician fees, blood products,
diagnostic tests, or medications
Reduction of hospital admissions and LOS
has greatest potential to reduce costs

UGI bleeding:Nomenclature
Hematemesis 25 %
Melena alone 25 %, 50 100 cc of blood
will render stool melenic
Hematochezia 15 %, seen in massive UGI
hemorrhage
Red blood hematemesis
Coffee ground emesis

Indications for Hospitalization

and Intensive Care
Traditional: Endoscopy on the day of
admission or on the day after
Recent studies: Complete endoscopic risk
stratification PRIOR to admission
Between 25- 30 % of patients with UGI
bleeding could be discharged from the
Emergency Department

Predictors of Outcome in UGI

bleeding
Clinical

Endoscopic

Age > 60 y

Low risk endoscopic

findings

Hemodynamic instability

High risk endoscopic

findings

Comorbidities
Hematemesis (red blood)
Coagulopathy

Ulcer Appearance and Prognosis

Appearance

Prevalence %

Rebleed % Mortality %

Clean base

42

Flat spot

20

10

Clot

17

22

Visible vessel

17

43

11

Active bleeding

18

55

11

Scoring System for Predicting Rebleeding and

Mortality
Variable
Age
<60
60-79
>79
Shock
None
Tachycardia
Hypotension
Comorbidity
None
CAD, CHF, other major comorbidity
Renal failure, liver failure, malignancy
Diagnosis
Mallory Weiss tear or no lesion observed
All ot
her diagnoses
Malignant lesion
Stigmas of recent hemorrhage
None or spot in ulcer base
Blood in the GI tract, clot, visible vessel
in ulcer base

Score
0
1
2
0
1
2
0
1
2
0
1
2
0
2

A simplified scoring
system based on
endoscopic and clinical
variables has been
developed
Rockhall TA et al.:
Selection of patients for
early discharge or
outpatient care after acute
upper gastrointestinal
haemorrhage. Lancet
1996:347: 1138-1140

Scoring is not Boring

Score

Rebleeding % Mortality %

1
2
3
4
5
6
7
8

3
5
12
13
17
30
40
48

0
0
2
4
8
15
20
39

LOS Guidelines for UGI

bleeding at UCSF
Clinical
Endoscopic Low
Low
Immediate discharge
Moderate
High

Moderate
23 h observation

High
ICU observation
(48 72 h hospitalization)
48 h observation
48-72 h observation ICU observation
(48-72 h hospitalization)
ICU observation
ICU observation
ICU observation
(72 h hospitalization) (72 h hospitalization) (72 h hospitalization)

Clinical Findings
Low
Age < 60 y
Initial SBP 100; vital
signs now normal
Transfusion requirements
<2U
No active major comorbid
disease
No liver disease
No moderate- or high risk
clinical feature
Endoscopic Findings
Clean ulcer < 2cm
Nonbleeding M-W tear
Esophagitis
Gastritis/duodenitis
No lesion identified and
no fresh blood seen

Moderate
Age 60 y
SBP 100 on admission
and mild ongoing
tachycardia
Transfusion requirement
2U
Stable major comorbid
disease
Liver disease no
coagulopathy
or encephalopathy
No high risk clinical
features

High
SBP < 100 and/or severe
ongoing tachycardia

Clean ulcer 2 cm
Ulcer with spot or clot
Bleeding M-W tear
successfully treated
Bleeding AVM
successfully treated

Bleeding ulcer
Visible vessel
Variceal bleeding

Portal gastropathy without

esophageal varices
Neoplasm

Transfusion requirement 5
U
Unstable major comorbid
disease
Decompensated liver disease

Any lesion with bleeding that

was not controlled at
endoscopy

Endoscopic Therapy in UGI

bleeding
Effectively reduces
Rebleeding
Need for Surgery
Mortality (by meta-analysis)
However, 10 20 percent of patients have
rebleeding after (initially successful)
endoscopic therapy

The Role of Adjunctive

Pharmacological Therapy
Clot stabilization: at a pH of above 6.0
pepsin is inactivated and cannot lyse clots
Effective clotting may not occur at a pH of
5.9 or lower
Antacids, iced saline gastric lavage and H2blockers and other interventions are
ineffective in reducing rebleeding rates

Proton Pump Inhibitors

NEJM 1997: high dose oral omeprazole effective in
reducing rebleeding rates. No endoscopic therapy
performed in this study from India
Two multicenter trials from Scandinavia showed benefit of
high dose I.V. omeprazole (1997)
Taiwanese study of 100 patients randomized between IV
omeprazole and cimetidine. Intragastric pH was around 6.0
for first 24 hours in omeprazole group but only between
4.5 to 5.5 for cimetidine group. 12 pts in the cimetidine
group and 2 pts in the omeprazole group rebled. No change
in LOS, number of procedures, or mortality (1998)

Effect of Intravenous Omeprazole on Recurrent Bleeding After

Endoscopic Treatment of Bleeding Peptic Ulcers
Lau JYW, Sung JJY, Lee KKC, et al.
N Eng J Med. 2000; 343: 310-316
Randomized, controlled, double-blind trial of 250 pts to evaluate
whether intravenous infusion of omeprazole (80 mg bolus, followed
by 8 mg/hr) is more effective than placebo in reducing rebleeding risk
over 30 days following endoscopic therapy
Well conceived, designed, executed and analyzed study
Patients included those with an actively bleeding ulcer or ulcers with a
non-bleeding visible vessel in whom endoscopic therapy was
successful in controlling bleeding
Endoscopic therapy consisted of a combination of epinephrine
injection plus thermocoagulation to the point of vessel obliteration

Results
Rebleeding: 6.7 % in omeprazole vs. 22.5 % in placebo
group (p < .001, Relative Risk 3.38, 95 % C.I. 1.60 7.13)
LOS: median 4 days omeprazole, 5 days placebo
(significant)
Transfusions: omeprazole mean 1.7, placebo 2.4
(significant)
Mortality: 5 omeprazole, 9 placebo (mortality rate 5.8 %)
(not significant)
Surgery: 3 omeprazole, 9 placebo (not significant)

PROTONIX (Pantoprazole Sodium)

Formulations

40-mg Delayed-Release Tablet

40-mg Lyophilized Powder for Injection

PROTONIX (Pantoprazole Sodium)

Specific Cysteine Binding Sites
Binds two cysteine residues critical for the
inhibition of gastric acid secretion
(Cys 813 and 822)

Modlin IM, Sachs G. Acid Related Diseases, Biology and Treatment. Schnetztor-Verlag. 1998:126-145.

PPI Pharmacology (Day 1 Data)

Parameter

Pantoprazole Lansoprazole Omeprazole Esomeprazole Rabeprazole

40 mg
30 mg
20 mg
40 mg
20 mg
5.55

N/A

N/A

N/A

N/A

2.4

1.7

0.5-3.5

1.5

2-5

11.1

N/A

N/A

4.32

N/A

~1

~1.5

~0.5-1

1.5

1-2

10-80 mg

15-60 mg

Nonlinear

Nonlinear

10-40 mg

Absolute
Bioavailability

77%

>80%

30%-40%
(20-40 mg)

64%

52%

Food Effect

Tmax

Cmax
AUC 50%

Not affected

AUC
33%-53%

N/A

Cmax
(mol/mL)

Tmax
(hr)

AUC0-24
(molhr/L)

T1/2
(hr)

Dose
Linearity

Prescribing Information for Aciphex (rabeprazole sodium), Nexium (esomeprazole magnesium),

Prevacid (lansoprazole), Prilosec (omeprazole), and PROTONIX (pantoprazole sodium).

PROTONIX (Pantoprazole Sodium)

40 mg vs. Prilosec (omeprazole) 40 mg

Intragastric pH
5
Pantoprazole 40 mg

Median pH

Omeprazole 40 mg
4.2

4.0
3.4

3
2

1.7

1
0

24-hour pH

Nighttime pH

n = 7 normal volunteers
Koop et al. 1994. Prilosec is a registered trademark of AstraZeneca LP.

PROTONIX I.V. (Pantoprazole Sodium) for Injection is indicated for the

short-term treatment (7 to 10 days) of gastroesophageal reflux disease
(GERD), as an alternative for patients who are unable to continue
taking PROTONIX Delayed-Release Tablets. Safety and efficacy of
PROTONIX I.V. for Injection as an initial treatment for GERD have not
been demonstrated.
The most frequently reported adverse events with PROTONIX I.V. for
Injection were abdominal pain, chest pain, rash, and pruritus.
PROTONIX is contraindicated in patients with known hypersensitivity to
any component of the formulation. Treatment with PROTONIX I.V. for
Injection should be discontinued as soon as the patient is able to be
treated with PROTONIX Delayed-Release Tablets.
Data on safety and effective dosing for conditions other than GERD
(including concomitant life-threatening upper gastrointestinal bleeds) are
not available. PROTONIX I.V. 40-mg once daily dosing does not raise
gastric pH to levels sufficient to contribute to the treatment of such lifethreatening conditions.
Please see full Prescribing Information.

PROTONIX I.V. (Pantoprazole Sodium)

for Injection in Inhibition of Acid Output
40 mg I.V. vs. Placebo
100

% Inhibition

80
60
PROTONIX I.V. 40 mg (n=8)
Placebo (n=4)

40
20
0
-20
-40

8am

10am

Noon 2pm

4pm

6pm

8pm

10pm 12pm

2am

4am

Hours
Data on file, Wyeth-Ayerst Laboratories. Study 100-US.
Pisegna JR et al. Am J Gastroenterol. 1999;94:2874-2880.

6am

8am

PROTONIX I.V. (Pantoprazole Sodium)

for Injection
Dosage and Administration

Dosage
The recommended dose is one
vial (the equivalent of 40 mg
pantoprazole) given once daily
by intravenous infusion for 7 to
10 days.

Administration
PROTONIX I.V. for Injection
should be administered
intravenously over a period of
approximately 15 minutes at a
rate not greater than 3 mg/min (7
mL/min). PROTONIX I.V. for
Injection should be administered
using the in-line filter provided.
The filter must be used to
remove the precipitates that may
form when the reconstituted drug
product is mixed with I.V.
solutions

PROTONIX I.V. for Injection Prescribing Information. Wyeth-Ayerst Laboratories, Philadelphia, Pa

Proton Pump Inhibitor Activation

in the NPO Patient

Acid is always secreted, but at varying levels

Multiple pathways for stimulation of acid secretion
not involving food including
Basal
Cephalic
Canalicular pH is always sufficient to activate PPIs
Blood contains protein and stimulates gastric acid
secretion when present in the stomach

Modlin IM, Sachs G, Acid Related Diseases, Biology and Treatment. 1998:126-145. Feldman M. In:
Feldman M, Scharschmidt BF, Sleisenger MH, et al. eds. Sleisenger & Fordtrans Gastrointestinal and Liver
Disease. 1998:587-603.

PROTONIX I.V. (Pantoprazole Sodium)

for Injection
Summary
Impressive acid suppression
No evidence of tolerance in a clinical study (oral
10 days; I.V. 7days)
Fast onset (within 15-30 minutes) and long acting
Generally well tolerated
No known clinically relevant drug interactions

Data on file, Wyeth-Ayerst Laboratories.