Which PPI is the BEST and MOST POWERFUL to helps stop Acute Upper Gastrointestinal Bleeding?

1. The Role of PPIs in
Upper Gastrointestinal Bleeding;
Which one is The Best?
Mangatas SM Manalu
Internal Medicine Department
Mayapada Hospital – South Jakarta

2. Definitions
• Upper GI bleed – arising
from the esophagus,
stomach, or proximal
duodenum
• Mid-intestinal bleed –
arising from distal
duodenum to ileocecal
valve
• Lower intestinal bleed –
arising from colon/rectum

3.  Upper GI Tract
◦ Proximal to the Ligament of Treitz
◦ 65 - 70% of GI Bleeds
 Mid Intestinal GI Tract
2-3 % of GI Bleeds
 Lower GI Tract
◦ Distal to the Ligament of Treitz
◦ 25 -30% of GI Bleeds

5. Differential Diagnosis of
Upper GI bleeding
Esophageal varices
Gastric varices
Erosive gastritis
Mallory Weiss tear
Reflux esophagitis
Gastric malignancy
Vascular malformations
Nose bleed
Aorto-enteric fistula
Gastric ulcer
Duodenal ulcer
Consider the following

6. Tabel 1. Penyebab Tersering Perdarahan SCBA
pada Pasien yang menjalani Endoskopi
di Pusat Endoskopi RSCM selama tahun 2001-2005
Konsensus Nasional Perdarahan Saluran Cerna Bagian Atas, PB-PGI, 2012

7.  Initial Assessment and Resuscitation
 History and Physical Examination
 Assessment of the bleeding source
 Differential Diagnosis
 Investigations
 Management
◦ Conservative
◦ Therapeutic

8.  Airway, Breathing and Circulation
 Vital Signs:
◦ Pulse, BP, Temperature, Respiratory
Rate
 Fluid and Resuscitation Plan
◦ Co-morbidities

9.  RR, HR, and BP can be used to estimate
degree of blood loss/hypovolaemia
Class I Class II Class III Class IV
Volume Loss
(ml)
0-750 750-1500 1500-2000 >2000
Loss (%) 0-15 15-30 30-40 >40
RR 14-20 20-30 30-40 >40
HR <100 >100 >120 >140
BP Unchanged Unchanged Reduced Reduced
Urine Output
(ml/hr)
>30 20-30 5-15 Anuric
Mental State Restless Anxious Anxious/conf
used
Confused/
lethargic

10.  Confirm the GI Bleed - Hemoptysis or
Hemetemesis ???
 Manner of Presentation of a GI Bleed
◦ Hemetemesis
◦ Malena
◦ Hematochezia
◦ Occult Blood loss
◦ Symptoms of Blood loss
 Is it only the GI Bleed ??
 Assessment of the bleed
◦ Dizziness, Syncope, Chest Pain, SOB

11. Bleeding etiology Leading History
Mallory -Weiss tear Multiple Emesis before hematemesis, alcoholism
Esophageal ulcer Dysphagia, Odynophagia, GERD,
Peptic ulcer Epigastric pain, NSAID or aspirin use
Stress gastritis Patient in an ICU, gastrointestinal bleeding occurring
after admission, respiratory failure, multiorgan failure
Varices, portal
gastropathy
Alcoholism, Cirrhosis
Gastric antral
vascular ectasia
Renal failure, cirrhosis
Malignancy Recent involuntary weight loss, dysphagia, cachexia,
early satiety
Angiodysplasia Chronic renal failure, hereditary hemorrhagic
telangiectasia
Aortoenteric fistula Known aortic aneurysm, prior abdominal aortic
aneurysm repair

12.  Anticoagulation (warfarin/heparin)
 Use of Drugs NSAIDs,Steroids,Bisphosphonates
 Similar episodes before
 H/o Jaundice in past
 H/o Abdominal Surgery
 H/o Alcoholism
 H/o Smoking or Tobacco abuse
 H/o Cocaine abuse

13.  Pt’s Consciousness, Orientation
 Pallor, Icterus, Clubbing, Pedal
Edema
 Lymphadenopathy, JVP
 Signs of Liver Failure
 Systemic Examination
◦ Abdomen, CVS, RS, CNS

14.  Alopecia, Pallor, Icterus, Fetor Hepaticus,
Glossitis, Parotid Swelling
 Leukonychia, Clubbing, Palmar Erythema,
Dupuytren’s Contracture, Asterexis
 Loss of Axillary hair, Spider naevi,
Gynaecomastia,
 Ascites, Splenomegaly, Caput Medusae
 Testicular Atrophy, Loss of Pubic Hair
 Pedal Edema

15. Stool color and origin/pace of bleeding
• Guaiac positive stool
– Occult blood in stool
– Does not provide any localizing information
– Indicates slow pace, usually low volume bleeding
• Melena
– Very dark, tarry, pungent stool
– Usually suggestive of UGI origin (but can be small
intestinal, proximal colon origin if slow pace)
• Hematochezia
– Spectrum: bright red blood, dark red, maroon
– Usually suggestive of colonic origin (but can be UGI origin
if brisk pace/large volume)

16.  Major causes
 Peptic ulcer disease
 Esophageal and gastric varices
 Hemorrhagic gastritis
 Esophagitis
 Duodenitis
 Mallory-Weiss tear
 Angiodysplasia
 Upper gastrointestinal malignancy
 Anastomotic ulcers (after bariatric surgery)
 Dieulafoy lesion

17.  Minor causes
 Gastric antral vascular ectasia (watermelon
stomach)
 Portal hypertensive gastropathy
 Gastric polyps
 Aortoenteric fistula
 Connective tissue disease
 Postprocedural: nasogastric tube erosions,
endoscopic biopsy, endoscopic polypectomy,
endoscopic sphincterotomy

18.  Complete Blood count, ESR,
 Liver and Renal Function Tests, Electrolytes
 Prothrombin Time and INR
 BUN / Creatinine – ratio > 30 sensitivity of
68% and a specificity of 98%
 Stool Occult Blood Test
 Grouping and Cross Matching
 ECG, Cardiac enzymes(if essential)
 HIV, HbsAg, AntiHCV Markers

19.  ABC’s
 Fluid Resucitation
 NG Tube insertion and Lavage
 Hemodynamically Unstable – Hypotension,
Tachycardia, Postural Changes Urgent
Endoscopy
 Hemodynamically Stable  Plan Early
Endoscopy
 Tranexamic Acid I.V (+ Vit K in Liver Cirrochis)
 IV PPI Therapy

20.  A grossly bloody aspirate in the atraumatic NG insertion
CONFIRMS a UGI Bleed
 The type of bleed
 Red blood - active bleeding
 Coffee ground - recently active bleeding.
 Continued aspiration of red blood - severe, active
hemorrhage.
 Clears the field for endoscopic visualization
 Prevent aspiration of gastric content
 However, lavage may not be positive if bleeding has
ceased or arises beyond a closed pylorus.

21. An algorithm in the management of acute nonvariceal GI bleeding
Acute upper GI bleeding
Initial resuscitation, airway, volume restoration, nasogastric tube,
empiric high-dose PPI, risk stratification using clinical factors
Signs of on-going bleeding; such as shock
and fresh hematemesis or hematochezia
Urgent endoscopy
Stable patient
Endoscopy next morning
Epinephrine injection + Thermocoagulation to
actively bleeding ulcers and ulcers with NBW
Clots elevated and treatment to underlying vessel
Bleeding stopped
Unable to control bleeding, access
or localize bleeding point in the
presence of massive bleeding.
Second re-bleed
Consider
early discharge
Low-risk ulcers; flat
pigments and clean base

22. Treatment in Harisson’s PIM (18 th ed-2012)
1. Laine L. Gastrointestinal Bleeding. In Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J, editors. Harrisons Princ Intern Med.
18th ed. New York: The McGraw-Hill Companies; 2012.

24.  Age > 60 yrs
 Comorbidities (Renal failure, Liver failure, CHF,
Malignancy)
 Variceal bleeding (as compared with nonvariceal
bleeding)
 Shock or hypotension on presentation
 Increasing number of units of blood transfused
 Active bleeding on Endoscopy
 Bleeding Ulcer of >2cm or a Spurting vessel
 Need for emergency surgery

25. TEST IQ
BAGAIMANA CARA
MEMBEDAKAN MANA YANG
SELEBRITIS dan
YANG BUKAN SELEBRITIS
(sok selebritis)
Dari foto ini???

27. JAWAB:
YANG SELEBRITIS TAHU BETUL
DI MANA LETAK KAMERA, MELIHAT KE
ARAH KAMERA SAAT DIFOTO KARENA
SUDAH BIASA BERPOSE, sedangkan
Yang SOK SELEBRITIS TIDAK TAHU
LETAK KAMERA “JULING”.......
LOL...!!...!!....!!!....

28. We Are Focusing on
Non Variceal
UGI’s Bleeding

30. Oesophagitis Angiodysplasia

32.  Gastric Carcinoma

34. • PPI Infusion
 IV Omeperazole 80mg bolus then 8mg/hr infusion or
Esomeprasole 40 mg bolus then 4 mg/hr infusion
• Endoscopic Therapy
 Bipolar Coagulation, Heater Probe, Injection
Therapy(Absolute Alcohol, 1:10,000 epinephrine),
Hemoclips
 Medical Management  After Acute Phase
◦ Antacids, H2 receptor Antagonists, oral PPIs,
◦ Cytoprotective Agents - Bismuth Preparations, Prostaglandin
Analogues
◦ H.Pylori Eradication
 Surgical Management
◦ Duodenal Ulcer
◦ Gastric Ulcer

35. Ann Intern Med. 2010;152:101-113.

36. Peran dari obat penekan asam
lambung
• Terapi farmakologis menggunakan obat yang mampu
menekan sekresi asam lambung merupakan pilihan yang
paling banyak digunakan sebagai standar pengobatan untuk
kasus perdarahan. Termasuk didalamnya untuk pencegahan
perdarahan ulang 1-5
• Tujuan terapi pada pasien tersebut adalah mencapai pH
dalam lambung (intragastric) diatas 6, sebuah kondisi dimana
proses pembentukan bekuan darah dapat stabil 1,6-7
1. Lin H-J, et al. Arch Intern Med 1998; 158: 54-8. 2. Lau JWY, et al. N Eng J Med 2000; 343: 310-6. 3. Liontiadis
GI, et al. Aliment Pharmacol ther 2005; 22: 169-74. 4. Sung JJ, et al. Ann Intern Med 2003; 139: 237-43. 5.
Barkun A, et al. Gastroenterology 2004; 126: A78 (Abstract). 6. Vorder Bruegge WF, et al. J Clin Gastroenterol
1990; 12: (Suppl 2): S35-40. 7. van Resburg, et al. Am J Gastroenterol 2003; 98: 2635-41

37. Tingkatan pH lambung yang disarankan pada
berbagai kasus penyakit asam lambung
pH lambung Indikasi
3.5
Penurunan kejadian perdarahan karena
stress mukosa lambung
4.5
Pepsin tidak aktif sebagai faktor agresif
mukosa lambung
=5 99.9% netralisasi asam
< 6
Pencegahan koagulasi dan aggregrasi
platelet darah
 6 Penurunan kejadian perdarahan ulang
8 Penghancuran pepsin
Stress-
Related
Mucosal
Disease
Prevention
of Ulcer
Rebleeding
Adapted from Vorder Bruegge WF, et al. J Clin Gastroenterol. 1990;12:S35–S40.

38. Stress Related Mucosal Disease perlu
pH>3.5
pH lambung Indikasi
3.5
Penurunan kejadian perdarahan karena
stress mukosa lambung
4.5
Pepsin tidak aktif sebagai faktor agresif
mukosa lambung
=5 99.9% netralisasi asam
< 6
Pencegahan koagulasi dan aggregrasi
platelet darah
 6 Penurunan kejadian perdarahan ulang
8 Penghancuran pepsin
Stress-
Related
Mucosal
Disease
Prevention
of Ulcer
Rebleeding
Adapted from Vorder Bruegge WF, et al. J Clin Gastroenterol. 1990;12:S35–S40.

39. • Stress-related mucosal disease
(SRMD) merupakan kondisi
berkesinambungan dari
kerusakan mukosa (superficial
mucosal damage) hingga
stress ulcer (focal deep
mucosal damage).
• Disebabkan iskemi mukosa,
SRMD biasanya dilihat pada
pasien yang dirawat di
Intensive Care Unit (ICU).
Stress-related mucosal disease dan
pH>3
Multiple ulcers of the stomach, occurring in a
chronically debilitated patient.

40. Stress Ulcers & Non Stress Ulcers –
perbedaan patofisiologi
Stress ulcer Non-stress ulcer (PUD)
• Multiple
• Acid/pepsin secretory mucosa
• Lack of chronic inflammation
• Asymptomatic (mostly!)
• Usually solitary
• Distal stomach/duodenum
• Chronic inflammation
• Symptomatic

41. Faktor Risiko perdarahan lambung karena
Stress Ulcer
• Respiratory failure
• Coagulopathy
• Increased risk with increased
severity of illness
• Multiple trauma
• Age >65
• Corticosteroids
• Prolonged NG tube placement
• NSAIDs
• Major surgery
• Respiratory failure
• Renal failure
• Acute hepatic failure
• Multiple organ failure
• Alcoholism
• Increase IgA antibody to HP
• Head injury
• Sepsis
• Burns >30–35% BSA
Curr Med Res Opin. 2005;21(1):11-18.

42. Terapi pada kasus Stress Ulcer
Curr Med Res Opin. 2005 Jan;21(1):11–18.
• Current preventative treatment strategies
o Histamine 2 receptor antagonists (H2RAs) – Suppressing acid secretion
o Proton pump inhibitors (PPIs) - Suppressing acid secretion
o Sucralfate - provides a protective barrier against acid in the GI tract.
• In the past, H2RAs have been preferentially used over PPIs-available in liquid
and intravenous formulations.
• Currently, PPI are preferable-availability of suspension and IV formulations.
Penelitian membuktikan bahwa PPI memberikan efikasi yang
lebih baik pada pencegahan stress Ulcer dibandingkan H2RA

43. pH>6 dibutuhkan untuk pencegahan
perdarahan berulang
pH lambung Indikasi
3.5
Penurunan kejadian perdarahan karena
stress mukosa lambung
4.5
Pepsin tidak aktif sebagai faktor agresif
mukosa lambung
=5 99.9% netralisasi asam
< 6
Pencegahan koagulasi dan aggregrasi
platelet darah
 6 Penurunan kejadian perdarahan ulang
8 Penghancuran pepsin
Stress-
Related
Mucosal
Disease
Prevention
of Ulcer
Rebleeding
Adapted from Vorder Bruegge WF, et al. J Clin Gastroenterol. 1990;12:S35–S40.

44. pH intragastric >=6
dibutuhkan untuk
mencegah disagregasi
platelet pada kasus
perdarahan
gastrointestinal yang
diebabkan oleh ulkus
Target pH intragastrik pada
kasus perdarahan ulkus
peptikum
Green FW, et al. Gastroenterology 1978;74:38–43

45. Proton Pump InhibitorspH up to 6

48. Efektivitas PPI dalam
menurunkan kejadian
perdarahan berulang pada
pasien dengan perdarahan non
variceal
Barkun AN, et al. Ann Intern Med. 2010;152:101-113

49. Percentage of time pH>6 during first 3 hours
with esomeprazole iv (healthy volunteers)
0
20
40
60
80
100
Mean fraction of first 3 hours (%)
*p<0.05 versus 80 mg + 8 mg/hour
Baseline 40 mg
+ 8 mg/hour
80 mg
+ 4 mg/hour
80 mg
+ 8 mg/hour
120 mg
+8 mg/hour
120 mg (2hours)
+ 8 mg/hour
2%
23.3%*
36.7%*
46.7% 46.7% 43.3%
Röhss K, et al. Intl J Clin Pharm Ther 2007;45:345–54
n=25 n=23 n=24 n=24 n=22 n=20

50. Comparison of acid control
between PPIs;
Which one is the best???
http://www.ncbi.nlm.nih.gov/pubmedhealt
h/PMH0008767/#summary.t1

52. Esomeprazole

56. Intragastric pH with high-dose iv PPI
therapy (Eso Vs Panto)
• Clinical pharmacology studies
• H. pylori-negative healthy volunteers
• 24 hour iv infusion
1Röhss K, et al. Intl J Clin Pharm Ther 2007;45:345–54; 2Metz DC, et al. Aliment Pharmacol Ther 2006;23:985–95
n Median/mean Time pH>6
24-hour pH (0–24 hours)
Esomeprazole
80 mg + 8 mg/hour1 25 5.8 12.6
Pantoprazole
80 mg + 8 mg/hour2 36 5.0 5.5–6.7
* This is not “ a head to head” study

57. Day #1 Day #5
Once-daily dosing with esomeprazole 40 mg i.v. provides
faster and more pronounced intragastric acid control than
pantoprazole 40 mg

58. Esomeprazole 40 mg IV satu kali sehari lebih cepat dan lebih efektif mengontrol
keasaman lambung dibandingkan pantoprazole 40 mg IV

59. Rata Rata Lama Pengontrolan pH Intragastric ( Jam )
Esomeprazole i.v 40 mg
Pantoprazole i.v 40 mg
Esomeprazole 40 mg i.v. lebih mampu mempertahankan pH > 4
lebih lama dibandingkan pantoprazole 40 mg i.v
Grafik pH 24-jam intragastrik

61. Prosentase lama Pengontrolan Asam Lambung selama
monitoring 24 Jam (Eso Vs Lanso)
Esomeprazole 40 mg i.v mempertahankan pH > 4 lebih lama
dibandingkan lansoprazole 30mg i.v.

67. ESOMEPRAZOLE
pada pencegahan perdarahan ulang ulkus Peptikum
Pasien perdarahan ulkus peptikum yang mengalami perdarahan ulang,
yang diterapi dengan esomeprazol secara signifikan lebih sedikit
dibandingkan plasebo, baik dalam waktu 7 hari ataupun 30 hari
pemberian.
n= 375 n= 389

70. Esomeprazole beats GERD more than others

73.  Safety
 Tolerability
 Effectivity
 Cost
 Availability
International Pharmaceutical Society, Council Statement, 2012

76.  Esomeperazole : Some Drug interactions and side effects
 Initially, there was some worry that PPIs might increase the risk of
developing stomach cancer. Those concerns were unfounded, but
others have taken their place, partly because people often take PPIs
on a daily basis for years, so the total exposure to the drug ends up
being quite significant. Here’s a rundown of the some of the drug
interactions and side effects that are causing concern:
 Interaction with clopidogrel. Clopidogrel (sold as Ceruvin, Clopilet,
and Plavix) is a drug that discourages the formation of artery-
clogging blood clots and is often taken by people with heart disease
to prevent heart attacks and stroke. But clopidogrel has a significant
downside: it’s hard on the lining of the stomach and intestines, so it
increases the risk of gastrointestinal bleeding. To keep those bleeds
from happening, doctors have often prescribed a PPI with
clopidogrel, especially if the patient is also taking aspirin. Like
clopidogrel, aspirin makes blood clots less likely to form, and dual
clopidogrel-aspirin therapy is recommended after placement of an
artery-opening coronary stent. But aspirin, too, is rough on the
gastrointestinal lining.
 The trouble is that PPIs — and omeprazole in particular — inhibit an
enzyme called CYP2C19 that’s crucial to one of the metabolic steps
that activates clopidogrel and its effects. In 2009, the FDA issued a
strong warning that said patients taking clopidogrel should avoid
taking omeprazole (and, secondarily, the related drug Nexium)
because they may cut clopidogrel’s effectiveness in half.

77.  Fracture risk. Some studies have shown an association between PPIs and the risk of fracture
— particularly hip fracture — while others have not. The FDA decided in 2010 that there was
enough evidence of fracture risk to warrant a warning about it. Calcium is absorbed in the
small intestine, not the stomach. But low stomach acid levels can have downstream effects,
especially in the duodenum, and some research shows that one of them could be reduced
absorption of calcium, which could lead to osteoporosis, weaker bones, and, consequently,
a greater chance of breaking a bone. The fracture risk is probably pretty small, but it’s
another reason for not taking a PPI unless necessary.
 Pneumonia risk. Several studies have shown that people taking PPIs seem to be more likely
to get pneumonia than those who aren’t. The association has been documented among
people living in the community and hospital patients alike. Normally, stomach acid creates a
fairly inhospitable environment for bacteria, but if acid levels are reduced by PPIs, the
bacteria count can go up. The thinking is that in people with GERD who take PPIs, bacteria-
laden stomach contents may travel up the esophagus and then get inhaled into the windpipe
and lungs, where the bacteria cause pneumonia.
 C. difficile risk. People typically develop Clostridium difficile infections in the hospital after
taking antibiotics that have disrupted the natural bacterial ecology of the large intestine.
The infections cause diarrhea but can also become a lot more serious, even life-threatening.
Studies have shown a fairly strong statistical correlation between PPI use and C. difficile
infection, although it’s still just a correlation and not proof of direct cause and effect. Some
experimental evidence suggests that PPIs may change conditions in the gut to be more
favorable to C. difficile bacteria.
 Iron and B12 deficiency. Stomach acid helps render the iron and vitamin B12 from food into
forms that are readily absorbed. So there was worry that an unintended consequence of PPIs
would be deficiencies of this vitamin and mineral because of lower stomach acid levels. But
research has shown that if there is any effect, it’s mild, so those concerns have been
largely allayed.

78. Terima Kasih
Mohon maaf jika
ada yang kurang
berkenan