1. Mark Topazian, M.D. December 16, 2010
GI Bleeding
Mark Topazian, M.D.
December 16, 2010

2. Critical Care Grand Rounds Disclosure Summary Mark D. Topazian, MD
Has responded with a disclosure
Will discuss off-label/investigative use(s):
Sandoz, Ethicon Octreotide, Dermabond

3. Critical Care Grand Rounds Disclosure Summary Continued
Planning committee members who have nothing to disclose:
Sean M. Caples, DO, Co-Director
Juan N. Pulido, MD, Co-Director
J. Christopher Farmer, MD
Kim Jones, Program Coordinator
Disclosure Summary
As a provider accredited by ACCME, College of Medicine, Mayo Clinic (Mayo School of CME), must ensure balance, independence, objectivity and scientific rigor in its educational activities. Course Director(s), Planning Committee Members, Faculty, and all others who are in a position to control the content of this educational activity are required to disclose all relevant financial relationships with any commercial interest related to the subject matter of the educational activity. Safeguards against commercial bias have been put in place. Faculty also will disclose any off label and/or investigational use of pharmaceuticals or instruments discussed in their presentation. Disclosure of this information will be published in course materials so those participants in the activity may formulate their own judgments regarding the presentation.

4. Learning Objectives
Identify predictors of morbidity and mortality in patients with acute gastrointestinal hemorrhage
Describe the management approach to gastrointestinal hemorrhage
Understand the evidence basis for pharmacologic and endoscopic therapies
Review important recent developments in this field

5. GI Bleeding is an important clinical problem
Incidence: 100/100,000/year
Mortality: 3% to 10%
Silverstein GIE 2002; Cutler DDS 1981; Lanas AJG 2009

6. Risk stratification
Pharmacology
Interventional Strategies
Prevention

7. Interventional Strategies Prevention
Rebleeding
Mortality
Early intervention
Risk stratification
Pharmacology
Interventional Strategies
Prevention

8. Interventional Strategies Prevention
Rebleeding
Mortality
Early intervention
Risk stratification
Pharmacology
Interventional Strategies
Prevention
PPI
Octreotide
ASA/clopidigrel

9. Interventional Strategies Prevention
Rebleeding
Mortality
Early intervention
Risk stratification
Pharmacology
Interventional Strategies
Prevention
PPI
Octreotide
ASA/clopidigrel
Endoscopy
Angiography

10. Interventional Strategies Prevention
Rebleeding
Mortality
Early intervention
Risk stratification
Pharmacology
Interventional Strategies
Prevention
PPI
Octreotide
ASA/clopidigrel
Endoscopy
Angiography
Primary
Secondary

11. Non-Variceal Bleeding
Predictors of re-bleeding and death
Variceal Bleeding
Size of the initial bleed
Severity of liver disease
Infection (SBP)
Non-Variceal Bleeding
Size of the initial bleed
Age > 65 years
Comorbidities
Endoscopic stigmata

12. Non-Variceal Bleeding
Predictors of re-bleeding and death
Variceal Bleeding
Size of the initial bleed
Severity of liver disease
Infection (SBP)
Non-Variceal Bleeding
Size of the initial bleed
Age > 65 years
Comorbidities
Endoscopic stigmata

13. Non-Variceal Bleeding
Predictors of re-bleeding and death
Variceal Bleeding
Size of the initial bleed
Severity of liver disease
Infection (SBP)
Non-Variceal Bleeding
Size of the initial bleed
Age > 65 years
Comorbidities
Endoscopic stigmata

14. Non-Variceal Bleeding
Predictors of re-bleeding and death
Variceal Bleeding
Size of the initial bleed
Severity of liver disease
Infection (SBP)
Non-Variceal Bleeding
Size of the initial bleed
Age > 65 years
Comorbidities
Endoscopic stigmata

15. to factors affecting outcome, BMJ 1970
Schiller, Truelove, Williams. Hematemesis and melena with special reference
to factors affecting outcome, BMJ 1970

16. Bedside estimation of hypovolemia
No bedside test is reliable for diagnosis of moderate acute blood loss
Supine tachycardia and/or hypotension are specific but insensitive (often absent) in severe acute blood loss ( ml)
2 signs are sensitive and specific for diagnosis of severe acute blood loss:
Postural pulse increment ≥ 30 bpm
Severe postural dizziness (unable to stand for VS)
McGee JAMA 1999

17. Bedside diagnosis of hypovolemia
No bedside test is reliable for diagnosis of moderate acute blood loss
Supine tachycardia and/or hypotension are specific but insensitive (often absent) in severe acute blood loss ( ml)
2 signs are sensitive and specific for diagnosis of severe acute blood loss:
Postural pulse increment ≥ 30 bpm
Severe postural dizziness (unable to stand for VS)
McGee JAMA 1999

18. Bedside diagnosis of hypovolemia
No bedside test is reliable for diagnosis of moderate acute blood loss
Supine tachycardia and/or hypotension are specific but insensitive (often absent) in severe acute blood loss ( ml)
2 signs are sensitive and specific for diagnosis of severe acute blood loss:
Postural pulse increment ≥ 30 bpm
Severe postural dizziness (unable to stand for VS)
McGee JAMA 1999

19. Melena, hematemesis, hematochezia
Melena implies acute loss of at least 250 ml blood in the UGI tract
Pace of melena
Hematemesis implies rapid UGI bleeding
Fatality rate doubled c/w melena
Hematochezia is usually due to LGIB
May be due to duodenal ulcer
Schiff AJMS 1942, Schiller 1970, Jensen 2005, and others

20. NG aspirate and lavage
NG aspirate for diagnosis of upper vs. lower GI bleed
poor specificity (42% - 84%) and sensitivity (54% - 91%)
NG lavage for prognosis of UGI bleeding
Failure to clear with > 10 liters lavage predicts ongoing bleeding
Endoscopic findings are better prognosticators
Complication rate of NG tube placement is 1%
NG aspiration may promote rebleeding from varices
Palamadessi SAEM 2010

21. Blatchford, Lancet 2000

22. 2 or more of the following:
Blatchford Score
Low risk
All of the following:
Normal pulse and BP
Near-normal BUN and Hb
No liver, heart disease
High risk
2 or more of the following:
BUN > 30 mg/dL
Hb < 10
Hypotension
Hepatic or cardiac disease

23. Endoscopic stigmata in peptic ulcers
Clean-based ulcer
Flat spot
Visible vessel
Adherent clot
Active bleeding

24. Endoscopic stigmata in peptic ulcers
Clean-based ulcer
Flat spot
Visible vessel
Adherent clot
Active bleeding
Rebleeding: 3%

25. Endoscopic stigmata in peptic ulcers
Clean-based ulcer
Flat spot
Visible vessel
Adherent clot
Active bleeding
Rebleeding: 10%

26. Endoscopic stigmata in peptic ulcers
Clean-based ulcer
Flat spot
Visible vessel
Adherent clot
Active bleeding
Rebleeding: 50%

27. Endoscopic stigmata in peptic ulcers
Clean-based ulcer
Flat spot
Visible vessel
Adherent clot
Active bleeding
Rebleeding: 25% - 40%

28. Endoscopic stigmata in peptic ulcers
Clean-based ulcer
Flat spot
Visible vessel
Adherent clot
Active bleeding
Rebleeding: 90%

29. PPI therapy PPI before endoscopy Fewer endoscopic stigmata
No effect on rebleeding, surgery, or mortality
Sreeharan (Cochrane) 2010; Wu WJG 2010; Wang AIM 2010 ; and others

30. PPI therapy PPI before endoscopy Fewer endoscopic stigmata
No effect on rebleeding, surgery, or mortality
PPI after endoscopy
Improves outcomes in pts requiring endoscopic Rx
No difference between high and regular dose Rx
Sreeharan (Cochrane) 2010; Wu WJG 2010; Wang AIM 2010 ; and others

31. PPI therapy PPI before endoscopy Fewer endoscopic stigmata
No effect on rebleeding, surgery, or mortality
PPI after endoscopy
Improves outcomes in pts requiring endoscopic Rx
No difference between high and regular dose Rx
PPI dose
1-4x daily dose
vs.
2-6x daily dose IV
plus cont. infusion
Sreeharan (Cochrane) 2010; Wu WJG 2010; Wang AIM 2010 ; and others

32. Octreotide therapy Mechanism Prevents post-prandial
increase in mesenteric
blood flow
Gotzsche (Cochrane) 2006; and others

33. Octreotide therapy Mechanism Octreotide vs. placebo
Prevents post-prandial
increase in mesenteric
blood flow
Octreotide vs. placebo
Less transfusion (0.7 units)
Less failure of initial endoscopic Rx (RR 0.7)
Balloon tamponade rare
No difference in rebleeding or mortality
Gotzsche (Cochrane) 2006; and others

34. Octreotide therapy Mechanism Octreotide vs. placebo
Prevents post-prandial
increase in mesenteric
blood flow
Octreotide vs. placebo
Less transfusion (0.7 units)
Less failure of initial endoscopic Rx (RR 0.7)
Balloon tamponade rare
No difference in rebleeding or mortality
How to use octreotide
Patients with suspected variceal hemorrhage
Bolus of 0 to 50 mcg, infusion of 25 – 250 mcg/hr
Begin before endoscopy and continue for 3 – 5 days
Gotzsche (Cochrane) 2006; and others

35. Gotzsche (Cochrane) 2006

36. Gotzsche (Cochrane) 2006

37. Other Drug Rx for Portal HTN
Vasopressin
Absence of controlled data
Systemic risks
Vasopressin analogues
Terlipressin is effective in European trials
Beta blockers
Not used in the acute setting
Decrease risk of rebleeding after discharge

38. Antibiotics Infectious complications increase mortality in cirrhotics
Numerous controlled trials of antibiotic Rx
Chavez-Tapia (Cochrane), 2010

39. Antibiotics Infectious complications increase mortality in cirrhotics
Numerous controlled trials of antibiotic Rx
Improvements with antibx:
Bacterial infections (RR 0.36)
Rebleeding (RR 0.53)
Mortality (RR 0.79)
Chavez-Tapia (Cochrane), 2010

40. Antibiotics Infectious complications increase mortality in cirrhotics
Numerous controlled trials of antibiotic Rx
Antibiotics used
Oral quinolones
Quinolones + beta-lactams
Cephalosporins
Carbapenems
Improvements with antibx:
Bacterial infections (RR 0.36)
Rebleeding (RR 0.53)
Mortality (RR 0.79)
Chavez-Tapia (Cochrane), 2010

41. ASA Should we stop ASA in patients with acute GI bleeding?
Sung AIM 2010

42. ASA Should we stop ASA in patients with acute GI bleeding?
156 patients with acute GI hemorrhage
ASA for cardiovascular or cerebrovascular disease
EGD: stigmata of recent hemorrhage requiring endoscopic Rx
Randomized to ASA 80 mg/day or placebo for 8 weeks
Sung AIM 2010

43. ASA Should we stop ASA in patients with acute GI bleeding?
156 patients with acute GI hemorrhage
ASA for cardiovascular or cerebrovascular disease
EGD: stigmata of recent hemorrhage requiring endoscopic Rx
Randomized to ASA 80 mg/day or placebo for 8 weeks
ASA
Recurrent bleeding: 10%
Mortality: 1%
(cardiac 1)
Placebo
Recurrent bleeding: 5%
Mortality: 13%
(cardiac 5, GI 3, pneumonia 2)
Sung AIM 2010

44. ASA Plavix? Should we stop ASA in patients with acute GI bleeding?
156 patients with acute GI hemorrhage
ASA for cardiovascular or cerebrovascular disease
EGD: stigmata of recent hemorrhage requiring endoscopic Rx
Randomized to ASA 80 mg/day or placebo for 8 weeks
ASA
Recurrent bleeding: 10%
Mortality: 1%
(cardiac 1)
Placebo
Recurrent bleeding: 5%
Mortality: 13%
(cardiac 5, GI 3, pneumonia 2)
Plavix?
Sung AIM 2010

45. Clopidogrel Clopidogrel does not cause peptic ulcer
but increases bleeding risk, particularly
in patients with a history of peptic ulcer
Interaction with PPIs
Clopidogrel → active metabolite by CYP2C19
Omeprazole is also metabolized by CYP2C19
Omeprazole: ↓ levels of the active clopidogrel metabolite
Dikman APT 2009, Siller-Matula 2010, and others

46. Clopidogrel Interaction with PPIs
Clopidogrel → active metabolite by CYP2C19
Omeprazole is also metabolized by CYP2C19
Omeprazole: ↓ levels of the active clopidogrel metabolite
Dikman APT 2009, Siller-Matula 2010, and others

47. Clopidogrel Interaction with PPIs
Clopidogrel → active metabolite by CYP2C19
Omeprazole is also metabolized by CYP2C19
Omeprazole: ↓ levels of the active clopidogrel metabolite
PPI together with clopidogrel:
likely ↑ risk major cardiovascular events
likely↓ risk GI bleed
Effect may be greatest in slow metabolizers
Dikman APT 2009, Siller-Matula 2010, and others

48. Furuta BJCP 2010

49. Clopidogrel/PPI interaction
Possible strategies
Avoid PPI when not indicated
Sequence CYP2C19 genotype
Substitute H2 receptor antagonists
Stagger clopidogrel and PPI doses
Increase clopidogrel dose
Add or substitute ASA
Dikman APT 2009, Siller-Matula 2010, Furuta 2010, and others

50. Principles of endoscopic hemostasis
Identify and target the point source of bleeding
Only treat lesions that have a high likelihood of rebleeding
Endoscopic Rx decreases rebleeding rate by > 50%
Repeat endoscopic Rx is usually effective in those who rebleed

51. Gastric Varices

52. Minnesota Tube

56. Early TIPS?
TIPS prevents bleeding but is associated with liver failure
TIPS is a rescue treatment
Garcia-Pagan NEJM 2010

57. Early TIPS?
TIPS prevents bleeding but is associated with liver failure
TIPS is a rescue treatment
63 patients with variceal hemorrhage
Childs-Pugh score of 7 – 13 (B or C)
All received endoscopic and pharmacologic Rx
Randomized to standard care or early TIPS
Garcia-Pagan NEJM 2010

58. Early TIPS?
TIPS prevents bleeding but is associated with liver failure
TIPS is a rescue treatment
63 patients with variceal hemorrhage
Childs-Pugh score of 7 – 13 (B or C)
All received endoscopic and pharmacologic Rx
Randomized to standard care or early TIPS
Standard Care
Rebleeding (1 year) 45%
Death (1 year) %
Early TIPS
Rebleeding (1 year) 3%
Death (1 year) %
Garcia-Pagan NEJM 2010

59. Stress Ulcer Prophylaxis
Pathophysiology
Ischemia (Curling’s ulcers)
↑Acid (Cushing’s ulcers)
Cook NEJM 1994, Cook CCM 1999, Lin 2010, and others

60. Stress Ulcer Prophylaxis
Pathophysiology
Ischemia (Curling’s ulcers)
↑Acid (Cushing’s ulcers)
Risk factors
Mechanical ventilation
Coagulopathy
Renal failure
Burns, Trauma, Transplant
Cook NEJM 1994, Cook CCM 1999, Lin 2010, and others

61. Stress Ulcer Prophylaxis
Pathophysiology
Ischemia (Curling’s ulcers)
↑Acid (Cushing’s ulcers)
Risk factors
Mechanical ventilation
Coagulopathy
Renal failure
Burns, Trauma, Transplant Rx
PPI ≥ H2RA
Cook NEJM 1994, Cook CCM 1999, Lin 2010, and others

62. Prevention of late re-bleeding
Peptic Ulcer
Test for h pylori
- C13 breath test, bx
- confirm eradication
Long term antisecretory Rx
Gisbert (Cochrane) 2004, Ding WJG 2009, and others

63. Prevention of late re-bleeding
Variceal hemorrhage
Eradicate varices
- Elective band ligation
Beta blockers
Gisbert (Cochrane) 2004, Ding WJG 2009, and others