1. 2010/10/14 Presented by R4 謝岳哲 Supervisor VS 薛承君 Moderator VS 黃集仁
EBM (HE)
2010/10/14
Presented by R4 謝岳哲
Supervisor VS 薛承君
Moderator VS 黃集仁

5. Evidence to be reviewed
The efficacy of lactulose
The role of neomycin
Any new agents for HE?
The role and efficacy of flumazenil in HE

6. Level of evidence

9. Introduction
To access the effects of non-absorbable disaccharides in pts with HE

10. Methods Inclusion: RCTs before Mar 2003 P: patients with HE
I: non-absorbable disaccharides
C: no treatment / placebo
O: mortality, improvement of HE

11. Trial included

12. Outcome

13. Outcome

14. Outcome

15. Outcome

16. Conclusion
No sufficient evidence to determine whether lactulose/lacitol have a benefit effect on pts with HE
Only low quality studies showed significant effect

17. Methods Inclusion: RCTs before Mar 2003 P: patients with HE
I: non-absorbable disaccharides
C: antibiotics
O: mortality, improvement of HE

18. Trial included

19. Outcome

20. Outcome

21. Outcome

22. Outcome

23. Outcome

24. Conclusion Underpowered trials
Abx appeared to be superior to non-absorbable disaccharides in improving HE and lowering blood NH3
Given the placebo controlled trial (Blanc and Struss), risk of resistence, potential severe adverse effect, there is insufficient evidence to recommend antibiotics for HE

26. Introduction
Open-label prospective randomized trial to evaluate the efficacy of rifaximin to lactulose
Rifaximin: derivatives of rifamycin, not absorbed by oral administration, against aerobics, anaerobics, G(+) and G(-) bacteria

27. Methods
Inclusion: DLC and HE, signs of 1st to 3rd degree HE and blood NH3 > 75 μmol/L

28. Methods Exclusion: 64 enrolled and 54 entered the trial Age <18
major neuropsychiatric illness
intestinal obstruction or inflammatory bowel disease
Hypersensitivity to rifamycin or disaccharides
Cr > 2X normal
diuretics, antacids or cathartics within the 12 hour
on antibiotics during the preceding 7 days
64 enrolled and 54 entered the trial

29. Patient characteristics

30. Patient characteristics

31. Methods
Medication:
Randomized to each arm (for 7 days)
Rifaximin 1200mg/day in 3 divided doses
Lactulose 90ml/day
HE index=(grade of mental state) × 3+(grade of number connection test)+(grade of flapping tremor)+(grade of blood ammonia)

32. Outcome

33. Outcome

34. Outcome

35. Outcome Adverse events:
One pt with rifaximin complained of abdominal pain
One pt with lactulose had severe diarrhea
No pt withdraw from the exam

36. Conclusion
Both rifaximin and lactulose were effective in the majority of patients. Blood NH3, flapping tremor, mental status, and NCT was significantly improved by rifaximin and lactulose
The posttreatment levels of these measures were similar for the rifaximin and lactulose-treated groups, as was the HE index
Rifaximin proved to be as safe and as effective as lactulose for the treatment of Korean patients with hepatic encephalopathy.

42. Introduction
Liver failure  accumulation of substance binding to GABA receptor
Flumazenil: antagonizes endogenous BZD-like substances
To exam the beneficial and harmful effect of flumazenil in pts with HE

43. Methods Inclusion: RCTs before Jan 2004 P: Pts with HE I: Flumazenil
C: Placebo
O: Recovery, Improvement, Survival, QOL, adverse events

44. Flumazenil regimen Short term regimen (< 10 mins)
1mg bolus (Klotz 1989; Zhu 1998)
2mg bolus (Lacetti 2000; Pomier 1994)
1mg stat and 0.5mg q30min, total 3mg (Amodio 1997)
0.1mg/min for 10 mins (Cadranel 1995)
Long term regimen (>10 mins)
1mg/hr x 5 hrs (Dursun 2003)
0.4mg0.8mg1mg 1mg/hr x 3 hrs (Gyr 1996)

45. Trial included (I)

46. Trial included (II)

47. Outcome

48. Outcome

49. Outcome

50. Outcome

51. Outcome

52. Outcome

53. Outcome

54. Conclusion
Flumazenil has a significant beneficial effect on short-term improvement of HE
No significant effect on recovery or survival
flumazenil may be considered for pts with chronic liver disease and HE, but cannot be recommended for routine clinical use

56. Flumazenil
At this time, a formal recommendation on the use of these drugs cannot be made on the basis of evidence-based data.
Flumazenil (1 mg bolus i.v.) is indicated for patients with HE and suspected BZD intake.
Although flumazenil has been reported to occasionally cause seizures, such findings have not been described in patients with HE.

57. Consider flumazenil in suspect BZD related HE

58. Thanks for your attention!