1. Hepatic Encephalopathy protocol - EMB review
Presented by R4 劉政忠
Supervised by MA 錢凱平 醫師
Moderator MA 陳日昌 部長

5. Question 1
The indication of brain CT in p’t suspect HE

6. Hepatic Encephalopathy
(Review)
Med Clin N Am 92 (2008) 795–812
Santiago J. Munoz, MD

7. Hepatic encephalopathy (Review)
The neurologic examination in HE demonstrates non-localizing signs of diffuse neuropsychologic dysfunction, as in other metabolic encephalopathies
17.4% of HE episodes exhibited focal neurologic signs
Hepatic encephalopathy (Review)
Med Clin N Am 92 (2008) 795–812
Santiago J. Munoz, MD

8. Hepatic encephalopathy (Review)
Focal neurologic signs or seizures
appropriate brain imaging
Head CT or MRI is important to exclude structural lesions as causes of an abnormal mental status
Hepatic encephalopathy (Review)
Med Clin N Am 92 (2008) 795–812
Santiago J. Munoz, MD

9. A CT scan is recommended to exclude structural abnormalities in patients with
focal neurologic signs
severe encephalopathy
lack of precipitating factors
not recover after adequate treatment
Schiff's Diseases of the Liver 10th ed. 2006

10. 2009 UpToDate
A CT scan of the brain is indicated in every patient with overt HE if clinical findings suggest that another cause
The CT scan can demonstrate the presence of generalized or localized cerebral edema

11. Question 2
Is lactulose the most effective pharmacologic therapy for patients with hepatic encephalopathy at present ?

12. The Cochrane Database of Systematic Reviews
Nonabsorbable disaccharides for hepatic encephalopathy
The Cochrane Library
2008, Issue 4
Author(s): Als-Nielsen B, Gluud LL, Gluud C

13. The Cochrane Database of Systematic Reviews
Objectives
To assess the beneficial and harmful effects of nonabsorbable disaccharides (lactulose or lactitol) for patients with hepatic encephalopathy
The Cochrane Database of Systematic Reviews
Nonabsorbable disaccharides for hepatic encephalopathy
The Cochrane Library 2008, Issue 4

14. The Cochrane Database of Systematic Reviews
Methods-1
Types of studies:
All randomised trials
Types of participants:
Patients diagnosed as having hepatic encephalopathy in connection with acute or chronic liver disease or fulminant hepatic failure
Types of intervention
Lactulose or lactitol  no intervention or placebo
Lactulose or lactitol  antibiotics.
Lactulose  lactitol
The Cochrane Database of Systematic Reviews
Nonabsorbable disaccharides for hepatic encephalopathy
The Cochrane Library 2008, Issue 4

15. The Cochrane Database of Systematic Reviews
Methods-2
Types of outcome measures:
Primary outcomes
Number of patients with no improvement
All-cause mortality
Secondary outcomes
Number and type of adverse events
Quality of life
Cost-effectiveness
Plasma ammonia concentrations
The Cochrane Database of Systematic Reviews
Nonabsorbable disaccharides for hepatic encephalopathy
The Cochrane Library 2008, Issue 4

16. Results

17. Nonabsorbable disaccharides  no intervention or placebo
Mortality
no statistically significant effect (RR 0.41, 95%CI 0.02 to 8.68, four trials)
The risk of no improvement
Reduce the risk (RR 0.62, 95% CI 0.46 to 0.84, six trials)
Blood ammonia
↓ an average of 13.9 μg/dl (95%CI to 0.3, four trials)
The Cochrane Database of Systematic Reviews
Nonabsorbable disaccharides for hepatic encephalopathy
The Cochrane Library 2008, Issue 4

18. Nonabsorbable disaccharides  Antibiotics
Mortality
no statistically significant difference (RR 0.90, 95% CI 0.48 to 1.67, five trials)
The risk of no improvement
Significantly higher risk no improvement (RR 1.24, 95% CI 1.02 to 1.50, 10 trials)
Blood ammonia
Higher concentration at the end of treatment
Adverse event
no statistically significant difference (RR 1.62, 95% CI 0.57 to 4.58, eight trials)
The Cochrane Database of Systematic Reviews
Nonabsorbable disaccharides for hepatic encephalopathy
The Cochrane Library 2008, Issue 4

19. The Cochrane Database of Systematic Reviews
Lactulose  Lacitol
no statistically significant difference on mortality (two trials) or risk of no improvement (four trials)
The Cochrane Database of Systematic Reviews
Nonabsorbable disaccharides for hepatic encephalopathy
The Cochrane Library 2008, Issue 4

20. The Cochrane Database of Systematic Reviews
Conclusions
Questions the beneficial effects of nonabsorbable disaccharides
There is insufficient high-quality evidence to support this treatment (nonabsorbable disaccharides)
Antibiotics appeared to be superior to nonabsorbable disaccharides in improving hepatic encephalopathy
The Cochrane Database of Systematic Reviews
Nonabsorbable disaccharides for hepatic encephalopathy
The Cochrane Library 2008, Issue 4

21. 2009 UpToDate treatment of HE
Identification and correction of precipitating causes
Measures to lower the blood ammonia concentration

22. Drug therapy for lower blood ammonia
Initiating drug therapy with lactulose or lactitol (Grade 2C)
While a well-performed, placebo-controlled study has not been performed
extensive clinical experience supporting its efficacy

23. Question 3
Alternative pharmacologic treatment

24. Poorly absorbed antibiotics are often used as adjunctive therapies
Neomycin
Metronidazole
More recently, rifaximin has been very effective without the known side effects of neomycin or metronidazole
Harrison's Principles of Internal Medicine 16th ed. 2005

25. Rifaximin
Oral antibiotic
Tx for traveler’s diarrhea and HE

26. Rifaximin  nonabsorbable disaccharides
Rifaximin was effective in improving behavioral, laboratory, mental status, and intellectual abnormalities associated with HE
Rifaximin  nonabsorbable disaccharides
Some studies demonstrated superior and more rapid improvement in S/S
less hospitalization, shorter duration of hospitalization, and lower hospital charges
Adverse effects
minor GI complaints
Rifaximin for the treatment of hepatic encephalopathy
Pharmacotherapy Aug;28(8):
Lawrence KR, Klee JA

27. Well-designed studies are needed in the future
Rifaximin was at least equally effective as and in some studies superior to nonabsorbable disaccharides in relieving S/S
Well-designed studies are needed in the future
Rifaximin for the treatment of hepatic encephalopathy
Pharmacotherapy Aug;28(8):
Lawrence KR, Klee JA

28. Rifaximin has demonstrated better efficacy and safety profiles compared with lactulose and neomycin
no randomized, placebo-controlled studies have assessed the efficacy and long-term safety outcomes
Rifaximin for the treatment of hepatic encephalopathy
Am J Health Syst Pharm May 1;65(9):818-22

29. 2009 UpToDate
Second-line therapy with non-absorbed antibiotics (not improved within 48hrs)
Neomycin (Grade 2C)
Rifaximin

30. Back to our protocol Brain CT Lactulose Neomycin Rifaximin
目前沒有一個客觀的標準 or guideline (ex. GCS)
Seizure
Focal neurologic sign
Clinically suspect structure brain lesion
Lactulose
仍是首選治療藥物 (雖然evidence不夠強)
Neomycin
2nd choice
Clinically no improved after lactulose
Can not tolerate to lactulose
Rifaximin
本院無此藥
未來性??

31. Thanks for your attention!!