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

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

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

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

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

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

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

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

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

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

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

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

Results

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 -28.0 to 0.3, four trials) The Cochrane Database of Systematic Reviews Nonabsorbable disaccharides for hepatic encephalopathy The Cochrane Library 2008, Issue 4

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

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

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

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

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

Question 3 Alternative pharmacologic treatment

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

Rifaximin Oral antibiotic Tx for traveler’s diarrhea and HE

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. 2008 Aug;28(8):1019-32. Lawrence KR, Klee JA

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. 2008 Aug;28(8):1019-32. Lawrence KR, Klee JA

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. 2008 May 1;65(9):818-22

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

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??

Thanks for your attention!!