TY - JOUR

T1 - Dopamine agents for hepatic encephalopathy

AU - Junker, Anders Ellekær

AU - Als-Nielsen, Bodil

AU - Gluud, Christian

AU - Gluud, Lise Lotte

PY - 2014

Y1 - 2014

N2 - BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have therefore been assessed as a potential treatment for patients with hepatic encephalopathy.OBJECTIVES: To evaluate the beneficial and harmful effects of dopamine agents versus placebo or no intervention for patients with hepatic encephalopathy.SEARCH METHODS: Trials were identified through the Cochrane Hepato-Biliary Group Controlled Trials Register (January 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12 of 12, 2013), MEDLINE (1946 to January 2014), EMBASE (1974 to January 2014), and Science Citation Index-Expanded (1900 to January 2014). Manual searches in reference lists, conference proceedings, and online trial registers were also performed.SELECTION CRITERIA: Randomised trials were included, irrespective of publication status or language. The primary analyses included data from randomised trials using a parallel-group design or the first period of cross-over trials. Paired data from cross-over trials were included in sensitivity analyses.DATA COLLECTION AND ANALYSIS: Three review authors extracted data independently. Random-effects meta-analyses were performed as the result of an expected clinical heterogeneity. Fixed-effect meta-analyses, meta-regression analyses, subgroup analyses, and sensitivity analyses were performed to evaluate sources of heterogeneity and bias (systematic errors). Trial sequential analysis was used to control the risk of play of chance (random errors).MAIN RESULTS: Five trials that randomly assigned 144 participants with overt hepatic encephalopathy that were published during 1979 to 1982 were included. Three trials assessed levodopa, and two trials assessed bromocriptine. The mean daily dose was 4 grams for levodopa and 15 grams for bromocriptine. The median duration of treatment was 14 days (range seven to 56 days). None of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy in the primary analyses (15/80 (19%) versus 14/80 (18%); odds ratio (OR) 2.99, 95% confidence interval (CI) 0.09 to 100.55; two trials) or when paired data from cross-over trials were included (OR 1.04, 95% CI 0.75 to 1.43). Clear evidence of intertrial heterogeneity was identified both in the primary analysis (I(2) = 65%) and when paired data from cross-over trials were included (I(2) = 40%).Dopamine agents had no beneficial or harmful effect on mortality (42/144 (29%) versus 38/144 (26%); OR 1.11, 95% CI 0.35 to 3.54; five trials). Trial sequential analyses demonstrated that we lacked information to refute or recommend the interventions for all outcomes. Dopamine agonists did not seem to increase the risk of adverse events.AUTHORS' CONCLUSIONS: This review found no evidence to recommend or refute the use of dopamine agents for hepatic encephalopathy. More randomised placebo-controlled clinical trials without risks of systematic errors and risks of random errors seem necessary to permit firm decisions on dopamine agents for patients with hepatic encephalopathy.

AB - BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have therefore been assessed as a potential treatment for patients with hepatic encephalopathy.OBJECTIVES: To evaluate the beneficial and harmful effects of dopamine agents versus placebo or no intervention for patients with hepatic encephalopathy.SEARCH METHODS: Trials were identified through the Cochrane Hepato-Biliary Group Controlled Trials Register (January 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12 of 12, 2013), MEDLINE (1946 to January 2014), EMBASE (1974 to January 2014), and Science Citation Index-Expanded (1900 to January 2014). Manual searches in reference lists, conference proceedings, and online trial registers were also performed.SELECTION CRITERIA: Randomised trials were included, irrespective of publication status or language. The primary analyses included data from randomised trials using a parallel-group design or the first period of cross-over trials. Paired data from cross-over trials were included in sensitivity analyses.DATA COLLECTION AND ANALYSIS: Three review authors extracted data independently. Random-effects meta-analyses were performed as the result of an expected clinical heterogeneity. Fixed-effect meta-analyses, meta-regression analyses, subgroup analyses, and sensitivity analyses were performed to evaluate sources of heterogeneity and bias (systematic errors). Trial sequential analysis was used to control the risk of play of chance (random errors).MAIN RESULTS: Five trials that randomly assigned 144 participants with overt hepatic encephalopathy that were published during 1979 to 1982 were included. Three trials assessed levodopa, and two trials assessed bromocriptine. The mean daily dose was 4 grams for levodopa and 15 grams for bromocriptine. The median duration of treatment was 14 days (range seven to 56 days). None of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy in the primary analyses (15/80 (19%) versus 14/80 (18%); odds ratio (OR) 2.99, 95% confidence interval (CI) 0.09 to 100.55; two trials) or when paired data from cross-over trials were included (OR 1.04, 95% CI 0.75 to 1.43). Clear evidence of intertrial heterogeneity was identified both in the primary analysis (I(2) = 65%) and when paired data from cross-over trials were included (I(2) = 40%).Dopamine agents had no beneficial or harmful effect on mortality (42/144 (29%) versus 38/144 (26%); OR 1.11, 95% CI 0.35 to 3.54; five trials). Trial sequential analyses demonstrated that we lacked information to refute or recommend the interventions for all outcomes. Dopamine agonists did not seem to increase the risk of adverse events.AUTHORS' CONCLUSIONS: This review found no evidence to recommend or refute the use of dopamine agents for hepatic encephalopathy. More randomised placebo-controlled clinical trials without risks of systematic errors and risks of random errors seem necessary to permit firm decisions on dopamine agents for patients with hepatic encephalopathy.

KW - Bromocriptine

KW - Dopamine Agonists

KW - Hepatic Encephalopathy

KW - Humans

KW - Levodopa

KW - Randomized Controlled Trials as Topic

U2 - 10.1002/14651858.CD003047.pub3

DO - 10.1002/14651858.CD003047.pub3

M3 - Review

C2 - 24515383

VL - 2

SP - 1

EP - 37

JO - Cochrane Database of Systematic Reviews

JF - Cochrane Database of Systematic Reviews

SN - 1361-6137

M1 - CD003047

ER -