Benzodiazepine receptor antagonists for hepatic encephalopathy

  • Review
  • Intervention

Authors

  • Bodil Als-Nielsen,

    Corresponding author
    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Cochrane Hepato-Biliary Group, Copenhagen, Denmark
    • Bodil Als-Nielsen, Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Dept. 3344, Blegdamsvej 9, Copenhagen, DK-2100, Denmark. bodil.als@dadlnet.dk.

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  • Lise Lotte Gluud,

    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Cochrane Hepato-Biliary Group, Copenhagen, Denmark
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  • Christian Gluud

    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Cochrane Hepato-Biliary Group, Copenhagen, Denmark
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Abstract

Background

Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.

Objectives

To evaluate the beneficial and harmful effects of benzodiazepine receptor antagonists for patients with hepatic encephalopathy.

Search methods

Eligible trials were identified through The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE and EMBASE (last search: January 2004), reference lists of relevant articles, authors of trials, and pharmaceutical companies.

Selection criteria

Randomised trials comparing any benzodiazepine receptor antagonist versus placebo or no intervention for hepatic encephalopathy.

Data collection and analysis

Two reviewers independently included trials and extracted data. Binary outcomes are reported as risk difference (RD) with 95% confidence intervals (CI) based on a random effects model. Statistical heterogeneity was explored by a chi-squared test with significance set at P < 0.1. The inconsistency across trials was assessed by I2. Potential sources of heterogeneity were explored through subgroup analyses.

Main results

Thirteen randomised trials with 805 patients were included. Eight trials used a crossover design. All trials were double-blind and assessed flumazenil versus placebo. Data on all outcomes could not be extracted from all trials. The included patients had a favourable prognosis (361/390 [93%] survived in the flumazenil group versus 345/376 [92%] in the placebo group). Flumazenil had a significant beneficial effect on improvement of hepatic encephalopathy at the end of treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials). Flumazenil had no significant effect on recovery (RD 0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD 0.01; 95% CI -0.05 to 0.07, 10 trials). Flumazenil may be associated with adverse events, but trial results were heterogeneous.

Authors' conclusions

Flumazenil had a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis and a highly favourable prognosis. Flumazenil had no significant effect on recovery or survival. Considering the fluctuating nature of hepatic encephalopathy, future trials should use a parallel design and assess if treatment with flumazenil leads to a sustained improvement or increased recovery and survival. Until this has been demonstrated, flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.

摘要

背景

Benzodiazepine接受器拮抗劑治療肝性腦病變

肝性腦病變可能與連結大腦受體複合體的物質聚集抑制神經有關。Benzodiazepine接受器拮抗劑可能有助於肝性腦病變的病人。

目標

評估Benzodiazepine接受器拮抗劑對肝性腦病變病人的利弊

搜尋策略

經由Cochrane HepatoBiliary Group Controlled Trials Register、Cochrane Library的Cochrane Controlled Trials Register 、MEDLINE和EMBASE (最近一次搜索: 2004年1月),相關文章的參考文獻清單、試驗作者和製藥公司,找出符合資格的試驗。

選擇標準

針對肝性腦病變,Benzodiazepine接受器拮抗劑和安慰劑或無處置比較的隨機試驗。

資料收集與分析

兩位作者獨立收錄試驗和提取資料。根據隨機效應模型,二分法結果以風險差異(risk difference,RD)與其95%信賴區間(CI)呈現。統計學意義異質性以卡方檢驗探究,顯著性設定為P < 0.1。 試驗間不一致性以I2評估。潛在異質性的來源經由亞組分析來評估。

主要結論

共收納13項隨機試驗,共805位病人參與。8項試驗使用交叉設計。所有試驗採取雙盲法,評估Flumazenil相對安慰劑的結果。無法從所有試驗中擷取到所有結果的資料。參與試驗的病人中Flumazenil組的病人存活預後良好 (361/390 [93%],相對於安慰劑組的病人是345/376 [92%])。治療結束時,Flumazenil可顯著改善肝性腦病變(RD 0.28; 95% CI 0.20 – 0.37, 8項試驗)。Flumazenil對於痊癒(RD 0.13; 95% CI −0.09 0.36, 2項試驗)或死亡率(RD 0.01; 95% CI −0.05 – 0.07, 10項試驗)沒有顯著影響。 Flumazenil可能造成不良事件,但是各試驗的結果卻各不相同。

作者結論

Flumazenil對短期顯著改善肝硬化病人的肝性腦病變與高度良好的預後。Flumazenil對於痊癒或存活率沒有顯著效果。考慮到肝性腦病變波動性的特性,未來的試驗應使用平行設計來評估Flumazenil是否能持續改善或增加痊癒與存活率。直到本回顧提出為止,Flumazenil或許可以考慮用於治療慢性肝病和肝性腦病變的病人,但無法建議常規臨床使用。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

Flumazenil可短期改善慢性肝病病人的肝性腦病變。肝性腦病變是指精神狀態變化,肝衰竭病人表現從輕度腦功能變化跡象到深度昏迷。肝性腦病變可能因大腦中的受體複合體被啟動所造成。Flumazenil透過抑制此受體複合體來改善症狀。本回顧發現Flumazenil可以短期改善有某些慢性肝病病人的肝性腦病變並有高度良好預後。

Plain language summary

Flumazenil causes short-term improvement of hepatic encephalopathy in patients with chronic liver disease

Hepatic encephalopathy refers to changes in mental state, ranging from minor signs of altered brain function to deep coma occurring in patients with liver failure. Hepatic encephalopathy may be caused by an activation of a receptor-complex in the brain. Flumazenil, which inhibits this receptor-complex, might ameliorate the symptoms. This review found that flumazenil leads to a short-term improvement of hepatic encephalopathy in some patients with chronic liver disease and a highly favourable prognosis.

Laički sažetak

Flumazenil uzrokuje kratkotrajno poboljšanje hepatičke encefalopatije u pacijenata s kroničnom bolesti jetre

Hepatička encefalopatija naziv je za promjene mentalnog stanja, u rasponu od manjih znakova promijenjene funkcije mozga do duboke kome, koje se javljaju u pacijenata sa zatajenjem jetre. Hepatička encefalopatija bi mogla biti uzrokovana aktivacijom receptorskog kompleksa u mozgu. Lijek flumazenil koji blokira (inhibira) taj receptorski kompleks bi možda mogao poboljšati simptome. Ovim Cochrane sustavnim pregledom literature utvrđeno je da flumazenil dovodi do kratkotrajnog poboljšanja hepatičke encefalopatije u nekih pacijenata s kroničnim zatajenjem jetre i jako povoljnom prognozom.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

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