Excitatory amino acid inhibitors for traumatic brain injury

 

Abstract

Background

Glutamate is the principal excitatory neurotransmitter in the brain. Injury to the brain can cause an ionic imbalance in cerebral tissue, creating an excitotoxic cascade involving glutamate and other excitatory amino acids, that leads to neuronal death in the tissue surrounding the original injury site. Research has centred around inhibiting this increase in excitatory amino acid during injury either pre- or post-synaptically. Animal studies appeared promising, but as yet, those results have not been repeated in human clinical trials.

Objectives

To assess systematically the efficacy of excitatory amino acid inhibitors on improving patient outcome following traumatic brain injury.

Search methods

Searches of the databases; CENTRAL, MEDLINE, EMBASE, IDdb3, and Science Citation Index were carried out. Searches were also carried out on online clinical trial registers; ClinicalTrials (http://clinicaltrials.gov) and Current Controlled Trials (http://controlled-trials.com/mrct). General Internet searches were carried out using selected terms from the original search strategy and individual drug names. Authors of published works and associated pharmaceutical companies were contacted. Searches were last carried out in January 2003.

Selection criteria

Trials were included if they were randomised, double-blind, controlled trials where excitatory amino acid inhibitors were administered to patients with traumatic brain injury, within 24 hours of sustaining that injury, and compared to a control group.

Data collection and analysis

Twelve trials, involving eight compounds, were identified that appeared to fit the inclusion criteria. Further investigation excluded three of these trials. Two of the remaining trials are ongoing. Of the seven included studies, one trial did not report GOS data and we were unable to acquire them. Three trials have not been published and the data were not made available to us. One trial is currently being prepared for publication, leaving two trials where data were available. Data were extracted by two independent reviewers.

Main results

Data were available for two of the seven relevant trials identified, with 760 recruited participants. Mortality is similar between patients who receive excitatory amino acid inhibitors and those that receive placebo: odds ratio (OR) 1.11; 95% confidence interval (CI) 0.78, 1.60. Patients who have a favourable outcome six months after injury are also similar between treatment and placebo groups: OR 0.86; 95% CI 0.64, 1.16.

Authors' conclusions

The case for efficacy of excitatory amino acid inhibitor therapy remains unproven. To date, no product has proven to be efficacious (as determined by the criteria applied) for improving the outcomes of brain-injured patients. Early termination, unpublished, and underpowered studies limit a clear appreciation of the merits of this form of intervention. Additional studies, some of which remain in progress, may more clearly define the efficacy and effectiveness issues.

 

Plain language summary

There is not enough evidence about the effects of excitatory amino acid inhibiting drugs on traumatic brain injury, but more research is worthwhile

Brain injury can start a cascade of damage to brain tissue. Release into the brain of excess excitatory amino acids is thought to begin this process. Drugs which stop the release of excitatory amino acids or which block them may reduce brain damage. Studies have been done in patients with stroke as well as traumatic brain injury. The review found that the results from most drug trials with brain injured patients have not been published. There is therefore not enough evidence about the effects of excitatory amino acid inhibiting drugs for traumatic brain injury, and more published trials are needed.

 

摘要

背景

興奮性氨基酸抑制劑用於腦外傷

Glutamate是一種腦部主要的興奮性神經傳遞物質。腦部受傷會造成腦部組織內的離子不平衡，製造出具有興奮毒性的glutamate及其他的興奮性氨基酸，其導致原本受傷部位的神經死亡。研究圍繞在抑制受傷期間突觸前或後這種興奮性氨基酸的增加。動物研究似乎是有希望的，但至今，這些結果尚未被重複在人類的臨床試驗中。

目標

系統性地評估興奮性氨基酸抑制劑對於改善腦外傷患者結果的效益。

搜尋策略

線上檢索資料庫：CENTRAL，MEDLINE，EMBASE，IDdb3，以及Science Citation Index。線上檢索臨床試驗登記資料庫。一般的網路線上檢索。聯絡已發表文章的作者及相關的藥廠。

選擇標準

納入隨機，雙盲，對照試驗，其興奮性氨基酸抑制劑給予24小時內持續承受腦外傷的患者，並與對照組比較。

資料收集與分析

辨別到12篇是符合納入標準的試驗，共包含八種化合物。進一步評估後排除其中三篇試驗。其餘兩篇試驗正在進行中。納入研究的七篇試驗中，有一篇沒有報告GOS的資料且我們也無法獲得其資料。三篇試驗尚未發表且我們也無法取得資料。一篇試驗目前正在準備發表，剩下兩篇試驗的資料可以獲得。由兩名獨立的審查者摘錄資料。

主要結論

確定的七篇相關試驗中可取得其中兩篇的資料，共納入760名研究對象。接受興奮性氨基酸抑制劑與那些接受安慰劑的病患間其死亡率相同：odds ratio (OR)為1.11; 95% confidence interval (CI)為0.78至1.60。治療與安慰劑組中病患在受傷後六個月產生有利結果的比率也相同：OR為0.86; 95% CI為0.64至1.16。

作者結論

對於興奮性氨基酸抑制劑療法的效益仍然未能得到證實。至今，沒有化學生成物被證實對於改善腦受傷患者結果是有效益的(如經由實用的標準來確定)。提前終止，未發表，及低檢定力的研究限制了這種形式介入措施其優點的評價。其他一些留待進展的研究也許更清楚地定義這項議題的效益及效果。

翻譯人

本摘要由高雄榮民總醫院金沁琳翻譯。

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

總結

沒有關於興奮性氨基酸抑制藥物對於腦外傷之足夠的證據，但值得進行更多的研究。腦受傷會開始一連串的腦部組織損傷。大腦釋放過多的興奮性氨基酸被認為是這一過程的開始。阻止釋放興奮性氨基酸或破壞他們的藥物也許會減少腦部損傷。已完成中風與腦外傷患者的研究。回顧發現大部分腦外傷患者的藥物實驗結果尚未被發表。因此沒有關於興奮性氨基酸抑制藥物對於腦外傷效果的足夠證據，且需要更多已發表的試驗。