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