gms | German Medical Science

Objective: The reduction of secondary brain injury following acute cerebral insults such as ischemic stroke, aneurysmal subarachnoid hemorrhage (aSAH), intracerebral hemorrhage (ICH), traumatic brain injury (TBI) and intracranial infection remains challenging. The effect of exclusive therapeutic targeting of secondary brain injury on outcome across these entities remains unclear. The purpose of this meta-analysis was to analyze the effect of treatment in previous pharmaceutical or interventional trials on sole reduction of secondary brain injury following aforementioned entities.

Method: A systematic review of the Medline database was conducted until April 2014 for all randomized, controlled, blinded clinical trials on ischemic stroke, aSAH, ICH, TBI and intracranial infection using mortality and poor outcome (i.e. score of 3-6 on modified Rankin Scale, 1-3 on Glasgow Outcome Scale or less than or equal to 70% on Barthel Index) as endpoints. Studies targeting primary pathomechanisms (e.g. thrombolysis and recanalization for ischemic stroke or antibiotics for meningitis) or potentially targeting both primary but also potentially secondary brain injury (e.g. surgical evacuation of intracerebral hemorrhage) were excluded. Risk of bias analysis was performed. Effect sizes were analyzed using Review Manager, as supplied by the Cochrane Collaboration and expressed as pooled risk ratio (RR) estimates with 95% confidence intervals (CI).

Results: Out of a total of 3817 studies, ultimately data from 130 studies on a total of 53,393 patients was included in the analysis. In the pooled analysis of all trials on pharmaceutical or interventional reduction of secondary brain injury, there was no significant effect of experimental treatment on mortality for ischemic stroke [RR 1.01 (95% CI: 0.93 - 1.09)], aSAH [RR 0.91 (95% CI: 0.83 - 1.00)], ICH [RR 0.93 (95% CI: 0.82 - 1.04)], TBI [1.01 (95% CI 0.92 - 1.11)] and intracranial infection [RR 0.93 (95% CI 0.84 - 1.04)]. Similar results were obtained when analyzing poor outcome.

Conclusions: Our results underline the strong association of primary brain injury and functional outcome. Additionally, insensitive therapeutic targets or outcome measures as well as other methodological limitations in previous clinical trials might contribute to the apparently marginal treatment effects when attempting to modify secondary brain injury. Improved translational models might provide a better understanding for the implementation of new therapeutic targets in future clinical trials.