Considerable effort and resources have been devoted to preserving life in patients with severe closed traumatic brain injury (TBI). We sought to identify temporal trends in mortality rates of these patients from the late 1800s to the present. We searched the literature for articles on severe TBI, abstracting numbers of patients studied, numbers of deaths, and years of patient entry. Mortality rates were calculated for each study, and meta-regression was used to pool data and to test for significant temporal trends. We reviewed 207 case series comprising more than 140,000 cases of severe closed TBI admitted to hospital over a span of almost 150 years. Since the late 1800s mortality has fallen by almost 50%. However, the rate has varied considerably among the four epochs chosen. Between 1885 and 1930, mortality decreased at a rate of 3% per decade. From 1970 to 1990, mortality declined at a rate of 9% per decade. Both changes are significant. There was no observed improvement in mortality between 1930 and 1970, nor is progress evident since 1990. The authors discuss possible reasons for the apparently intermittent progress in TBI survival over time.

Aggressive ICP monitoring and treatment of patients with severe TBI is associated with a statistically significant improvement in outcome. This improvement occurs independently of temporal effects.

Delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality for patients surviving the rupture of an intracranial aneurysm. Despite an association between vasospasm and DCI, thrombosis and thromboembolism may also contribute to DCI. In this study we investigate the time course of intravascular microclot formation after experimental subarachnoid hemorrhage (SAH) and assess the effects of the following two drugs on microclot burden: mutant thrombin-activated urokinase-type plasminogen activator (scFv/uPA-T), which is bound to red blood cells for use as a thromboprophylactic agent, and clazosentan, an endothelin antagonist. In the first study, adult male C57BL/6 mice were sacrificed at 24 (n=5), 48 (n=6), 72 (n=8), and 96 (n=3) hours after SAH induced by filament perforation of the anterior cerebral artery. Sham animals (n=5) underwent filament insertion without puncture. In the second study, animals received scFv/uPA-T (n=5) 3 hours after hemorrhage, clazosentan (n=5) by bolus and subcutaneous pump after SAH just prior to skin closure, or a combination of scFv/uPA-T and clazosentan (n=4). Control (n=6) and sham (n=5) animals received saline alone. All animals were sacrificed at 48 hours and underwent intra-cardiac perfusion with 4% paraformaldehyde. The brains were then extracted and sliced coronally on a cryostat and processed for immunohistochemistry. An antibody recognizing thrombin–anti-thrombin complexes was used to detect microclots on coronal slices. Microclot burden was calculated for each animal and compared among groups. Following SAH, positive anti-thrombin staining was detected bilaterally in the following brain regions, in order of decreasing frequency: cortex; hippocampus; hypothalamus; basal ganglia. Few microclots were found in the shams. Microclot burden peaked at 48 hours and then decreased gradually. Animals receiving scFv/uPA-T and scFv/uPA-T+clazosentan had a lower microclot burden than controls, whereas animals receiving clazosentan alone had a higher microclot burden (p<0.005). The overall mortality rate in the time course study was 40%; mortality was highest among control animals in the second study. Intravascular microclots form in a delayed fashion after experimental SAH. Microclots may be safely reduced using a novel form of thromboprophylaxis provided by RBC-targeted scFv/uPA-T and represent a potential target for therapeutic intervention in the treatment of DCI.

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