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.

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.

Object. Despite being common practice for decades and being recommended by national guidelines, aggressive monitoring and treatment of patients with severe traumatic brain injury (TBI) have not been supported by convincing evidence. Methods. The authors reviewed trials and case series reported after 1970 in which patients were treated for severe closed TBI, and mortality rates and favorable outcomes at 6 months after injury were analyzed. The patient groups were divided into those with and without intracranial pressure (ICP) monitoring and intensive therapy, and the authors performed a meta-analysis to assess the effects of treatment intensity on outcome. Results. Although the mortality rate fell during the years reviewed, it was consistently similar to 12% lower among patients in the intense treatment group (p < 0.001). Favorable outcomes did not change significantly over time, and were 6% higher among the aggressively treated patients (p = 0.0105). Conclusions. 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. (DOI: 10.3171/2009.8.JNS09738)

BACKGROUND: Recent reports have documented a wide range of outcomes after treatment of severe traumatic brain injury at trauma centers throughout the world.METHODS: In an effort to test the contribution of geography to treatment outcome, we compared case series published from 1975 to 2009. Trauma centers were divided into those from the United States, other developed countries, and the developing world. We pooled data on mortality rates using meta-analytic techniques, and corrected for temporal trends and other covariates using meta-regression.RESULTS: Our search yielded 231 case series, totaling more than 121,000 cases. There was a decrease in mortality over time in all three geographic locales. The small advantage the United States had versus other high and moderate income countries tended to decrease over time, whereas low income countries reported significantly greater mortality, and their rates decreased more slowly over time.CONCLUSIONS: Low income countries have the highest mortality rates in treating patients with severe closed traumatic brain injury. The lower intensity of treatment appears to be the largest contributor to the discrepancy, and other possible causes are discussed.

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.

Could voluntary insurance markets exist in developing countries? We used data from the World Health Survey for eleven countries to estimate, at different income levels, variation in total medical spending and spending for hospitals, physicians, and outpatient drugs. The goal was to generate estimates of risk premiums that consumers might pay for insurance coverage and to calculate likely insurance administrative costs. We conclude that insurance covering either hospital spending or total spending is feasible for much of the population, but not insurance for physician services or medicines. Spending varies by income, so insurance markets should be segmented by income.