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Brain Trauma Stroke
Table 1: Statin Mechanisms of Action in the
rupture and onset of SAH matched 1:2 to a control cohort of 40 SAH
Central Nervous System
patients who were not previously on statin therapy. The primary outcome
for this study was functional outcome at 14 days post-SAH as measured
Statin Pleiotropic Effects Vasospasm Pathogenesis by Barthel Index and Modified Lawton Physical Self-Maintenance Exam
Improve endothelial function ‚ Endothelial dysfunction
scale scores. Secondary outcomes examined in this study were 14-day
Upregulate endothelial nitric ‚ Reduced nitric oxide and
mortality, Modified Rankin Scale (mRS), DCI, infarction, or elevated mean
oxide synthase (eNOS) eNOS activity
velocity on TCD. The statin cohort had significantly better functional
Inhibit platelet aggregation ‚ Platelet activation
outcomes, decreased DCI and other cerebral infarction, and lower mean
Inhibit vascular smooth-muscle- ‚ Vascular smooth-muscle-cell
cell proliferation proliferation
velocity measured by TCD, indicating a lower incidence of vasospasm.
PKC and RhoK inhibition ‚ PKC and RhoK activation
However, the study also showed that mortality and overall outcome
Anti-inflammatory ‚ Vascular inflammation
(measured by mRS scores) were similar between the groups despite
Free radical scavenger ‚ Superoxide free radical release
improvements in surrogate markers of vasospasm and cerebral ischemia.
Enhanced fibrinolysis ‚ Microthrombi formation
Another study, performed by Singhal et al., examined the effects
PKC = protein kinase C; RhoK = Rho kinase.
of various pre-admission medication exposures on the incidence of
upregulation of endothelial NO synthase and promoting vasodilation.
22
vasospasm.
32
Researchers identified 514 patients who were admitted with
Some studies have also suggested that statins can attenuate leukocyte aneurysmal SAH between 1995 and 2003. Using logistic regression, the
migration to the site of endothelial damage.
30
All of these effects target the authors found that statin use prior to hospitalization was possibly
underlying causes of vasospasm and support the hypothesis and hope associated with increased risk for developing vasospasm (p=0.05). On
that statins may be effective in the prevention and amelioration of review of their data, the authors discovered that all patients who
vasospasm in humans (see Table 1). presented to the hospital on statin had their statin medication stopped
after admission for SAH. They postulate that it is the abrupt cessation of
Animal Studies statin that may be associated with increased risk for vasospasm, and
Animal studies have shown that statins have the potential to reduce cautioned against this practice. However, another retrospective study
vasospasm, DCI, and vasospasm-related infarcts. McGirt et al. showed that conducted by Moskowitz et al. reported a different result:
33
after reviewing
mice pre-treated with statins have decreased incidence of vasospasm and aneurysmal SAH patient files from 1997 to 2004, researchers concluded
better neurological outcome.
31
Mice were administered subcutaneous that prior statin use decreased the incidence of angiographic vasospasm
simvastatin or placebo for 14 days, then underwent right anterior cerebral post-SAH. They also concluded that discontinuation of statin did not
artery perforation or sham surgery. Results showed decreased vasospasm increase incidence of vasospasm, contrary to the Singhal et al. study.
in simvastatin-treated mice versus controls, as shown by a significantly
larger right middle cerebral artery (MCA) diameter. Pre-treated mice also Lastly, Kramer et al. explored empirically the results of a protocol change
had increased cerebral endothelial NO synthase protein and experienced in May 2006 at the University of Virginia Neuroscience ICU where patients
better neurological outcome compared with non-treated mice. This study admitted with SAH were administered simvastatin 80mg/day for two
prompted further investigation because it provided the groundwork by weeks.
5
They conducted a retrospective cohort study of SAH patients
which statins may influence cerebral NO synthesis and therefore play a admitted between November 2004 and February 2007, and compared
role in reducing vasospasm. incidence of vasospasm before and after this new protocol. After a review
of the charts, 150 patients were included in the analysis, with 71 patients
Although their first study proved statin pre-treatment could decrease who had received statin. Primary outcomes included radiographic (by
vasospasm after SAH in mice, pre-treatment in the human model is not CTA) and symptomatic vasospasm, and delayed cerebral infarction. The
feasible as aneurysmal SAH is difficult to predict. McGirt et al. followed results revealed that there was no significant difference in improvement
up with another study to investigate statin treatment after SAH in seen in the statin-treated versus non-treated group.
rabbits in order to better model the human disease.
30
Researchers
injected blood into the cisterna magna of rabbits in order to model a Prospective Human Data
posterior circulation aneurysmal SAH, followed by subcutaneous There are now several small pilot prospective randomized studies of
simvastatin or placebo administration. The results showed that statin use for the prevention of vasospasm after SAH. Tseng et al.
vasospasm, as measured by basilar artery diameter, was decreased in randomized 80 aneurysmal SAH patients in England into a treatment
rabbits treated with simvastatin versus control. The data also revealed group that received oral pravastatin dosed at 40mg/day or a control group
a significant decrease of inflammation in the cerebral blood vessels. that received placebo.
34
Patients began treatment with pravastatin or
placebo within 72 hours of stroke onset and were treated for 14 days. The
Human Data treatment group showed a significant decrease in vasospasm (defined by
Retrospective Human Data TCD criteria) of 32% compared with the control group, and also a 42%
The last several years have provided clinical data regarding the use of decrease of severe vasospasm. The results also showed an 83% decrease
statins in humans to improve outcome after aneurysmal SAH. One of the in DCI. Furthermore, there were no reported risks associated with
first studies, conducted by Parra et al., investigated the effect of prior pravastatin treatment and therefore the study garnered more confidence
statin use on outcome after SAH.
4
This retrospective matched case– in the safety of statin use to prevent vasospasm. A follow-up study was
control study included 20 SAH patients on statins prior to their aneurysm conducted by Tseng et al. to compare the outcomes of those who
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