The secondary outcome measured was patient disposition.
We defined DCI as an acute decline in neurologic status documented by a decrease in glasgow coma scale of at least 2 points, depressed level of consciousness or new focal neurologic sign lasting at least 1 hour, and not explained by other disease processes such as hydrocephalus, electrolyte abnormalities or infection, that was concomitant with evidence of vasospasm by cerebral angiography or transcranial doppler. The primary outcomes of interest were the development of DCI and mortality. Development of delayed cerebral ischemia (DCI) was also determined using patient records including clinical notes, laboratory data, and imaging studies. Hunt Hess grade, modified fisher score and aneurysm location were collected from the admission history and physical and based on first CT scan or angiogram. To determine if increased 14, 15-EET plays a protective role against the development of vasospasm after SAH, we subjected mice with genetic deletion of sEH, which has higher 14, 15-EET, to experimental SAH and found that these mice were protected from the decrease in microvascular perfusion after SAH compared to WT mice.īaseline demographic and physiologic data were collected from electronic medical records. Patients with the highest levels of both eicosanoids were more likely to go on to experience DCI. Along with the already documented increase in 20-HETE we also found that 14, 15-EET is elevated in SAH patients compared to non-hemorrhage controls. To investigate if 14, 15-EET is altered after SAH in humans, we sampled the CSF in a cohort of SAH patients at high risk for DCI, whose neurologic status on admission necessitated the placement of an external ventricular drain. Levels of 14, 15-EET in brain are regulated by their synthesis via cytochrome P450 epoxygenases in endothelium and astrocytes, and their metabolism primarily by the enzyme soluble epoxide hydrolase (sEH). Namely, 14, 15-epoxyeicosatrienoic acids (14, 15-EET) has been shown to preferentially dilate cerebral microvessels and act as a neuroprotectant in models of cerebral ischemia.
It is not known if other P450 eicosanoids with vasodilator properties play a potentially opposing role in SAH. These lipid effector molecules were first implicated in DCI with the discovery of elevated CSF levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in human SAH patients and in animal models of SAH. Ĭytochrome P450 eicosanoids are produced by microvascular endothelium and astrocytes. While large vessel vasospasm has been largely attributed to alterations in endothelin-1 and nitric oxide signaling, less is understood about microvascular vasospasm despite its significant contribution to DCI. Different vasoactive molecular mediators exert varying levels of influence on vessel tone along the branches of the vascular tree. These constrictions occur at several places along the vascular tree, from large conduit arteries, which are easily detectable by angiography, down to the smallest penetrating arterioles detectable only by perfusion computed tomography. The best characterized pathological feature associated with DCI is severe constriction of cerebral arteries, or vasospasm, which leads to hypoperfusion and ischemia in dependent brain regions. There are few known risk factors, no reliable predictive test, and few preventative treatments for the development of DCI. Current monitoring and treatment strategies require prolonged intensive care unit stays, at high institutional and patient cost. DCI occurs in 30% of survivors, usually between 3 and 14 days after the initial hemorrhage. An estimated 33,000 patients suffer from aneurysmal subarachnoid hemorrhage (SAH) in the US annually, which has a mortality rate of 20–40% and a very high rate of disability among survivors, primarily attributed to delayed cerebral ischemia (DCI).
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