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      The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage

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          Abstract

          The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions.

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          Most cited references147

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          Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor.

          Endothelium-derived vascular relaxing factor (EDRF) is a humoral agent that is released by vascular endothelium and mediates vasodilator responses induced by various substances including acetylcholine and bradykinin. EDRF is very unstable, with a half-life of between 6 and 50 s, and is clearly distinguishable from prostacyclin. The chemical structure of EDRF is unknown but it has been suggested that it is either a hydroperoxy- or free radical-derivative of arachidonic acid or an unstable aldehyde, ketone or lactone. We have examined the role of superoxide anion (O-2) in the inactivation of EDRF released from vascular endothelial cells cultured on microcarrier beads and bioassayed using a cascade of superfused aortic smooth muscle strips. With this system, we have now demonstrated that EDRF is protected from breakdown by superoxide dismutase (SOD) and Cu2+, but not by catalase, and is inactivated by Fe2+. These findings indicate that O-2 contributes significantly to the instability of EDRF.
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            Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage.

            Aneurysmal subarachnoid hemorrhage (aSAH) is a medical emergency characterized by the accumulation of blood in the subarachnoid space surrounding the brain. The acute treatment of aSAH is well documented but less is known about the long-term effects of aSAH on cognition and day-to-day functioning. We reviewed all studies in the past 10 years that have focused on the effects of aSAH on cognition and day-to-day functioning. Sixty-one empirical studies examining cognitive and functional outcome in patients with aSAH met inclusion criteria. Survivors of aSAH commonly experience deficits in memory, executive function, and language. These cognitive impairments interact to affect patients' day-to-day functioning, including activities of daily living, instrumental activities of daily living, return to work, and quality of life. Deficits in cognition and day-to-day functioning are further compounded by depression, anxiety, fatigue, and sleep disturbances. Much remains to be learned about the brain changes underlying cognitive and functional deficits, including the role of diffuse brain damage and secondary complications like vasospasm and elevated intracranial pressure. A consideration of these issues is necessary to obtain a better understanding of how aSAH affects cognition and day-to-day functioning in the long-term.
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              Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2).

              Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality. In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311. In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI -4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (-18%, -45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH. Actelion Pharmaceuticals. Copyright © 2011 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                J Cereb Blood Flow Metab
                J. Cereb. Blood Flow Metab
                Journal of Cerebral Blood Flow & Metabolism
                Nature Publishing Group
                0271-678X
                1559-7016
                December 2013
                25 September 2013
                1 December 2013
                : 33
                : 12
                : 1825-1837
                Affiliations
                [1 ]Department of Neuroradiology, Aarhus University Hospital , Aarhus, Denmark
                [2 ]Center of Functionally Integrative Neuroscience and MINDLab, Aarhus University , Aarhus, Denmark
                [3 ]Hammel Neurorehabilitation Hospital , Hammel, Denmark
                [4 ]Department of Anesthesiology and Critical Care Medicine, Aarhus University Hospital , Aarhus, Denmark
                [5 ]Department of Neurosurgery, Aarhus University Hospital , Aarhus, Denmark
                Author notes
                [* ]Center of Functionally Integrative Neuroscience and MINDLab/Department Neuroradiology, Aarhus University Hospital , Building 10G, 5th Floor, Nørrebrogade 44 DK-8000 Aarhus, Denmark. E-mail: leif@ 123456cfin.dk
                Article
                jcbfm2013173
                10.1038/jcbfm.2013.173
                3851911
                24064495
                7515b3fd-cd68-4ccf-9341-ffe51d8a08f4
                Copyright © 2013 International Society for Cerebral Blood Flow & Metabolism, Inc.

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 22 June 2013
                : 31 August 2013
                : 08 September 2013
                Categories
                Review Article

                Neurosciences
                edema,capillary transit time heterogeneity,subarachnoid hemorrhage,microcirculation,delayed cerebral ischemia,vasospasm

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