{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:55:24Z","timestamp":1789088124812,"version":"build-2803163510"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["437644"],"award-info":[{"award-number":["437644"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2021,8,20]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>Secondary brain hypoxia portends significant mortality in ischemic brain diseases; yet, our understanding of hypoxic ischemic brain injury (HIBI) pathophysiology in humans remains rudimentary.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>To quantify the impact of secondary brain hypoxia on injury to the neurovascular unit in patients with HIBI.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              We conducted a prospective interventional study of invasive neuromonitoring in 18 post\u2013cardiac arrest patients with HIBI. The partial pressures of brain tissue O\n              <jats:sub>2<\/jats:sub>\n              (PbtO\n              <jats:sub>2<\/jats:sub>\n              ) and intracranial pressure were directly measured via intraparenchymal microcatheters. To isolate the cerebrovascular bed, we conducted paired sampling of arterial and jugular venous bulb blood and calculated the transcerebral release of biomarkers of neurovascular injury and inflammation in the patients with HIBI and 14 healthy volunteers for control comparisons. Ten patients with HIBI exhibited secondary brain hypoxia (PbtO\n              <jats:sub>2<\/jats:sub>\n              &lt;20 mmHg), while 8 exhibited brain normoxia (PbtO\n              <jats:sub>2<\/jats:sub>\n              \u226520 mmHg). In the patients with secondary brain hypoxia, we observed active cerebral release of glial fibrillary acidic protein (\u2212161 [\u22123695 to \u221275] pg\/mL;\n              <jats:italic>P<\/jats:italic>\n              =0.0078), neurofilament light chain (\u2212231 [\u2212370 to \u221211] pg\/mL;\n              <jats:italic>P<\/jats:italic>\n              =0.010), total tau (\u221232 [\u2212310 to \u22123] pg\/mL;\n              <jats:italic>P<\/jats:italic>\n              =0.0039), neuron-specific enolase (\u221214\u2009890 [\u2212148\u2009813 to \u22123311] pg\/mL;\n              <jats:italic>P<\/jats:italic>\n              =0.0039), and ubiquitin carboxy-terminal hydrolase L1 (\u221214.7 [\u221237.7 to \u22124.1] pg\/mL;\n              <jats:italic>P<\/jats:italic>\n              =0.0059) indicating de novo neuroglial injury. This injury was unrelated to the systemic global ischemic burden or cerebral endothelial injury but rather was associated with cerebral release of IL-6 (interleukin-6; \u221210.3 [\u221243.0 to \u22124.2] pg\/mL;\n              <jats:italic>P<\/jats:italic>\n              =0.0039). No cerebral release of the aforementioned biomarkers was observed in patients with HIBI with brain normoxia or the healthy volunteers. Hyperosmolar therapy in the patients with secondary brain hypoxia reduced the partial pressure of jugular venous O\n              <jats:sub>2<\/jats:sub>\n              -to-PbtO\n              <jats:sub>2<\/jats:sub>\n              gradient (39.6 [34.1\u201351.1] versus 32.0 [24.5\u201339.2] mm\u2009Hg;\n              <jats:italic>P<\/jats:italic>\n              =0.0078) and increased PbtO\n              <jats:sub>2<\/jats:sub>\n              (17.0 [9.1\u201319.7] versus 20.2 [11.9\u201322.7] mm\u2009Hg;\n              <jats:italic>P<\/jats:italic>\n              =0.039) suggesting improved cerebrovascular-to-parenchymal O\n              <jats:sub>2<\/jats:sub>\n              transport.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Secondary brain hypoxia is associated with de novo neuroglial injury and cerebral release of IL-6. Mitigating cerebrovascular-to-parenchymal limitations to O\n              <jats:sub>2<\/jats:sub>\n              transport is a promising therapeutic strategy for patients with HIBI with secondary brain hypoxia.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Registration:<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT03609333.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.121.319157","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T13:33:10Z","timestamp":1626874390000},"page":"583-597","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":85,"title":["Brain Hypoxia Is Associated With Neuroglial Injury in Humans Post\u2013Cardiac Arrest"],"prefix":"10.1161","volume":"129","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-0059","authenticated-orcid":true,"given":"Ryan L.","family":"Hoiland","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Pharmacology and Therapeutics, Vancouver General Hospital (R.L.H., D.E.G.), University of British Columbia, Vancouver, Canada."},{"name":"Department of Cellular and Physiological Sciences, Faculty of Medicine (R.L.H.), University of British Columbia, Vancouver, Canada."},{"name":"Centre for Heart, Lung, and Vascular Health, School of Health and Exercise Sciences, Faculty of Health and Social Development (R.L.H., P.N.A.), University of British Columbia, Vancouver, Canada."},{"name":"International Collaboration on Repair Discoveries, Vancouver, BC, Canada (R.L.H., C.L.W., J.C., S.S., V.H.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip N.","family":"Ainslie","sequence":"additional","affiliation":[{"name":"Centre for Heart, Lung, and Vascular Health, School of Health and Exercise Sciences, Faculty of Health and Social Development (R.L.H., P.N.A.), University of British Columbia, Vancouver, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl L.","family":"Wellington","sequence":"additional","affiliation":[{"name":"Djavad Mowafaghian Centre for Brain Health, Department of Pathology and Laboratory Medicine, Faculty of Medicine (C.L.W., J.C., S.S.), University of British Columbia, Vancouver, Canada."},{"name":"School of Biomedical Engineering (C.L.W.), University of British Columbia, Vancouver, Canada."},{"name":"International Collaboration on Repair Discoveries, Vancouver, BC, Canada (R.L.H., C.L.W., J.C., S.S., V.H.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cooper","sequence":"additional","affiliation":[{"name":"Djavad Mowafaghian Centre for Brain Health, Department of Pathology and Laboratory Medicine, Faculty of Medicine (C.L.W., J.C., S.S.), University of British Columbia, Vancouver, Canada."},{"name":"International Collaboration on Repair Discoveries, Vancouver, BC, Canada (R.L.H., C.L.W., J.C., S.S., V.H.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Stukas","sequence":"additional","affiliation":[{"name":"Djavad Mowafaghian Centre for Brain Health, Department of Pathology and Laboratory Medicine, Faculty of Medicine (C.L.W., J.C., S.S.), University of British Columbia, Vancouver, Canada."},{"name":"International Collaboration on Repair Discoveries, Vancouver, BC, Canada (R.L.H., C.L.W., J.C., S.S., V.H.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonny","family":"Thiara","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, Department of Medicine, Vancouver General Hospital (S.T., D.F., N.A.F., D.E.G., M.S.S.), University of British Columbia, Vancouver, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Foster","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, Department of Medicine, Vancouver General Hospital (S.T., D.F., N.A.F., D.E.G., M.S.S.), University of British Columbia, Vancouver, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A.","family":"Fergusson","sequence":"additional","affiliation":[{"name":"Division of Critical Care Medicine, Department of Medicine, Vancouver General Hospital (S.T., D.F., N.A.F., D.E.G., M.S.S.), University of British Columbia, Vancouver, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M.","family":"Conway","sequence":"additional","affiliation":[{"name":"Centre for Blood Research, Life Sciences Institute, University of British Columbia (E.M.C.), University of British Columbia, Vancouver, Canada."},{"name":"Division of Hematology, 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