{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:06:07Z","timestamp":1773421567419,"version":"3.50.1"},"reference-count":64,"publisher":"Wiley","issue":"23","license":[{"start":{"date-parts":[[2014,10,18]],"date-time":"2014-10-18T00:00:00Z","timestamp":1413590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Vasovagal syncope (a common form of fainting) is frequently associated with excessive breathing and leads to reductions in carbon dioxide (hypocapnia) and cerebral hypoperfusion. The prevention of hypocapnia during orthostatic stress has been shown to improve orthostatic tolerance, but it still remains to be quantified in a larger population, with a more sustained orthostatic stress.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Resting brain blood flow has been shown to impact orthostatic tolerance; however, the importance of resting brain blood flow <jats:italic>per se<\/jats:italic> in the pathophysiology of vasovagal syncope has not been clearly explicated.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our findings show that cerebral hypoperfusion either at rest or induced by hypocapnia at pre\u2010syncope do not impact on orthostatic tolerance, probably due to a compensatory increase in oxygen extraction of the brain.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>We examined two novel hypotheses: (1) that orthostatic tolerance (OT) would be prolonged when hyperventilatory\u2010induced hypocapnia (and hence cerebral hypoperfusion) was prevented; and (2) that pharmacological reductions in cerebral blood flow (CBF) at baseline would lower the \u2018CBF reserve\u2019, and ultimately reduce OT. In study 1 (<jats:italic>n<\/jats:italic>\u00a0=\u00a024; aged 25\u00a0\u00b1\u00a04\u00a0years) participants underwent progressive lower\u2010body negative pressure (LBNP) until pre\u2010syncope; end\u2010tidal carbon dioxide (<jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tjp6360-math-0001.png\" xlink:title=\"urn:x-wiley:00223751:tjp6360:equation:tjp6360-math-0001\"\/>) was clamped at baseline levels (isocapnic trial) or uncontrolled. In study 2 (<jats:italic>n<\/jats:italic>\u00a0=\u00a010; aged 25\u00a0\u00b1\u00a04\u00a0years), CBF was pharmacologically reduced by administration of indomethacin (INDO; 1.2 mg\u00a0kg<jats:sup>\u22121<\/jats:sup>) or unaltered (placebo) followed by LBNP to pre\u2010syncope. Beat\u2010by\u2010beat measurements of middle cerebral artery blood flow velocity (MCAv; transcranial Doppler), heart rate (ECG), blood pressure (BP; Finometer) and end\u2010tidal gases were obtained continuously. In a subset of subjects\u2019 arterial\u2010to\u2010jugular venous differences were obtained to examine the independent impact of hypocapnia or cerebral hypoperfusion (following INDO) on cerebral oxygen delivery and extraction. In study 1, during the isocapnic trial, <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tjp6360-math-0002.png\" xlink:title=\"urn:x-wiley:00223751:tjp6360:equation:tjp6360-math-0002\"\/> was successfully clamped at baseline levels at pre\u2010syncope (38.3\u00a0\u00b1\u00a02.7 <jats:italic>vs<\/jats:italic>. 38.5\u00a0\u00b1\u00a02.5\u00a0mmHg respectively; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.50). In the uncontrolled trial, <jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tjp6360-math-0003.png\" xlink:title=\"urn:x-wiley:00223751:tjp6360:equation:tjp6360-math-0003\"\/> at pre\u2010syncope was reduced by 10.9\u00a0\u00b1\u00a03.9\u00a0mmHg (<jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.001). Compared to the isocapnic trial, the decline in mean MCAv was 15\u00a0\u00b1\u00a04\u00a0cm\u00a0s<jats:sup>\u22121<\/jats:sup> (35%; <jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.001) greater in the uncontrolled trial, yet the time to pre\u2010syncope was comparable between trials (544\u00a0\u00b1\u00a0130 <jats:italic>vs<\/jats:italic>. 572\u00a0\u00b1\u00a0180\u00a0s; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.30). In study 2, compared to placebo, INDO reduced resting MCAv by 19\u00a0\u00b1\u00a04\u00a0cm\u00a0s<jats:sup>\u22121<\/jats:sup> (31%; <jats:italic>P<\/jats:italic>\u00a0\u2264\u00a00.001), but time to pre\u2010syncope remained similar between trials (placebo: 1123\u00a0\u00b1\u00a0138\u00a0s <jats:italic>vs<\/jats:italic>. INDO: 1175\u00a0\u00b1\u00a0212\u00a0s; <jats:italic>P<\/jats:italic>\u00a0=\u00a00.53). The brain extracted more oxygen in face of hypocapnia (34% to 53%) or cerebral hypoperfusion (34% to 57%) to compensate for reductions in delivery. In summary, cerebral hypoperfusion either at rest or induced by hypocapnia at pre\u2010syncope does not impact OT, probably due to a compensatory increase in oxygen extraction.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jphysiol.2014.280586","type":"journal-article","created":{"date-parts":[[2014,9,13]],"date-time":"2014-09-13T03:26:00Z","timestamp":1410578760000},"page":"5203-5219","source":"Crossref","is-referenced-by-count":42,"title":["Impact of hypocapnia and cerebral perfusion on orthostatic tolerance"],"prefix":"10.1113","volume":"592","author":[{"given":"Nia C. S.","family":"Lewis","sequence":"first","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health University of British Columbia, Okanagan  Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony R.","family":"Bain","sequence":"additional","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health University of British Columbia, Okanagan  Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David B.","family":"MacLeod","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Duke University Medical Center  Durham NC USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin W.","family":"Wildfong","sequence":"additional","affiliation":[{"name":"Centre for Heart, Lung and Vascular Health University of British Columbia, Okanagan  Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kurt J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Centre for Heart, 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