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Ten ultra\u2010elite apnoeists (six\u00a0men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end\u2010apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri\u2010iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 \u00b1 62\u00a0s during hypoxaemic hypercapnia to 959 \u00b1 201\u00a0s in hyperoxaemic hypercapnia (<jats:italic>P<\/jats:italic>\u00a0\u2264 0.001). Apnoea generally increased global cerebral blood flow (all <jats:italic>P<\/jats:italic>\u00a0\u2264 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.015\u20130.044). This was associated with a general net cerebral output (v &gt; a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.046 <jats:italic>vs<\/jats:italic>. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a &gt; v) and global cerebral blood flow (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.034 to &lt;0.001 <jats:italic>vs<\/jats:italic>. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative\u2013nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with <jats:italic>S<\/jats:italic>\u2010nitrosohaemoglobin consumption and plasma <jats:italic>S<\/jats:italic>\u2010nitrosothiol delivery during apnoea (all <jats:italic>P<\/jats:italic>\u00a0\u2265 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative\u2013nitrosative stress.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15928-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Local sampling of blood across the cerebral circulation in ultra\u2010elite apnoeists determined the extent to which severe end\u2010apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical\u2010mediated nitric oxide bioavailability and global cerebral bioenergetic function.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative\u2013nitrosative stress.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The apnoea\u2010induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Cerebral oxidative\u2013nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea\u2010induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp285555","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T09:27:31Z","timestamp":1707816451000},"page":"5659-5684","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Severe hypoxaemic hypercapnia compounds cerebral oxidative\u2013nitrosative stress during extreme apnoea: Implications for cerebral bioenergetic function"],"prefix":"10.1113","volume":"602","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0498-7095","authenticated-orcid":false,"given":"Damian M.","family":"Bailey","sequence":"first","affiliation":[{"name":"Neurovascular Research Laboratory, Faculty of Life Sciences and Education University of South Wales  Glamorgan 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