{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:35:38Z","timestamp":1781667338180,"version":"3.54.5"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,4,13]],"date-time":"2014-04-13T00:00:00Z","timestamp":1397347200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"funder":[{"DOI":"10.13039\/501100000317","name":"Action Medical Research","doi-asserted-by":"publisher","award":["SP4553"],"award-info":[{"award-number":["SP4553"]}],"id":[{"id":"10.13039\/501100000317","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Acta Anaesthesiol Scand"],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The highly selective \u03b1<jats:sub>2<\/jats:sub>\u2010adrenoreceptor agonist, dexmedetomidine, exerts neuroprotective, analgesic, anti\u2010inflammatory and sympatholytic properties that may be beneficial for perinatal asphyxia. The optimal safe dose for pre\u2010clinical newborn neuroprotection studies is unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Following cerebral hypoxia\u2010ischaemia, dexmedetomidine was administered to nine newborn piglets in a de\u2010escalation dose study in combination with hypothermia (whole body cooling to 33.5\u00b0C). Dexmedetomidine was administered with a loading dose of 1\u2009\u03bcg\/kg and maintenance infusion at doses from 10 to 0.6\u2009\u03bcg\/kg\/h. One additional piglet was not subjected to hypoxia\u2010ischaemia. Blood for pharmacokinetic analysis was sampled pre\u2010insult and frequently post\u2010insult. A one\u2010compartment linear disposition model was used to fit data. Population parameter estimates were obtained using non\u2010linear mixed effects modelling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>All dexmedetomidine infusion regimens led to plasma concentrations above those associated with sedation in neonates and children (0.4\u20130.8\u2009\u03bcg\/l). Seven out of the nine piglets with hypoxia\u2010ischaemia experienced periods of bradycardia, hypotension, hypertension and cardiac arrest; all haemodynamic adverse events occurred in piglets with plasma concentrations greater than 1\u2009\u03bcg\/l. Dexmedetomidine clearance was 0.126\u2009l\/kg\/h [coefficient of variation (<jats:styled-content style=\"fixed-case\">CV<\/jats:styled-content>) 46.6.%] and volume of distribution was 3.37\u2009l\/kg (<jats:styled-content style=\"fixed-case\">CV<\/jats:styled-content> 191%). Dexmedetomidine clearance was reduced by 32.7% at a temperature of 33.5\u00b0C. Dexmedetomidine clearance was reduced by 55.8% following hypoxia\u2010ischaemia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Dexmedetomidine clearance was reduced almost tenfold compared with adult values in the newborn piglet following hypoxic\u2010ischaemic brain injury and subsequent therapeutic hypothermia. Reduced clearance was related to cumulative effects of both hypothermia and exposure to hypoxia. High plasma levels of dexmedetomidine were associated with major cardiovascular complications.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aas.12318","type":"journal-article","created":{"date-parts":[[2014,4,14]],"date-time":"2014-04-14T02:06:46Z","timestamp":1397441206000},"page":"733-742","source":"Crossref","is-referenced-by-count":44,"title":["Pharmacokinetics of dexmedetomidine combined with therapeutic hypothermia in a piglet asphyxia model"],"prefix":"10.1111","volume":"58","author":[{"given":"M.","family":"EZZATI","sequence":"first","affiliation":[{"name":"Institute for Women's Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"BROAD","sequence":"additional","affiliation":[{"name":"Institute for Women's Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"KAWANO","sequence":"additional","affiliation":[{"name":"Institute for Women's Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"FAULKNER","sequence":"additional","affiliation":[{"name":"Institute for Women's Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"HASSELL","sequence":"additional","affiliation":[{"name":"Institute for Women's Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"FLEISS","sequence":"additional","affiliation":[{"name":"Centre for the Developing Brain Kings College St Thomas' Campus  London UK"},{"name":"Inserm, U676  Paris France"},{"name":"University Paris Diderot Sorbonne Paris Cite UMRS 676  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"GRESSENS","sequence":"additional","affiliation":[{"name":"Centre for the Developing Brain Kings College St Thomas' Campus  London UK"},{"name":"Inserm, U676  Paris France"},{"name":"University Paris Diderot Sorbonne Paris Cite UMRS 676  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I.","family":"FIERENS","sequence":"additional","affiliation":[{"name":"Institute for Women's Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"ROSTAMI","sequence":"additional","affiliation":[{"name":"Institute for Women's Health University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"MAZE","sequence":"additional","affiliation":[{"name":"Department of Anesthetics and Perioperative Care University of California San Francisco  San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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