{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T03:36:20Z","timestamp":1782963380361,"version":"3.54.5"},"reference-count":29,"publisher":"BMJ","issue":"12","license":[{"start":{"date-parts":[[2023,12,9]],"date-time":"2023-12-09T00:00:00Z","timestamp":1702080000000},"content-version":"unspecified","delay-in-days":8,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000664","name":"Health Technology Assessment Programme","doi-asserted-by":"publisher","award":["HTA 16\/93\/01"],"award-info":[{"award-number":["HTA 16\/93\/01"]}],"id":[{"id":"10.13039\/501100000664","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The NIHR Clinical Research Network","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2023,11,17]]},"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of \u22122 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence\/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.<\/jats:p>\n                    <jats:p>The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either\/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2\u2009days in MV duration, we aim to recruit 1437 patients (479 per group) in 40\u201350 UK ICUs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The Scotland A REC approved the trial (18\/SS\/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.gov\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03653832\">NCT03653832<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2023-078645","type":"journal-article","created":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T11:27:27Z","timestamp":1702207647000},"page":"e078645","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B Trial): protocol for a multicentre phase 3 pragmatic clinical and cost-effectiveness randomised trial in the UK"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct03653832","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03653832","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3590-8540","authenticated-orcid":false,"given":"Timothy Simon","family":"Walsh","sequence":"first","affiliation":[{"name":"The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5722-9090","authenticated-orcid":false,"given":"Leanne M","family":"Aitken","sequence":"additional","affiliation":[{"name":"City University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrine A","family":"McKenzie","sequence":"additional","affiliation":[{"name":"University of Southampton, Southampton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Boyd","sequence":"additional","affiliation":[{"name":"Edinburgh Clinical Trials Unit, The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alix","family":"Macdonald","sequence":"additional","affiliation":[{"name":"The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel","family":"Giddings","sequence":"additional","affiliation":[{"name":"The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hope","sequence":"additional","affiliation":[{"name":"NHS Lothian, Edinburgh, 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