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
Introduction 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 out...
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BMJ Publishing Group
2023-12-01
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| author | John Norrie Stephen Morris Daniel Francis McAuley Bronagh Blackwood Paul Dark Matt P Wise Anthony C Gordon Kalliopi Kydonaki Timothy Simon Walsh David Hope Christopher Weir Gavin Perkins Nazir I Lone Benedict Creagh-Brown Julia Boyd Michael Reade Richard Anthony Parker Leanne M Aitken Valerie J Page Alasdair MacLullich Cathrine A McKenzie Alix Macdonald Annabel Giddings Lydia Emerson Robert Glen |
| author_facet | John Norrie Stephen Morris Daniel Francis McAuley Bronagh Blackwood Paul Dark Matt P Wise Anthony C Gordon Kalliopi Kydonaki Timothy Simon Walsh David Hope Christopher Weir Gavin Perkins Nazir I Lone Benedict Creagh-Brown Julia Boyd Michael Reade Richard Anthony Parker Leanne M Aitken Valerie J Page Alasdair MacLullich Cathrine A McKenzie Alix Macdonald Annabel Giddings Lydia Emerson Robert Glen |
| author_sort | John Norrie |
| collection | DOAJ |
| description | Introduction 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.Methods and analysis 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 −2 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.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 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40–50 UK ICUs.Ethics and dissemination 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.Trial registration number ClinicalTrials.gov NCT03653832. |
| format | Article |
| id | doaj-art-ca882e250b3f4906a633eda573496be4 |
| institution | OA Journals |
| issn | 2044-6055 |
| language | English |
| publishDate | 2023-12-01 |
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| spelling | doaj-art-ca882e250b3f4906a633eda573496be42025-08-20T01:47:34ZengBMJ Publishing GroupBMJ Open2044-60552023-12-01131210.1136/bmjopen-2023-078645Alpha 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 UKJohn Norrie0Stephen Morris1Daniel Francis McAuley2Bronagh Blackwood3Paul Dark4Matt P Wise5Anthony C Gordon6Kalliopi Kydonaki7Timothy Simon Walsh8David Hope9Christopher Weir10Gavin Perkins11Nazir I Lone12Benedict Creagh-Brown13Julia Boyd14Michael Reade15Richard Anthony Parker16Leanne M Aitken17Valerie J Page18Alasdair MacLullich19Cathrine A McKenzie20Alix Macdonald21Annabel Giddings22Lydia Emerson23Robert Glen24Usher Institute, Edinburgh Clinical Trials Unit, University of Edinburgh No. 9, Bioquarter, Edinburgh, UKPrimary Care Unit, University of Cambridge, Cambridge, UKWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Sciences, Queen`s University Belfast, Belfast, UKWellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, UKIntensive Care Unit, University of Manchester, Greater Manchester, UKDepartment of Adult Critical Care, University Hospital of Wales, Cardiff, UKSection of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, UKDepartment of Nursing, Midwifery & Social Care, Edinburgh Napier University, Edinburgh, UKThe University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UKsenior lecturer in medical educationEdinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UKClinical Trials Unit, University of Warwick, Birmingham, UKDepartment of Anaesthesia, Critical Care and Pain Medicine, Usher Institute, University of Edinburgh, Edinburgh, UKDeptartment of Critical Care, Royal Surrey NHS Foundation Trust, Guildford, UKEdinburgh Clinical Trials Unit, The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UKDepartment of Intensive Care Medicine, Royal Brisbane and Women`s Hospital, Brisbane, Queensland, Australia4 Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UKSchool of Health & Psychological Sciences, City, University of London, London, UKIntensive Care, West Hertfordshire Hospitals NHS Trust, Watford, UK1University of Edinburgh, Edinburgh, UKDepartment of Pharmacy and Critical Care, University Hospital Southampton NHS Foundation Trust, Southampton, UKThe University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UKThe University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UKCity University of London, London, UKNHS Lothian, Edinburgh, UKIntroduction 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.Methods and analysis 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 −2 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.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 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40–50 UK ICUs.Ethics and dissemination 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.Trial registration number ClinicalTrials.gov NCT03653832.https://bmjopen.bmj.com/content/13/12/e078645.full |
| spellingShingle | John Norrie Stephen Morris Daniel Francis McAuley Bronagh Blackwood Paul Dark Matt P Wise Anthony C Gordon Kalliopi Kydonaki Timothy Simon Walsh David Hope Christopher Weir Gavin Perkins Nazir I Lone Benedict Creagh-Brown Julia Boyd Michael Reade Richard Anthony Parker Leanne M Aitken Valerie J Page Alasdair MacLullich Cathrine A McKenzie Alix Macdonald Annabel Giddings Lydia Emerson Robert Glen 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 BMJ Open |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://bmjopen.bmj.com/content/13/12/e078645.full |
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