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
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
Affiliations
John Norrie
Usher Institute, Edinburgh Clinical Trials Unit, University of Edinburgh No. 9, Bioquarter, Edinburgh, UK
Stephen Morris
Primary Care Unit, University of Cambridge, Cambridge, UK
Daniel Francis McAuley
Centre for Experimental Medicine, Queen`s University Belfast, Belfast, UK
Bronagh Blackwood
Wellcome-Wolfson Institute for Experimental Medicine, Queen`s University Belfast, Belfast, UK
Paul Dark
Intensive Care Unit, University of Manchester, Greater Manchester, UK
Matt P Wise
Department of Adult Critical Care, University Hospital of Wales, Cardiff, UK
Anthony C Gordon
Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, UK
Kalliopi Kydonaki
Edinburgh Napier University, Edinburgh, UK
Timothy Simon Walsh
The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK
David Hope
NHS Lothian, Edinburgh, UK
Christopher Weir
Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh, Edinburgh, UK
Gavin Perkins
Clinical Trials Unit, University of Warwick, Birmingham, UK
Nazir I Lone
The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK
Benedict Creagh-Brown
Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK
Julia Boyd
Edinburgh Clinical Trials Unit, The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK
Michael Reade
University of Queensland, Brisbane, Queensland, Australia
Richard Anthony Parker
Edinburgh Clinical Trials Unit, University of Edinburgh, Edinburgh, UK
Leanne M Aitken
City University of London, London, UK
Valerie J Page
Intensive Care, West Hertfordshire Hospitals NHS Trust, Watford, UK
Alasdair MacLullich
Geriatric Medicine Unit, University of Edinburgh, Edinburgh, UK
Cathrine A McKenzie
University of Southampton, Southampton, UK
Alix Macdonald
The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK
Annabel Giddings
The University of Edinburgh Usher Institute of Population Health Sciences and Informatics, Edinburgh, 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 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.
