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

Timothy Simon Walsh, Leanne M. Aitken, Cathrine A. McKenzie, Julia Boyd, Alix Macdonald, Annabel Giddings, David Hope, John Norrie, Christopher Weir, Richard Anthony Parker, Nazir I. Lone, Lydia Emerson, Kalliopi Kydonaki, Benedict Creagh-Brown, Stephen Morris, Daniel Francis McAuley, Paul Dark, Matt P. Wise, Anthony C. Gordon, Gavin PerkinsMichael Reade, Bronagh Blackwood, Alasdair MacLullich, Robert Glen, Valerie J. Page

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Abstract

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.

Original languageEnglish
Article numbere078645
Pages (from-to)e078645
Number of pages53
JournalBMJ Open
Volume13
Issue number12
Early online date10 Dec 2023
DOIs
Publication statusPublished - 10 Dec 2023

Keywords

  • Adrenergic alpha-2 Receptor Agonists - therapeutic use
  • Adult
  • Adult intensive & critical care
  • Clinical Trial
  • Clinical Trials, Phase III as Topic
  • Clinical trials
  • Clonidine - therapeutic use
  • Cost-Benefit Analysis
  • Critical Illness - therapy
  • Dexmedetomidine - therapeutic use
  • Humans
  • Hypnotics and Sedatives - therapeutic use
  • Intensive Care Units
  • Multicenter Studies as Topic
  • Pain - chemically induced
  • Propofol - therapeutic use
  • Quality of Life
  • Randomized Controlled Trials as Topic
  • Respiration, Artificial
  • United Kingdom

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