Alpha2 agonists for sedation to produce better outcomes for adults with critical illness: a synopsis of the A2B RCT with cost-effectiveness and process evaluation

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Parts of this abstract have been reproduced with permission from Walsh TS, Parker RA, Aitken LM, McKenzie CA, Emerson L, Boyd J, et al .; A2B Trial Investigators. Dexmedetomidine- or clonidine-based sedation compared with propofol in critically ill patients: the A2B randomized clinical trial. JAMA 2025; 334 :32–45. https://doi.org/10.1001/jama.2025.7200. Copyright © 2025, American Medical Association. All rights reserved, including those for text and datamining, AI training, and similar technologies. Background Most mechanically ventilated intensive care unit patients require sedation and analgesia for comfort. Current usual care is propofol-based sedation plus an opioid analgesic. The alpha2 agonists dexmedetomidine and clonidine are potential alternative sedatives, but their clinical and cost-effectiveness are uncertain. Objective(s) To evaluate the clinical and cost-effectiveness and safety of alpha2 agonists (dexmedetomidine and clonidine) compared with propofol for sedating adult intensive care unit patients. Design and methods Pragmatic open-label three-arm trial. Embedded process and economic evaluation. Setting and participants Forty-one intensive care units in the UK. Recruitment from December 2018 to October 2023. Participants were 1437 adults within 48 hours of starting mechanical ventilation expected to require ≥ 48 hours of mechanical ventilation [analysis population: propofol ( N = 471), dexmedetomidine ( N = 457), and clonidine-based ( N = 476) sedation]. Median time from intubation to randomisation was 21.0 (first, third quartile: 13.2, 31.3) hours. Interventions In all groups, bedside algorithms targeted a Richmond Agitation Sedation Scale of −2 to + 1 unless clinicians requested deeper sedation. Intervention groups’ algorithms supported alpha2-agonist up-titration and propofol down-titration followed by sedation primarily with allocated alpha2 agonist. Supplemental propofol was permitted if required. Outcomes Primary outcome was time to successful extubation, analysed allowing for death as a competing risk. Secondary outcomes included mortality, sedation quality, rates of delirium and cardiovascular adverse events. Long-term outcomes included: experience of intensive care unit care; anxiety, depression and post-traumatic stress; cognitive function; health-related quality of life. Results Mean (standard deviation) patient age was 59.2 (14.9) years; 901 (65%) male. The sub-distribution hazard ratio for time to successful extubation for dexmedetomidine versus propofol was 1.09 (95% confidence interval 0.96 to 1.25; p = 0.20) and for clonidine versus propofol was 1.05 (0.95 to 1.17; p = 0.34), with hazard ratio > 1 favouring alpha2 agonist. Median (95% confidence interval) hours from randomisation to successful extubation was: propofol 162 (136 to 170); dexmedetomidine 136 (117 to 150); and clonidine 146 (124 to 168). There was no effect interaction with age, sepsis status, median Sequential Organ Failure Assessment Score, or median Prediction of Delirium in intensive care unit patients' delirium risk score. Delirium rates were similar, but agitation occurred at higher rate than propofol with both alpha2 agonists [dexmedetomidine vs. propofol risk ratio (95% confidence intervals) 1.54 (1.21 to 1.97); clonidine vs. propofol 1.55 (1.22 to 1.97)]. Rates of severe bradycardia (rate < 50/minute) were higher with both alpha2 agonists compared with propofol [dexmedetomidine vs. propofol rate ratio (95% confidence interval) 1.62 (1.36 to 1.93); clonidine vs. propofol 1.58 (1.33 to 1.88)]. Mortality was similar over 180 days follow-up [dexmedetomidine vs. propofol hazard ratio (95% confidence interval) 0.98 (0.77 to 1.24); clonidine vs. propofol 1.04 (0.82 to 1.31)]. Process evaluation indicated a range of contextual factors at intensive care unit and individual level that influenced intervention delivery, including: intensive care unit culture, prior clinician opinions/beliefs, staffing pressures (exacerbated by the COVID-19 pandemic), clinician experience and concerns about alpha2-agonist side effects. There was no difference in cost-effectiveness between the groups. Limitations This was a pragmatic unblinded trial, with associated risk of performance and ascertainment bias. Future work Future trials should explore the effectiveness of alpha2 agonists as sedatives in other populations, for example paediatric critical care and acute brain injury. Conclusions In mechanically ventilated critically ill patients, neither dexmedetomidine- nor clonidine-based sedation was superior for major clinical outcomes or more cost-effective compared with propofol-based sedation. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/93/01.

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