Propofol

Grand Rounds August 15, 2025: Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients: The A2B Randomized Clinical Trial – Addressing a Complex Clinical Question With Novel Integrated Methodological Approaches (Tim Walsh, MD, FFICM; Chris Weir, PhD; Richard Parker, MsC)

Posted on by terren.green@duke.edu

Speakers

Professor Tim Walsh, MD, FFICM
Chair of Critical Care, Usher Institute, University of Edinburgh

Professor Chris Weir, PhD
Chair of medical statistics, Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh

Richard Parker MSc, Research Fellow
Edinburgh Clinical Trials Unit, Usher Institute, University of Edinburgh

Keywords

Dexmedetomidine; Clonidine; Propofol; Sedation; Critical care; Mechanical ventilation.

Key Points

  • Critically ill, mechanically ventilated patients often require sedation for comfort. Avoiding deep sedation, agitation, and delirium is a priority in these patients. To accomplish this, current usual care for sedation internationally is the GABAergic agent propofol along with an opioid or other analgesia, but the alpha-2 agonists Dexmedetomidine or Clonidine are increasingly being used in the ICU.
  • Dexmedetomidine is licensed for ICU sedation and is believed to achieve a lighter level of sedation compared with propofol, but has a higher cost and, some studies have shown, a potentially higher rate of mortality in younger ICU patients. Clonidine, despite widespread use in the UK, is not licensed for ICU sedation and has a limited evidence base but is lower in cost.
  • This 3-arm, A2B pragmatic open-label effectiveness trial compared dexmedetomidine plus an opioid analgesic or clonidine plus an opioid analgesic with propofol plus an opioid analgesic in 1404 critically ill, mechanically ventilated patients (457 dexmedetomidine, 476 clonidine, 471 standard care [propofol]) in 41 ICUs across the UK from December 2018-December 2024.
  • The trial’s primary outcome was time to successful extubation post-randomization, and secondary outcomes included sedation quality, time to optimum sedation, delirium, ICU mortality, ICU length of stay, and drug related adverse events. Hypothesis for clonidine and dexmedetomidine were determined through 2 separate 3-stage pathways.
  • There were no significant differences found in either dexmedetomidine or clonidine compared with propofol (sHR 1.09, 95% CR 0.96 to 1.25, P =0.20; sHR 1.05, 95% CR 0.95 to 1.17, P=0.34; respectively) for the cumulative incidence of time to extubation. There were also no statistically significant differences in the percent of patients successfully extubated within 7 days, patient survival time to ICU mortality, outcome by age, SOFA score, or PRE-DELIRIC risk score. Unlike previous studies, no interaction was found between age and mortality in this study.
  • Rates of agitation were higher in the dexmedetomidine and clonidine groups, but rates of pain behavior, unnecessary deep sedation, and overall optimum sedation did not reach statistically significant differences compared with the propofol group. There were higher rates of severe bradycardia and cardiac arrythmia in the dexmedetomidine arm.
  • Interviews with clinical and research staff showed that multiple factors influence sedation practice within the trial context including context-specific sedation ‘culture’; clinician preference and equipoise; staff capacity, training, and capability; safety concerns; and engrained practices such as more deeply sedating patients overnight.

Discussion Themes

The latest European Society of Intensive Care Medicine guidelines, which don’t include the data from this trial, leave the decision to use dexmedetomidine or propofol up to clinician judgement. Trial data don’t support using clonidine widely, but if used, ICU staff should be confident with and have support for any adverse effects.

While delirium is associated with a range of outcomes like mortality and cost of care, no trial has shown that altering delirium translates into a benefit on those outcomes. A primary outcome of mortality would have needed a large number of participants, making the trial much more difficult to accomplish. For this reason, time to successful extubation was chosen as the primary outcome for this trial.

This A2B trial was not a blinded trial. Blinded drug trials have their place but are not really feasible pragmatic real-world trials. In addition, the cost of blinding this A2B trial would have been very high. Also, patients had strong views that they wanted the clinicians to know what drug they were delivering so they would be prepared to handle any adverse events.

Read more about the protocol and results of this A2B randomized clinical trial of sedation in clinically ill patients.