Critically ill patients requiring invasive mechanical ventilation often need continuous sedation for pain and anxiety. Propofol, a GABA potentiator, and Dexmedetomidine, an α2-adrenergic receptor agonist, are commonly used sedatives in intensive care units, though finding the single best agent has been debated for decades. Propofol can provide deep sedation but is associated with hypotension and, in high or prolonged doses, the potentially fatal Propofol-related Infusion Syndrome (PRIS), characterized by metabolic acidosis, cardiac dysfunction, hyperlipidemia, and rhabdomyolysis, with mortality estimates up to 37%.

Dexmedetomidine typically provides less deep sedation and often requires additional agents for profound levels. Its use is linked to hypotension and bradycardia, which is often dose-limiting. Clonidine, another α2 agonist with an enteral/oral route, is also considered for sedation minimization.

Current best practice emphasizes minimizing and regularly interrupting sedation to achieve the least effective dose. Previous trials comparing dexmedetomidine and propofol found that while dexmedetomidine led to more arousable and cooperative patients, major clinical outcomes like mortality, ventilator-free days, and delirium/coma-free days were similar between the two agents.

The A2B trial, reported by Walsh and colleagues in JAMA, is a multicenter, open-label, 3-group randomized clinical trial comparing Dexmedetomidine-based or Clonidine-based sedation against Propofol-based sedation in critically ill adults on invasive mechanical ventilation expected to continue for at least 48 hours. Clinicians in the α2 agonist groups were permitted to use adjunctive propofol if necessary despite reaching maximum α2 agonist doses or due to dose-limiting side effects.

While guidance was provided, clinical teams retained discretion over specific sedation targets, dose, duration, mechanical ventilation weaning, and extubation timing, enhancing the study’s generalizability. The investigators hypothesized that α2 agonist-based sedation would reduce the time from randomization to successful extubation (defined as remaining ventilator-free for 48 hours post-extubation). Secondary outcomes included 180-day mortality, delirium, and bradycardia.

The trial enrolled over 1400 patients across 41 UK ICUs from late 2018 to late 2023.

Patient characteristics were well-balanced at baseline, with sepsis being a common admission diagnosis. Despite most patients initially receiving propofol and opiates, very few had prior exposure to dexmedetomidine or clonidine before enrollment.

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