Alpha2-adrenergic receptor agonists didn't get critically ill patients off the ventilator quicker than propofol in the head-to-head A2B trial.
Median time from randomization to successful extubation came in at 136 hours for dexmedetomidine and 146 hours for clonidine -- neither significantly faster than propofol, which came in at 162 hours (P=0.20 and 0.34, respectively).
Nor was there better sedation quality or less delirium over 180 days with the two alpha2-adrenergic receptor agonists, reported Timothy S. Walsh, MD, of the Royal Infirmary of Edinburgh in Scotland, at the American Thoracic Society annual meeting in San Francisco. Results were simultaneously published in JAMA.
The findings should be reassuring for clinicians, suggesting that they should use their best judgment regarding the available choices, argued Edward T. Qian, MD, MSc, and Todd W. Rice, MD, MSc, both of Vanderbilt University Medical Center in Nashville, Tennessee.
"For example, clinicians may favor propofol if they desire deeper sedation or alpha2-adrenergic receptor agonists if they prefer lighter sedation," Qian and Rice wrote in an accompanying editorial. "Bradycardia might result in avoidance of alpha2-adrenergic receptor agonist-based sedation. If enteral sedation is desired, clonidine appears to be a reasonable option, especially if trying to avoid using benzodiazepines and antipsychotics."
"Ultimately," they concluded, "the search for the single best sedative agent may be a hopeless endeavor because critically ill patients might benefit from a dynamic sedation strategy that prioritizes different agents at different phases of a patient's critical illness."
The pragmatic trial included 1,404 adults (mean age 59.2 years, 64% male, mean APACHE II score 20.3) at 41 intensive care units in the U.K. The trial ran from December 2018 through October 2023 with a 6-month pause during the COVID-19 pandemic.
Enrollment was within 48 hours (median 21.0) of starting mechanical ventilation that was expected to continue for at least 48 hours for patients receiving propofol plus an opioid for sedation and analgesia at baseline.
Participants were randomly assigned open-label to one of the three sedatives targeting a Richmond Agitation-Sedation Scale score of −2 to 1, unless clinicians requested deeper sedation. The algorithm allowed supplemental use of propofol as needed, which the dexmedetomidine and clonidine groups got on more than 75% of mechanical ventilation days, albeit at lower doses than the propofol group, the editorialists noted.
Subgroup analyses showed no interactions of time to successful extubation with age, sepsis status, median Sequential Organ Failure Assessment score, or median delirium risk score.
Among the secondary outcomes, both alpha2-adrenergic receptor agonists showed 54-55% greater risk of agitation than with propofol, both statistically significant differences. Both also had higher rates of bradycardia greater than 50 bpm (RR 1.62 with dexmedetomidine, 95% CI 1.36-1.93, and RR 1.58 with clonidine, 95% CI 1.33-1.88).
Mortality at 180 days was similar across groups, as was the proportion of patients receiving mechanical ventilation 7 days after randomization.
Limitations of the trial included its unblinded design, "which might introduce post-randomization differences in care among the groups because many clinicians would not likely feel comfortable extubating with a continuous infusion of propofol (which causes respiratory depression) but may extubate while the patient is receiving continuous or intermittent alpha2-adrenergic receptor agonists," the editorialists noted.
They also pointed to lack of clearly defined post-extubation respiratory support protocols, that spontaneous breaths while receiving noninvasive ventilation were not considered "successful extubation," and lack of clarity on whether the guideline-recommended practice of extubating to noninvasive ventilation was applied similarly across all sedative groups.
Another complicating factor was nonexclusive use of sedation agents, Qian and Rice noted: "This adjunctive use of propofol is pragmatic in that this is how a sedation strategy prioritizing alpha2-adrenergic receptor agonists might need to be implemented in clinical care, especially when patients require deeper levels of sedation. However, one of the ways that alpha2-adrenergic receptor agonists may decrease the time to successful extubation is by allowing lighter sedation. Unfortunately, multiple secondary measures (including the Richmond Agitation-Sedation Scale and time to first day without any unnecessary deep sedation) were similar among the three groups, suggesting that patients in this study may have experienced deeper than intended levels of sedation."
Disclosures
This study was supported by the National Institute for Health and Care Research.
Walsh disclosed no relationships with industry.
Qian and Rice reported that they practice at an institution that has designed, coordinated, and participated in the clinical trials of sedation cited in their editorial. Rice also reported relationships with Cumberland Pharmaceuticals, Cytovale, and Sanofi as well as grants paid to his institution from the U.S. Department of Defense and CDC.
Primary Source
JAMA
Source Reference: Walsh TS, et al "Dexmedetomidine- or clonidine-based sedation compared with propofol in critically ill patients: The A2B randomized clinical trial" JAMA 2025; DOI: 10.1001/jama.2025.7200.
Secondary Source
JAMA
Source Reference: Qian ET, Rice TW "The search for the single best sedative" JAMA 2025; DOI: 10.1001/jama.2025.7359.
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.