Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients: The A2B Randomized Clinical Trial

Abstract

Importance: Whether α2-adrenergic receptor agonist-based sedation, compared with propofol-based sedation, reduces time to extubation in patients receiving mechanical ventilation in the intensive care unit (ICU) is uncertain.

Objective: To evaluate whether dexmedetomidine- or clonidine-based sedation reduces duration of mechanical ventilation compared with propofol-based sedation (usual care).

Design, setting, and participants: Pragmatic, open-label randomized clinical trial conducted at 41 ICUs in the UK including adults who were within 48 hours of starting mechanical ventilation, were receiving propofol plus an opioid for sedation and analgesia, and were expected to require mechanical ventilation for 48 hours or longer. The median time from intubation to randomization was 21.0 (IQR, 13.2-31.3) hours. Recruitment occurred from December 2018 to October 2023; the last follow-up occurred on December 10, 2023.

Interventions: The bedside algorithms used targeted a Richmond Agitation-Sedation Scale score of -2 to 1 (unless clinicians requested deeper sedation). The algorithms supported uptitration in the dexmedetomidine- and clonidine-based sedation intervention groups and supported downtitration for propofol-based sedation followed by sedation primarily with the allocated sedation (dexmedetomidine or clonidine). If required, supplemental use of propofol was permitted.

Main outcomes and measures: The primary outcome was time from randomization to successful extubation. The secondary outcomes included mortality, sedation quality, rates of delirium, and cardiovascular adverse events.

Results: Among the 1404 patients in the analysis population (mean age, 59.2 [SD, 14.9] years; 901 [64%] were male; and the mean APACHE II score was 20.3 [SD, 8.2]), the subdistribution hazard ratio (HR) for time to successful extubation was 1.09 (95% CI, 0.96-1.25; P = .20) for dexmedetomidine (n = 457) vs propofol (n = 471) and was 1.05 (95% CI, 0.95-1.17; P = .34) for clonidine (n = 476) vs propofol (n = 471). The median time from randomization to successful extubation was 136 (95% CI, 117-150) hours for dexmedetomidine, 146 (95% CI, 124-168) hours for clonidine, and 162 (95% CI, 136-170) hours for propofol. In the predefined subgroup analyses, there were no interactions with age, sepsis status, median Sequential Organ Failure Assessment score, or median delirium risk score. Among the secondary outcomes, agitation occurred at a higher rate with dexmedetomidine vs propofol (risk ratio [RR], 1.54 [95% CI, 1.21-1.97]) and with clonidine vs propofol (RR, 1.55 [95% CI, 1.22-1.97]). Compared with propofol, the rates of severe bradycardia (heart rate <50/min) were higher with dexmedetomidine (RR, 1.62 [95% CI, 1.36-1.93]) and clonidine (RR, 1.58 [95% CI, 1.33-1.88]). Compared with propofol, mortality was similar over 180 days for dexmedetomidine (HR, 0.98 [95% CI, 0.77-1.24]) and clonidine (HR, 1.04 [95% CI, 0.82-1.31]).

Conclusions and relevance: In critically ill patients, neither dexmedetomidine nor clonidine was superior to propofol in reducing time to successful extubation.

Trial registration: ClinicalTrials.gov Identifier: NCT03653832.

Figure 1.. Flow Diagram for Screening, Randomization, and Follow-Up in the Study

ICU indicates intensive care unit. ^aOne patient in the clonidine-based sedation group was randomized twice in error. ^bThere were 307 patients with an unknown reason, 81 were incarcerated individuals, 66 had an untreated heart block, 57 had Guillain-Barre syndrome, 49 were previously enrolled in the trial, 41 had myasthenia gravis, 36 were pregnant, 32 were receiving ventilation assistance at home, and 4 had an allergy to an interventional medicinal product. ^cThere were 574 patients with an unspecified reason, 27 needed an interpreter, 7 died prior to randomization, and 4 were not able to be randomized because the randomization system was unavailable. ^dThe primary outcome was time from randomization to successful extubation (defined as extubation followed by 48 hours of spontaneous breathing without mechanical ventilation). ^eData were omitted for 14 patients due to a serious breach at single study site, 7 did not have valid consent recorded, 7 withdrew consent for use of their data, 4 were randomized in error, and 1 was withdrawn by their next of kin.

Figure 2.. Cumulative Incidence Plot for Time From Randomization to Successful Extubation

The median duration of follow-up was 4.7 days (IQR, 2.0-9.8 days) for dexmedetomidine; 4.9 days (IQR, 2.0-10.8 days) for clonidine; and 5.0 days (IQR, 2.2-11.2 days) for propofol. There were initially 456 patients at risk in the dexmedetomidine group rather than 457 because information on ultimate extubation status was not available for 1 patient (eAppendix 15 in Supplement 2).

Figure 3.. Box-and-Whisker Plots Showing the Highest Richmond Agitation-Sedation Scale (RASS) Scores Achieved

Includes patients who have not yet achieved the primary outcome. Each box represents the IQR; the bottom and top of the boxes are the first and third quartiles, respectively, with the median shown as a horizontal line inside each box. The whiskers extend to the minimum and maximum values within 1.5 times the IQR from the quartiles. Any values outside the whiskers are represented by circles to identify them as potential outliers. Unless deep sedation was requested by medical staff, bedside algorithms indicated a target RASS score of −2 to 1; score range, −5 (unresponsive) to 4 (combative).

Figure 4.. Predefined Subgroup Analyses

PRE-DELIRIC indicates prediction of delirium in intensive care unit (ICU) patients; SOFA, Sequential Organ Failure Assessment. ^aComprises 10 risk factors for delirium (available within 24 hours of ICU admission). The score provides an estimated percentage of risk (range, 0%-100%); 0% to 20% indicates low risk; 20% to 40%, moderate risk; 40% to 60%, high risk; and greater than 60%, very high risk. The median score was 73%. ^bAssesses organ failure for 6 organs. A score of 0 was given for no organ failure and 4 for severe organ failure. The maximum score was 20; higher scores are associated with greater risk of death in the ICU. The median score (excluding neurological score) was 8. The neurological score is often omitted in non–neurological populations receiving sedation.