Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients
Timothy Walsh, Richard Parker, Leanne M. Aitken, Cathrine McKenzie, Lydia M. Emerson, Julia Boyd, Alix Macdonald, Gayle Beveridge, A E B Giddings, David Hope, S. Rodman Irvine, Sharon Tuck, Nazir Lone, Kalliopi Kydonaki, John Norrie, David Brealey, David Antcliffe, Michael Reay, Alan Williams, Jeremy Bewley, Ben Creagh‐Brown, Daniel F. McAuley, Paul Dark, Matt P. Wise, Anthony Gordon, Gavin D. Perkins, Michael C. Reade, Bronagh Blackwood, Alasdair M. J. MacLullich, Robert Glen, Valérie Page, Christopher J. Weir, Christopher J. Weir, Natalie Pattison, Barry Williams, Louise Rose, Paul Mouncey, John Prowle, David Wellsted, Timothy Walsh, Stephen J. Brett, Tim Walsh, Christoper Weir, John Norrie, Julian Bion, John Norrie, Matt Stevenson, Alistair Nichol, Timothy Walsh, Maria Amamio, Lucy Barclay, Sophie Birch, Kate Briton, Sarah Clark, J. Crossan, Katherine Doverman, Sarah Clark, Lucy MacDonald, Corrienne McCulloch, Nikolas Rae, Scott A. Simpson, Jo Singleton, M Wishart, Ruth Thompson, Jo Singleton, Rachel Fairlie, Ruth Thompson, Neill Aitken, Sarah Ackroyd, Valeria Alicino, Sam Talbot, Thomas Anderson, R Davies Andrew, Andrew Baigey, J. Kenneth Baillie, Calum Barnetson, Ruth Begbie, Richie Biggers, Calum Barnetson, Ruth Begbie, David Birrell, Will Calkin, Keegan Chuavilong, R Cowden, Will Calkin, Coral Darjee, Simon Davies, Annemarie Docherty, Luke Dornan, Mark Dunn, Stuart Edwardson, Luke Dornan, Mark Dunn, David Griffith, Alasdair W. Hay, Amy Hu, Ali Hunter, Karen Jones, Helen Jordan, Ancy Joseph
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.