Dexmedetomidine- or Clonidine-Based Sedation Compared With Propofol in Critically Ill Patients
Authors: Timothy S. Walsh, Richard A. Parker, Leanne M. Aitken, Cathrine A. McKenzie, Lydia Emerson, Julia Boyd, Alix Macdonald, Gayle Beveridge, Annabel Giddings, David Hope, Sîan Irvine, Sharon Tuck, Nazir I. Lone, Kalliopi Kydonaki, John Norrie, David Brealey, David Antcliffe, Michael Reay, Alan Williams, Jeremy Bewley, Benedict Creagh-Brown, Daniel F. McAuley, Paul Dark, Matt P. Wise, Anthony C. Gordon, Gavin D. Perkins, Michael C. Reade, Bronagh Blackwood, Alasdair MacLullich, Robert Glen, Valerie J. Page, Christopher J. Weir, Natalie Pattison, Barry Williams, Louise Rose, Paul Mouncey, John Prowle, David Wellsted, Tim Walsh, Stephen Brett, Heather Charles, Christoper Weir, John Norrie, Julian Bion, Graeme McLennan, Matt Stevenson, Alistair Nichol, Timothy Walsh, Maria Amamio, Lucy Barclay, Sophie Birch, Kate Briton, Sarah Clark, Jessica Crossan, Katherine Doverman, David Hope, Lucy Macdonald, Corrienne McCulloch, Nicola Rae, Scott Simpson, Jo Singleton, Maggie Wishart, Ruth Thompson, Neill Aitken, Rachel Fairlie, Nabeel Salim, Sam Talbot, Sarah Ackroyd, Valeria Alicino, Euan Allan, Thomas Anderson, Rosemary Andrew, Andrew Baigey, Kenneth Baillie, Calum Barnetson, Ruth Begbie, Richie Biggers, Michael Blaney, Richard Broom, David Birrell, Will Calkin, Keegan Chuavilong, Rebecca Cowden, Thomas Cox, Coral Darjee, Simon Davies, Annemarie Docherty, Luke Dornan, Mark Dunn, Stuart Edwardson, Ross Gillespie, Jane Greenwood, David Griffith, Alasdair Hay, Amy Hu, Ali Hunter, Karen Jones, Helen Jordan, Ancy Joseph, Kallirroi Kefala, Stephanie Kelly, Laura Kemp, Bara Kubanova, Victoria Leng, John Livesey, Nazir Lone, James Lyon, Olivia Mansfield, Dean McAvoy, Aaron McClatchey, Jonathan Miller, Ananda Mirchandani, Peter Moffitt, Steven Morrison, Alexandra Muir, Kieran Nunn, John Ochiltree, Emily Ogden, Matthew Parks, Marc Pass, Rachael Penrose, Harry Putnam, Thomas Quinn, Jonathan Rhodes, Alexander Rollings, Stephen Ross, Ralph Shackleton, Manu Shankar, Sunil Sharma, Iain Slessor, Zack Slevin, Duncan Stickle, Louise Symons, Fiona Walker, Luke Walls, Ian Whiteford, Sue Yin Yong, Neil Young, Kevin Rooney, Michael Kinsella, Brian Digby, Michael Brett, Paul McConnell, Mark Henderson, Radha Sundaram, Lisa Gemmell, Fiona Christie, Philip Henderson, Fiona MacGregor, Steven Henderson, Natalie Rodden, Kirsty Fallon, Lynn Abel, Barbara McLaren, Emma Hughes, Deborah McGlynn, Nicola Thomson, Lauren Walker, Susan Currie, Natasha Parker, Donna Gillan, Farooq Brohi, Sarah Purvis, Michele Clark, Pam Race, Lynne Williams, Ahmed Shahin, Eusebius Nworah, Jonathan Gui, Li-Chin Cheng, Katelyn Stewart, Rebecca Cusack, Mark Tomlin, Clare Bolger, Rachel Burnish, Sue Jackson, Alice Baker, Jonathan Biss, Karen Salmon, Michael Carter, Catherine McKenzie, Razaz Elsheikh, Missy (Anne) Harrison, Charlotte Thomas, James Ward, Andrew Cumpstey, Ahilanandan Dushianthan, Ivan Kemp, Valerie Page, Xiaobei Zhao, Nazril Nordin, Ahmed Hegazy, Elvira Hoxha, Owen Hardaker, Chimenime Ede, Nailia Kotrikova, Acharya Devaraja, Thomas Stambach, Prasun Mukherjee, Mark Louie Guanco, Matthew P Wise, Jade Cole, Helen Hill, Jenny Brooks, Michelle Davies, Rhys Davies, Emma Thomas, Angharad Williams, Lauren Lodhi, Matt PG Morgan, Simon Ridler, Christopher Smith, Maria Faulkner, Alison Ivison, Laura McKay, Helen Jeffrey, Jude Price, Lucy Slater, Angela Davies, Edward Hughes, Matt Thomas, Dominic Janssen, Ian Thomas, Kate Crewdson, Christopher Newell, Robert Hirst, Stephen West, Agnieszka Skorko, Emma Gendall, Ruth Worner, Beverley Faulkner, Borislava Borislavova, Kati Hayes, Andrew Parsons, Elizabeth Goff, John Sowersby, Annie Wood, Kieran Oglesby, Idrisu Sanusi, Charlie Pope, Andrew Baird, Hayley Blackmore, Robert Healey, Philip Hopkins, Eleanor Corcoran, Gillian Selman, Clare Finney, Evita Pappa, John Smith, Emma Clarey, Maeve Cockrell, Sian Saha, Harriet Noble, Kevin O’Reilly, Maria Depante, Anna Broderick, Marianette Anne Axalan, Burt Vergara, Reena Mehta, Henrik Reschrieter, Sarah Patch, Julie Camsooksai, Sarah Jenkins, Madga Pomichowska, Ken Power, Spike Briggs, Elizabeth Woodward, Christopher Loew, James Bromilow, James Keegan, Matthew Taylor, Emma Langridge, Dinesh Kulandhaisamy, Saah Savage, Yasmin de’Ath, Charlotte Humphrey, Sue Roffe, Matthew Bayliss, Leanne Bartlett, Richard Gordon-Williams, Kate Tatham, Sam Smith, Isabel Noris, Sharjeel Tahir, Emma Yates, Shivali Patel, Tanith Westerman, Sekina Bakare, Hugh Furness, Emma Hunt, Reyhaneh Sadegh Zadeh, Maria Khan, William Sherwood, Claudio Addari, Roshni Manex, Nicole Whitehead, Fred Wilson, Luke Edwards, Kshiteeja Nalk, Sophie Biddle, Suzannah Lant, Francesca Holden, Shree Voralia, Nicola Ocean, Arun Sahni, Prakhar Srilastava, Sultan Iqbal, Shamil Tana, Vishal Venkat Raman, Zoszka Webb, Luke Parker, Arnold Dela Rosa, Miran Kadr, Eleanor Harvey, Ryan Howle, Aatif Husain, Olivia Morley, Sarah Loftus, Jenna Hutchinson, Shaman Jhanji, Ethel Black, David Parkinson, Ravishankar Raobaikady, Mark Borthwick, Christie James, Grace Polley, Neil Davidson, Sally Beer, Paula Hutton, Archana Bashyal, Jean Wilson, Soyamol Mathew, Jung Ryu, Jason Cupitt, Gareth Hardy, Leonie Benham, Robert Downes, Neil Flint, Michael Little, Ravindra Pochiraju, Prematie Andreou, Dawn Hales, Jessica Hailstone, Megha Mathews, Martin Huntley, Lorraine Stephenson, Jacqui Hussey, Hao-Ern Tan, Simon Holbrook, Hayley Kemp, David Earl, Richard Innes, Benjamin Plumb, Patricia Doble, Rebecca Purnell, Ashly Thomas, Muhammad Hamza Noor, Waqas Khaliq, Micheal Jennings, Bernd Oliver Rose, Rosaleeta Reece-Anthony, Sagira Khatun, Samantha Dickinson, Jayson Clarke, Charlie Cox, Adam Longley, Tariq Ali, Babita Gurung, Mohamed Moubarak, Alan Williams, Jonathan Ball, Susannah Leaver, Sarah Farnell-Ward, Maria Thanasi, Shreeja Dangol, Vince Ventura, Massimiliano Valcher, Christine Sicat, Nikki Yun, Rebecca Kanu, Maria Maiz Cordoba, Ha Trinh, Karen Lloyd, Romina Pepermans Saluzzio, Lijun Ding, Helen Farrah, Edna Fernandes, Chris Nutt, Jon Silversides, Danny McAuley, Peter McGuigan, Emmet Major, Elliott Lonsdale, Nerielle Fundano, Kathryn Ward, Christine Turley, Aisling O’Neill, Stephanie Finn, Jackie Green, Erin Collins, Julie McAuley, Jeanette Mills, Chris Wright, Michelle Growcott, Iain McCullagh, Stephen Wright, Ian Clement, Jonathan Shelton, Matthew Faulds, Thomas Hellyer, Harriet Morton, Christopher Pollard, Christopher White, Leigh Dunn, Verity Calder, Susan Taylor, Pamela Garcia, Benjamin Brown, James Savage, Maite Babio-Galan, Kimberley Webster, Tessa Wilkinson, Arti Gulati, Tara Shrestha, Carole Hays, Lauren Butler, Fatima Simoes, Margaret McNeil, Ian Storey, Simon Whiteley, Elizabeth Wilby, Susan Trott, Sarah Watts, Shailamma Mathew, Sheila Salada, Adam Neep, Nora Youngs, Clare Howcroft, Matthew Powell, Michael Adlam, Elankumaran  Paramasivam, Zoe Friar, David Antcliffe, Anthony Gordon, Dorota Banach, Roceld Rojo, Sonia Sousa Arias, Ziortza Fernandez de Pinedo Artaraz, Phoebe Coghlan, Amal Mohammed, Eleanor Jepson, Jenny Wong, Anita Tamang Gurung, Caoimhe O’Dwyer, Sara Perez Guillotin, Maie Templeton, James Hanison, Jonathan Bannard-Smith, Daniel Conway, Shoneen Abbas, Mohamad Aly, Stephen Benington, Teh Eng Hean, Daniel Hayley, Ellen McGuckin, Andrew Martin, Thomas Morris, William Musselbrook, Bhaskar Narayan, Thomas Wright, Chris Wheeler, Melanie Barker, Richard Clark, Emma Connaughton, Rose Jama, Deborah Paripoorani, Rachael Quayle, Anila Sukumaran, Charlotte Taylor, Megan Balmer, Saejohn Lingeswaran, Lauren Edmunds, Katharine Wylie, Andrew Owen, Gavin Perkins, Sean Munnelly, Daniel Park, Jo Gresty, Ellie Reeves, Celina Maliaykal, Teresa Melody, Jacobus Preller, Petra Polgarova, Cristina Bravoelvira, Sofia Teixeira, James Varley, Sapna Sharma Hajela, Kay Elston, Siobhan Campbell, Meike Keil, Muhammad Elbehery, Jocelyn Marshall, Susan Stevenson, Andrew Conway Morris, Prasad Gogineni Venkateskara, Michael Reay, Karen Reid, Rebecca Brown, Chinenyenwa Amareihe, Elliot Yates, Jia Luen Goh, Edward Jones, Aamer Mughal, David Brealey, Niall MacCallum, Samuel Clark, Deborah Smyth, Georgia Bercades, Ingrid Hass, Gladys Martir, Anna Reyes, Maria Alexandra Zapata Martinez, Laura Gallagher, Chi Yee Chung, Graeme Sanders, Vipal Chawla, Namrata Maheshwari, Tessa Glazebrook, Hollie Angel, Rebecca Squires, Hayley Dolan, Christopher Donnelly, Lucy Mires, Robert Musalagani, Suzanne Williams, Robin Heij, Peter Young, Mark Blunt, Gayathri Wijewardena, John Gibson, Aricsa Mariya Joshy, Jeremy Bewley, Kieron Rooney, Katie Sweet, Kim Wright, Lisa Grimmer, Denise Webster, Casandra Bazan Lacerot, Rachel Shiel, Eva Maria Hernandez Morano, Christina Coleman, Eleanor Daniel, Oluwatosin Komolafe, Josephine Bonnici, Linda Pipira, Rebekah Johnson, Anna Chillingworth, Ya-Hui Liang, Georgia Efford, Angeliki Kolovou, George Davies, Zoe Garland, Bethany Gumbrill, Ivan Collin, Matthew Gibbins, Thomas Brougham, Dan Harvey, William Phipps, Kathryn Harrold, Nick Plummer, Ben Lowe, Paul James, Sara Ahmed, Rukmini Ghosh, Omer Mohamed, Tanushree Santra, James Shilston, Andrew Russell, Viresh Patel, Upasana Topiwala, Habideen Bello, Julia Sampson, Lucy Ryan, Cecilia Peters, Megan Meredith, Louise Conner (now Hughes), Lucy Morris, Amy Clark, Alice Baddeley, Lisa Mcloughlin, Cate Walton, Treesa Joseph, Anju Thomas, Sophie Lubbock, David Ford, Alexandra McCoy, Tony N’Dungu, Ingeborg Welters, Vinoth Sankar, Alicia Waite, Brian Johnston, David Shaw, Vicki Waugh, Karen Williams, Maria Lopez Martinez, Maria Norris, Maria Arra Carlota Mahiya, Jamie Fernandez Roman, Jin-Xi Yuan, Silvia Manes, Caitlin Lythgoe, Ibrahim Almafreji, Josh Colfar, Laura Medhurst, Stephanie Beresford, Sofia Farina, Lema Imam, Syamlam Ali, Zachary Thomas, Francesca Bold, Katherine Hodson, Aleem Morenikeji, Daniel Watkin, Tamas Szakmany, Amy Cardwell, Anne Frawley, Marlies Ostermann, Gillian Radcliffe, Nicholas Barrett, Simon Sparkes, Adam Woodman-Bailey, Eirini Kosifidou, Aneta Bociek, Ellie Hendrie, Rosario Lim, Fabiola D’Amato, Sarah Fordyce, Benjie Cendreda, Kyma Morera Vas, Jacqueline Pan, Christopher Meddings, Vladimir Milic, Mike Barker, Jennifer Owusu-Afriyie, Carolin Engelhard, Malcolm Sim, Richard Appleton, Maximilian Ralston, Andrew Arnott, Izabela Orlikowska, Sophie Kennedy-Hay, Christopher Murray, Matthew Devine, Padraig Headley, John McCaffrey, Daniel Donnelly, Richard Young, Samantha Hagan, Victoria Adell, Elizabeth Murphy, Jian Quek, Stephen Wilson, Catherine Jardine, Mark Forrest, Emma Collins, Miqdad Ibrahim, Mark Wheeley, Mostafa Kodous, Mathew Blake, Victoria Lacey, Michael Eager, Robin Jootun, Janine Birch
Journal: JAMA (2025)

Importance Whether α 2 -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 &amp;amp;lt;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