Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial

Yahya Shehabi; Ary Serpa Neto; Belinda D Howe; Rinaldo Bellomo; Yaseen M Arabi; Michael Bailey; Frances E Bass; Suhaini Bin Kadiman; Colin J McArthur; Michael C Reade; Ian M Seppelt; Jukka Takala; Matt P Wise; Steve A Webb; SPICE III Study Investigators

doi:10.1007/s00134-021-06356-8

Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial

Intensive Care Med. 2021 Apr;47(4):455-466. doi: 10.1007/s00134-021-06356-8. Epub 2021 Mar 8.

Authors

Yahya Shehabi^{1

2}, Ary Serpa Neto^{3

4

5

6}, Belinda D Howe³, Rinaldo Bellomo^{3

5

6}, Yaseen M Arabi⁷, Michael Bailey^{3

5}, Frances E Bass^{8

9}, Suhaini Bin Kadiman¹⁰, Colin J McArthur¹¹, Michael C Reade^{12

13}, Ian M Seppelt^{14

15}, Jukka Takala¹⁶, Matt P Wise¹⁷, Steve A Webb^{3

18}; SPICE III Study Investigators

Collaborators

SPICE III Study Investigators:
C Mashonganyika, H McKee, A Tonks, A Donnelly, N Hemmings, S O'Kane, A Blakemore, M Butler, K Cowdrey, J Dalton, E Gilder, S Long, L McCarthy, S McGuinness, R Parke, Y Chen, C McArthur, R McConnochie, L Newby, R Bellomo, G Eastwood, L Peck, H Young, C Boschert, J Edington, J Fletcher, J Smith, K Nand, A Raza, T Sara, J Bennett-Britton, J Bewley, V Bodenham, L Cole, K Driver, L Grimmer, L Howie, C Searles, K Sweet, D Webster, A van Berkel, H Connor, J Dennett, M van Der Graaff, S Henderson, J Mehrtens, K Miller, E Minto, A Morris, S Noble, K Parker, L Bulfin, N Hart, K Shepherd, S Vij, S Dickson, E Elloway, C Ferguson, R Jackson, P MacNaughton, M Marner, R Squire, S Waddy, P Wafer, J Welbourne, P Ashcroft, D Chambler, S Dukes, A Harris, S Horton, S Sharpe, P Williams, S Williams, M Bailey, E Blazquez, D France, R Hutchison, A O'Connor, G Comadira, M Gough, M Tallott, M Bastick, R Cameron, S Donovan, K Ellis, A Gaur, R Gregory, J Naumoff, E Turner, M White, K F J Au, J Fratzia, S Treloar, C H Lim, Y Maseeda, A P Tan, C L Tang, C Y Yong, M Akaltan, S Berger, D Blaser, L Fazlija, M L Jong, M Lensch, R Ludwig, T Merz, K Nettelbeck, M Roth, M Schafer, J Takala, A Wehr, D Zacharias, R Amran, H N Ashraf, N Azmi, N Basri, H Burhanuddin, Y Hadinata, A Hamdan, S Kadiman, A I Y M Rashid, I N Sabran, S Sulaiman, I N Zabidi, A Al-Dawood, M Aljuaid, H Al Anizi, A Al Saeedi, Y Arabi, M Dbsawy, A Deeb, M Hegazy, I Magdi, E Clarey, E Corcoran, C Finney, C Harris, P Hopkins, H Noble, J Smith, L Thompson, T Williams, L A Dumlao, R Bassam, M A Hassan, N Naseem, M H Al-Kurdi, A M Al-Harthy, S Bernard, L Sebafundi, C Serban, S K Lim, N Mazidah, N Saidin, N Sjamsuddin, I T A Tan, N Zabidi, M Brain, S Mineall, M Kanhere, N Soar, N Abd Kadir, N H Abdullah, R Awang, Z Emperan, N S Husin, N I Ismail, S Z Ismail, F N A Mohd Khadzali, M F Norddin, J Aguila, C Bold, B Clatworthy, A Dias, C Hogan, A Kazemi, V Lai, R Song, A Williams, D Bhatia, L Bulfin, S Elliot, P Galt, K Lavrans, P Ritchie, A Wang, R Gresham, J Lowrey, K Masters, P Palejs, I Seppelt, F Symonds, L Weisbrodt, C Whitehead, M Babio-Galan, V Calder, I Clement, A Harrison, I McCullagh, C Scott, L Thompson, R Bevan, S Caniba, D Hacking, L Maher, M L Azzolini, P Beccaria, S Colombo, G Landoni, C Leggieri, C Luca, D Mamo, E Moizo, G Monti, M Mucci, A Zangrillo, M Albania, S Arora, Y Shi, A Abudayah, G Almekhlafi, E Al Amodi, S Al Samarrai, M Badawi, R Cubio Caba, O Elffaki, Y Mandourah, J Valerio, C Joyce, J Meyer, E Saylor, B Venkatesh, E Venz, J Walsham, K Wetzig, E Clarey, C Harris, P Hopkins, H Noble, L Thompson, T Williams, T M Khoo, J E S Liew, A N Sakthi, A Zulkurnain, A Bamford, C Bergin, R Carrera, L Cooper, L Despy, K Ellis, S Harkett, L Mee, E Reeves, C Snelson, E Spruce, G Cooper, R Hodgson, D Pearson, M Rosbergen, M N Ali, N I Bahar, A Ismail, W N W Ismail, N M Samat, N S M Piah, R Abd Rahman, M Duroux, M Ratcliffe, T Warhurst, U Buehner, E Williams, N Jacques, L Keating, S Macgill, K L Tamang, N Tolan, A Walden, R Bower, J Cranshaw, K Molloy, S Pitts, J Butler, R Dunlop, C Fourie, P Jarrett, M Lassig-Smith, A Livermore, S O'Donoghue, M Reade, T Starr, J Stuart, L Campbell, M Phillips, D Stephens, J Thomas, D Cooper, R McAllister, G Andrew, L Barclay, H Dawson, D M Griffith, D Hope, G Wojcik, C McCulloch, R Paterson, L Ascough, C Paisley, J Patrick-Heselton, D Shaw, V Waugh, K Williams, I Welters, D Barge, A Jordan, C MacIsaac, T Rechnitzer, F Bass, J Gatward, N Hammond, P Janin, A O'Connor, W Stedman, E Yarad, N A Razak, N Dzulkipli, S L Jong, K Asen, W L Voon, S Liew, J Ball, V Barnes, C Dalton, S Farnell-Ward, H Farrah, K Maher, J Mellinghoff, C Ryan, P Shirley, L Conlon, A Glover, I Martin-Loeches, E O'Toole, J Ewan, J Ferrier, E Litton, S A Webb, W Berry, U Blanco Alonso, A Bociek, S Campos, S Jawara, F Hanks, A Kelly, K Lei, C McKenzie, M Ostermann, R Wan, S Al-Soufi, S Leow, K McCann, C Reynolds, K Brickell, C Fahey, L Hays, N Hyde, A Nichol, D Ryan, J Brailsford, A Buckley, L Forbes, T Maguire, J Moore, L Murray, A Ghosh, M Park, S Said, J Smith, A Visser, H Z Abidin, S Ali, M H Hassan, S C Omar, W F W Shukeri, D Brealey, G Bercades, E Blackburn, N Macallum, A Macklin, J H Ryu, K Tam, D Smyth, A Arif, C Bassford, C Morgan, C Swann, G Ward, L Wild, A Bone, T Elderkin, D Green, D Sach, T Salerno, N Simpson, F Brohi, M Clark, L Williams, J Brooks, E Cocks, J Cole, J Curtin, R Davies, H Hill, M Morgan, N Palmer, C Whitton, M Wise, P Baskaran, M S Hasan, L Y Tham, R Sol Cruz, D Dinsdale, S Edney, C Firkin, F FitzJohn, G Hill, A Hunt, S Hurford, G Jones, H Judd, C Latimer-Bell, C Lawrence, E Lesona, L Navarra, Y Robertson, H Smellie, A M Vucago, P Young, H Dawson, D M Griffith, R Paterson, P Clark, J Kong, J Ho, V Nayyar, C Skelly

Affiliations

¹ Monash Health School of Clinical Sciences, Monash University, Clayton, VIC, 3186, Australia. Yahya.shehabi@monashhealth.org.
² Prince of Wales Clinical School of Medicine, University of New South Wales, Randwick, Sydney, 2031, Australia. Yahya.shehabi@monashhealth.org.
³ Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
⁴ Department of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil.
⁵ Data Analytics Research and Evaluation Centre (DARE), Faculty of Medicine, University of Melbourne and Austin Hospital, Heidelberg, Melbourne, VIC, Australia.
⁶ Department of Intensive Care, Austin Hospital, Melbourne, Australia.
⁷ College of Medicine, King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
⁸ Critical Care Division, The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁹ Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St Leonards, NSW, Australia.
¹⁰ Department of Anesthesiology and Intensive Care, IJN-UTM Cardiovascular Engineering Center, National Heart Institute, Kuala Lumpur, Malaysia.
¹¹ Department of Critical Care Medicine, Auckland City Hospital, University of Auckland, Auckland, New Zealand.
¹² Faculty of Medicine, University of Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.
¹³ Joint Health Command, Australian Defence Force, Canberra, Australia.
¹⁴ Sydney Medical School-Nepean, University of Sydney, Sydney, Australia.
¹⁵ Department of Clinical Medicine, Macquarie University, Sydney, Australia.
¹⁶ Department of Intensive Care, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁷ Adult Critical Care, University Hospital of Wales, Cardiff, UK.
¹⁸ Intensive Care Unit, Royal Perth Hospital, Perth, WA, Australia.

Abstract

Purpose: To quantify potential heterogeneity of treatment effect (HTE), of early sedation with dexmedetomidine (DEX) compared with usual care, and identify patients who have a high probability of lower or higher 90-day mortality according to age, and other identified clusters.

Methods: Bayesian analysis of 3904 critically ill adult patients expected to receive invasive ventilation > 24 h and enrolled in a multinational randomized controlled trial comparing early DEX with usual care sedation.

Results: HTE was assessed according to age and clusters (based on 12 baseline characteristics) using a Bayesian hierarchical models. DEX was associated with lower 90-day mortality compared to usual care in patients > 65 years (odds ratio [OR], 0.83 [95% credible interval [CrI] 0.68-1.00], with 97.7% probability of reduced mortality across broad categories of illness severity. Conversely, the probability of increased mortality in patients ≤ 65 years was 98.5% (OR 1.26 [95% CrI 1.02-1.56]. Two clusters were identified: cluster 1 (976 patients) mostly operative, and cluster 2 (2346 patients), predominantly non-operative. There was a greater probability of benefit with DEX in cluster 1 (OR 0.86 [95% CrI 0.65-1.14]) across broad categories of age, with 86.4% probability that DEX is more beneficial in cluster 1 than cluster 2.

Conclusion: In critically ill mechanically ventilated patients, early sedation with dexmedetomidine exhibited a high probability of reduced 90-day mortality in older patients regardless of operative or non-operative cluster status. Conversely, a high probability of increased 90-day mortality was observed in younger patients of non-operative status. Further studies are needed to confirm these findings.

Keywords: Critically ill; Dexmedetomidine; Mechanical ventilation; Mortality; Sedation.

Publication types

Randomized Controlled Trial

MeSH terms

Adult
Aged
Bayes Theorem
Critical Illness*
Dexmedetomidine*
Humans
Hypnotics and Sedatives
Intensive Care Units
Respiration, Artificial

Substances

Hypnotics and Sedatives
Dexmedetomidine