Dexmedetomidine and Propofol Sedation in Critically Ill Patients and Dose-associated 90-Day Mortality: A Secondary Cohort Analysis of a Randomized Controlled Trial (SPICE III)

Yahya Shehabi; Ary Serpa Neto; Rinaldo Bellomo; Belinda D Howe; 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:10.1164/rccm.202206-1208OC

Dexmedetomidine and Propofol Sedation in Critically Ill Patients and Dose-associated 90-Day Mortality: A Secondary Cohort Analysis of a Randomized Controlled Trial (SPICE III)

Am J Respir Crit Care Med. 2023 Apr 1;207(7):876-886. doi: 10.1164/rccm.202206-1208OC.

Authors

Yahya Shehabi^{1

2}, Ary Serpa Neto^{3

4

5}, Rinaldo Bellomo^{3

5

6}, Belinda D Howe³, Yaseen M Arabi⁷, Michael Bailey³, 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 and.
² School of Clinical Medicine and.
³ Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
⁴ Department of Critical Care Medicine, Hospital Israelita Albert Einstein, São Paulo, Brazil.
⁵ Department of Critical Care, Data Analytics Research and Evaluation Centre, Faculty of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
⁶ Department of Intensive Care, Austin Hospital, Melbourne, Victoria, 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, New South Wales, Australia.
⁹ Malcolm Fisher Department of Intensive Care, Royal North Shore Hospital, St. Leonards, New South Wales, 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, Australian Capital Territory, Australia.
¹⁴ Sydney Medical School-Nepean, University of Sydney, Sydney, New South Wales, Australia.
¹⁵ Department of Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia.
¹⁶ Department of Intensive Care Medicine, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁷ Adult Critical Care, University Hospital of Wales, Cardiff, United Kingdom; and.
¹⁸ Intensive Care Unit, Royal Perth Hospital, Perth, Western Australia, Australia.

PMID: 36215171
DOI: 10.1164/rccm.202206-1208OC

Abstract

Rationale: The SPICE III (Sedation Practice in Intensive Care Evaluation) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation. Objectives: To quantify the association of different infusion rates of dexmedetomidine and propofol, given in combination, with mortality and to determine if this is modified by age. Methods: We included 1,177 patients randomized in SPICE III to receive dexmedetomidine and given supplemental propofol, stratified by age (>65 or ⩽65 yr). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality. Measurements and Main Results: Younger patients (598 of 1,177 [50.8%]) received significantly higher doses of both sedatives compared with older patients to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 μg/kg/h) was associated with reduced adjusted mortality in younger but not older patients. This was consistent with multivariable regression modeling (hazard ratio, 0.59; 95% confidence interval, 0.43-0.78; P < 0.0001) adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients, using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality (hazard ratio, 1.30; 95% confidence interval, 1.03-1.65; P = 0.029). Conclusions: In patients ⩽65 years of age sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registered with www.clinicaltrials.gov (NCT01728558).

Keywords: age groups; intensive care; mechanical ventilation; respiratory; sedative effect.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Critical Illness / therapy
Dexmedetomidine* / adverse effects
Humans
Hypnotics and Sedatives / adverse effects
Propofol* / adverse effects
Respiration, Artificial

Substances

Propofol
Dexmedetomidine
Hypnotics and Sedatives

Associated data

ClinicalTrials.gov/NCT01728558