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.
Original language | English |
---|---|
Pages (from-to) | 455-466 |
Number of pages | 12 |
Journal | Intensive Care Medicine |
Volume | 47 |
Issue number | 4 |
DOIs | |
Publication status | Published - Apr 2021 |
Keywords
- Critically ill
- Dexmedetomidine
- Mechanical ventilation
- Mortality
- Sedation
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine
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In: Intensive Care Medicine, Vol. 47, No. 4, 04.2021, p. 455-466.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial
AU - The SPICE III Study Investigators
AU - Shehabi, Yahya
AU - Serpa Neto, Ary
AU - Howe, Belinda D.
AU - Bellomo, Rinaldo
AU - Arabi, Yaseen M.
AU - Bailey, Michael
AU - Bass, Frances E.
AU - Kadiman, Suhaini Bin
AU - McArthur, Colin J.
AU - Reade, Michael C.
AU - Seppelt, Ian M.
AU - Takala, Jukka
AU - Wise, Matt P.
AU - Webb, Steve A.
AU - Mashonganyika, C.
AU - McKee, H.
AU - Tonks, A.
AU - Donnelly, A.
AU - Hemmings, N.
AU - O’Kane, S.
AU - Blakemore, A.
AU - Butler, M.
AU - Cowdrey, K.
AU - Dalton, J.
AU - Gilder, E.
AU - Long, S.
AU - McCarthy, L.
AU - McGuinness, S.
AU - Parke, R.
AU - Chen, Y.
AU - McConnochie, R.
AU - Newby, L.
AU - Eastwood, G.
AU - Peck, L.
AU - Young, H.
AU - Boschert, C.
AU - Edington, J.
AU - Fletcher, J.
AU - Smith, J.
AU - Nand, K.
AU - Raza, A.
AU - Sara, T.
AU - Bennett-Britton, J.
AU - Bewley, J.
AU - Bodenham, V.
AU - Tang, C. L.
AU - Yong, C. Y.
AU - Wang, A.
AU - Tam, K.
AU - Ho, J.
N1 - Funding Information: SPICE III Study Investigators: Site investigators (alphabetically by institution and all in Australia unless specified as New Zealand [NZ], Ireland [IR], Italy [IT], Malaysia [MY], Saudi Arabia [SA], Switzerland [CH] or United Kingdom [UK]): Albury Base Hospital, Albury, NSW, C. Mashonganyika, H. McKee, A. Tonks; Altnagelvin Area Hospital, Londonderry, UK, A. Donnelly, N. Hemmings, S. O'Kane; Auckland City Hospital CVICU, Auckland, NZ, A. Blakemore, M. Butler, K. Cowdrey, J. Dalton, E. Gilder, S. Long, L. McCarthy, S. McGuinness, R. Parke; Auckland City Hospital DCCM, Auckland, NZ, Y. Chen, C. McArthur, R. McConnochie, L. Newby; Austin Health, Melbourne, VIC, R. Bellomo, G. Eastwood, L. Peck, H. Young; Bendigo Hospital, Bendigo, VIC, C. Boschert, J. Edington, J. Fletcher, J. Smith; Blacktown Hospital, Sydney, NSW, K. Nand, A. Raza, T. Sara; Bristol Royal Infirmary, Bristol, UK, J. Bennett-Britton, J. Bewley, V. Bodenham, L. Cole, K. Driver, L. Grimmer, L. Howie, C. Searles, K. Sweet, D. Webster; Central Gippsland Health, Sale, VIC, A. van Berkel, H. Connor, J. Dennett, M. van Der Graaff; Christchurch Hospital, Christchurch, NZ, S. Henderson, J. Mehrtens, K. Miller, E. Minto, A. Morris, S. Noble, K. Parker; Dandenong Hospital, Melbourne, VIC, L. Bulfin, N. Hart, K. Shepherd, S. Vij; Derriford Hospital, Derriford, UK, S. Dickson, E. Elloway, C. Ferguson, R. Jackson, P. MacNaughton, M. Marner, R. Squire, S. Waddy, P. Wafer, J. Welbourne; Dorset County Hospital, Dorchester, UK, P. Ashcroft, D. Chambler, S. Dukes, A. Harris, S. Horton, S. Sharpe, P. Williams, S. Williams; Dunedin Hospital, Dunedin, NZ, M. Bailey, E. Blazquez, D. France, R. Hutchison, A. O'Connor; Gold Coast University Hospital, Gold Coast, QLD, G. Comadira, M. Gough, M. Tallott; Gosford Hospital, Gosford, NSW, M. Bastick, R. Cameron, S. Donovan, K. Ellis, A. Gaur, R. Gregory, J. Naumoff, E. Turner, M. White; Hornsby Ku-Ring-Gai Hospital, Sydney, NSW, KFJ. Au, J. Fratzia, S. Treloar; Hospital Pulau Pinang, Pulau Pinang, MY, CH. Lim, Maseeda.Y, AP. Tan, CL. Tang, CY. Yong; Inselspital Bern University Hospital, Bern, CH, M. Akaltan, S. Berger, D. Blaser, L. Fazlija, ML. Jong, M. Lensch, R. Ludwig, T. Merz, K. Nettelbeck, M. Roth, M. Schafer, J. Takala, A. Wehr, D. Zacharias; Institut Jantung Negara, Kuala Lumpur, MY, R. Amran, HN. Ashraf, N. Azmi, N. Basri, H. Burhanuddin, Y. Hadinata, A. Hamdan, S. Kadiman, AIYM. Rashid, IN. Sabran, S. Sulaiman, I. N. Zabidi; King Abdulaziz Medical City, King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, SA, A. Al-Dawood, M. Aljuaid, H. Al Anizi, A. Al Saeedi, Y. Arabi, M. Dbsawy, A. Deeb, M. Hegazy, I. Magdi; Kings College Hospital, London, UK, E. Clarey, E. Corcoran, C. Finney, C. Harris, P. Hopkins, H. Noble, J. Smith, L. Thompson, T. Williams; King Saud Medical City, Riyadh, KSA, LA. Dumlao, R. Bassam, MA. Hassan, N. Naseem, MH. Al-Kurdi, AM. Al-Harthy; Knox Private Hospital, Melbourne, VIC, S. Bernard, L. Sebafundi, C. Serban; Kuala Lumpar General Hospital, Kuala Lumpur, MY, SK. Lim, N. Mazidah, N. Saidin, N. Sjamsuddin, ITA. Tan, N. Zabidi; Launceston General Hospital and Clifford Craig Medical Research Trust, Launceston, TAS, M. Brain, S. Mineall; Lyell McEwin Hospital, Adelaide, SA, M. Kanhere, N. Soar; Melaka General Hospital, Melaka, MY, N. Abd Kadir, NH. Abdullah, R. Awang, Z. Emperan, NS. Husin, NI. Ismail, SZ. Ismail, FNA. Mohd Khadzali, MF. Norddin; Middlemore Hospital, Auckland, NZ, J. Aguila, C. Bold, B. Clatworthy, A. Dias, C. Hogan, A. Kazemi, V. Lai, R. Song, A. Williams; Monash Medical Centre, Melbourne, VIC, D. Bhatia, L. Bulfin, S. Elliot, P. Galt, K. Lavrans, P. Ritchie, A. Wang; Nepean Hospital, Sydney, NSW, R. Gresham, J. Lowrey, K. Masters, P. Palejs, I. Seppelt, F. Symonds, L. Weisbrodt, C. Whitehead; Newcastle upon Tyne Hospitals (Freeman Hospital and Royal Victoria Infirmary), UK, M. Babio-Galan, V. Calder, I. Clement, A. Harrison, I. McCullagh, C. Scott, L. Thompson; North Shore Hospital, Auckland, NZ, R. Bevan, S. Caniba, D. Hacking, L. Maher; Ospedale San Raffaele, Milan, IT, ML. Azzolini, P. Beccaria, S. Colombo, G. Landoni, C. Leggieri, C. Luca, D. Mamo, E. Moizo, G. Monti, M. Mucci, A. Zangrillo; Prince of Wales, Sydney, NSW, M. Albania, S. Arora, Y. Shi; Prince Sultan Military Medical City, Riyadh, SA, A. Abudayah, G. Almekhlafi, E. Al Amodi, S. Al Samarrai, M. Badawi, R. Cubio Caba, O. Elffaki, Y. Mandourah, J. Valerio; Princess Alexandra Hospital, Brisbane, QLD, C. Joyce, J. Meyer, E. Saylor, B. Venkatesh, E. Venz, J. Walsham, K. Wetzig; Princess Royal University Hospital, London, UK, E. Clarey, C. Harris, P. Hopkins, H. Noble, L. Thompson, T. Williams; Queen Elizabeth Hospital, MY, TM. Khoo, JES. Liew, AN. Sakthi, A. Zulkurnain; Queen Elizabeth Hospital Birmingham, Birmingham, UK, A. Bamford, C. Bergin, R. Carrera, L. Cooper, L. Despy, K. Ellis, S. Harkett, L. Mee, E. Reeves, C. Snelson, E. Spruce; Queen Elizabeth Hospital Kings Lynn, UK, G. Cooper, R. Hodgson, D. Pearson, M. Rosbergen; Raja Perempuan Zainab II Hospital, Kota Bharu, MY, MN. Ali, NI. Bahar, A. Ismail, WNW. Ismail, NM. Samat, NSM. Piah, R. Abd Rahman; Redcliffe Hospital, Brisbane, QLD, M. Duroux, M. Ratcliffe, T. Warhurst; Rotorua Hospital, Rotorua, NZ, U. Buehner, E. Williams; Royal Berkshire Hospital, Reading, UK, N. Jacques, L. Keating, S. Macgill, KL. Tamang, N. Tolan, A. Walden; Royal Bournemouth Hospital, Bournemouth, UK, R. Bower, J. Cranshaw, K. Molloy, S. Pitts; Royal Brisbane and Women’s Hospital, Brisbane, QLD, J. Butler, R. Dunlop, C. Fourie, P. Jarrett, M. Lassig-Smith, A. Livermore, S. O'Donoghue, M. Reade, T. Starr, J. Stuart; Royal Darwin Hospital, Darwin, NT, L. Campbell, M. Phillips, D. Stephens, J. Thomas; Royal Hobart Hospital, Hobart, TAS, D. Cooper, R. McAllister; Royal Infirmary of Edinburgh, Scotland, UK, G. Andrew, L. Barclay, H. Dawson, DM. Griffith, D. Hope, G. Wojcik, C. McCulloch, R. Paterson; Royal Liverpool Hospital, Liverpool, UK, L. Ascough, C. Paisley, J. Patrick-Heselton, D. Shaw, V. Waugh, K. Williams, I. Welters; Royal Melbourne Hospital, Melbourne, VIC, D. Barge, A. Jordan, C. MacIsaac, T. Rechnitzer; Royal North Shore Hospital, Sydney, NSW, F. Bass, J. Gatward, N. Hammond, P. Janin, A. O'Connor, W. Stedman, E. Yarad; Sarawak General Hospital, Sarawak, MY, NA. Razak, N. Dzulkipli, SL. Jong, K. Asen, WL. Voon, S. Liew; St George's Hospital London, UK, J. Ball, V. Barnes, C. Dalton, S. Farnell-Ward, H. Farrah, K. Maher, J. Mellinghoff, C. Ryan, P. Shirley; St James University Hospital, Dublin, IR, L. Conlon, A. Glover, I. Martin-Loeches, E. O'Toole; St John of God Hospital Subiaco, Subiaco, WA, J. Ewan, J. Ferrier, E. Litton, SA. Webb; St Thomas Hospital, London, UK, , W. Berry, U. Blanco Alonso, A. Bociek, S. Campos, S. Jawara, F. Hanks, A. Kelly, K. Lei, C. McKenzie, M. Ostermann, R. Wan, St Vincent's Hospital, Sydney, NSW, S. Al-Soufi, S. Leow, K. McCann, C. Reynolds; St Vincent's University Hospital, Dublin, IR, K. Brickell, C. Fahey, L. Hays, N. Hyde, A. Nichol, D. Ryan; Sunshine Coast University Hospital and Nambour Hospital, Sunshine Coast, QLD, J. Brailsford, A. Buckley, L. Forbes, T. Maguire, J. Moore, L. Murray; The Northern Hospital, Melbourne, VIC, A. Ghosh, M. Park, S. Said; Toowoomba Hospital, Toowoomba, QLD, J. Smith, A. Visser; Universiti Sains Malaysia Hospital, MY, HZ. Abidin, S. Ali, MH. Hassan, SC. Omar, WFW. Shukeri; University College Hospital London, UK, D. Brealey, G. Bercades, E. Blackburn, N. Macallum, A. Macklin, JH. Ryu, K. Tam, D. Smyth; University Hospital of Coventry and Warwick, Coventry, UK, A. Arif, C. Bassford, C. Morgan, C. Swann, G. Ward, L. Wild; University Hospital Geelong, Geelong, VIC, A. Bone, T. Elderkin, D. Green, D. Sach, T. Salerno, N. Simpson; University Hospital of North Tees, Stockton-on-Tees, UK, F. Brohi, M. Clark, L. Williams; University Hospital of Wales, Cardiff, UK, J. Brooks, E. Cocks, J. Cole, J. Curtin, R. Davies, H. Hill, M. Morgan, N. Palmer, C. Whitton, M. Wise; University Malaya Medical Center, MY, P. Baskaran, MS. Hasan, LY. Tham; Wellington Regional Hospital, Wellington, NZ, 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, AM. Vucago, P. Young; Western General Hospital Scotland, Edinburgh, UK, H. Dawson, DM. Griffith, R. Paterson; Westmead Hospital, Sydney, NSW, P. Clark, J. Kong, J. Ho, V. Nayyar, C. Skelly. Funding Information: This manuscript received no funding from third parties. The parent SPICE studies, however, were supported by an unrestricted research Grant from Pfizer (Hospira Inc. IL)—USA Grant-in-Aide Program. Publisher Copyright: © 2021, Crown.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
KW - Critically ill
KW - Dexmedetomidine
KW - Mechanical ventilation
KW - Mortality
KW - Sedation
UR - http://www.scopus.com/inward/record.url?scp=85102253849&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102253849&partnerID=8YFLogxK
U2 - 10.1007/s00134-021-06356-8
DO - 10.1007/s00134-021-06356-8
M3 - Article
C2 - 33686482
AN - SCOPUS:85102253849
SN - 0342-4642
VL - 47
SP - 455
EP - 466
JO - Intensive Care Medicine
JF - Intensive Care Medicine
IS - 4
ER -