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

  • Shehabi, Yahya1, 2
  • Serpa Neto, Ary3, 4, 5, 6
  • Howe, Belinda D.3
  • Bellomo, Rinaldo3, 5, 6
  • Arabi, Yaseen M.7
  • Bailey, Michael3, 5
  • Bass, Frances E.8, 9
  • Kadiman, Suhaini Bin10
  • McArthur, Colin J.11
  • Reade, Michael C.12, 13
  • Seppelt, Ian M.14, 15
  • Takala, Jukka16
  • Wise, Matt P.17
  • Webb, Steve A.3, 18
  • Mashonganyika, C.
  • McKee, H.
  • Tonks, A.
  • Donnelly, A.
  • Hemmings, N.
  • O’Kane, S.
  • And 440 more
  • 1 Monash University,
  • 2 University of New South Wales,
  • 3 Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University,
  • 4 Hospital Israelita Albert Einstein,
  • 5 University of Melbourne and Austin Hospital,
  • 6 Austin Hospital,
  • 7 King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, King Abdulaziz Medical City,
  • 8 The George Institute for Global Health, University of New South Wales,
  • 9 Royal North Shore Hospital,
  • 10 IJN-UTM Cardiovascular Engineering Center, National Heart Institute,
  • 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 University of Sydney,
  • 15 Macquarie University,
  • 16 Department of Intensive Care, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  • 17 University Hospital of Wales,
  • 18 Royal Perth Hospital,
Published Article
Intensive Care Medicine
Springer Berlin Heidelberg
Publication Date
Mar 08, 2021
DOI: 10.1007/s00134-021-06356-8
PMID: 33686482
PMCID: PMC7939103
PubMed Central
  • Original


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. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06356-8.

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