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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 Y 1 , Serpa Neto A 2 , Howe BD 2 , Bellomo R 2 , Arabi YM 3 , Bailey M 2 Show all authors , Bass FE 4 , Kadiman SB 5 , McArthur CJ 6 , Reade MC 7 , Seppelt IM 8 , Takala J 9 , Wise MP 10 , Webb SA 2 , SPICE III Study Investigators

Affiliations 

  • 1 Monash Health School of Clinical Sciences, Monash University, Clayton, VIC, 3186, Australia. [email protected]
  • 2 Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
  • 3 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
  • 4 Critical Care Division, The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia
  • 5 Department of Anesthesiology and Intensive Care, IJN-UTM Cardiovascular Engineering Center, National Heart Institute, Kuala Lumpur, Malaysia
  • 6 Department of Critical Care Medicine, Auckland City Hospital, University of Auckland, Auckland, New Zealand
  • 7 Faculty of Medicine, University of Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia
  • 8 Sydney Medical School-Nepean, University of Sydney, Sydney, Australia
  • 9 Department of Intensive Care, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  • 10 Adult Critical Care, University Hospital of Wales, Cardiff, UK
Intensive Care Med, 2021 Apr;47(4):455-466.
PMID: 33686482 DOI: 10.1007/s00134-021-06356-8

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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