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Randomized Controlled Trial
. 2021 Apr;47(4):455-466.
doi: 10.1007/s00134-021-06356-8. Epub 2021 Mar 8.

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

Yahya Shehabi  1   2 , Ary Serpa Neto  3   4   5   6 , Belinda D Howe  3 , Rinaldo Bellomo  3   5   6 , Yaseen M Arabi  7 , Michael Bailey  3   5 , Frances E Bass  8   9 , Suhaini Bin Kadiman  10 , Colin J McArthur  11 , Michael C Reade  12   13 , Ian M Seppelt  14   15 , Jukka Takala  16 , Matt P Wise  17 , Steve A Webb  3   18 ; SPICE III Study Investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Yahya Shehabi et al. Intensive Care Med. 2021 Apr.

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.

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Conflict of interest statement

YS declares unrestricted research and educational Grant support from Pfizer (Hospira Inc IL) USA, Orion Pharma—Helsinki Finland in support of the SPICE Program. Speaker honorarium and travel reimbursements for educational symposia from Pfizer and Orion. MCR declares unrestricted research and educational grant support from Pfizer (Hospira Inc.—Melbourne) Australia. All authors filed in the COI ICMJE form.

Figures

Fig. 1
Fig. 1
Age-related heterogeneity of treatment effect—dexmedetomidine and mortality. OR odds ratio. Values less than 1 indicate lower mortality. a Marginal effect plot for the interaction between the allocation group and age, as a continuous variable, for 90-day mortality. b The posterior distribution of mortality, depicted as odds ratios. The probability of benefit (OR < 1) is 97.7% in patients > 65 years old with 98.5% probability of harm in patients ≤ 65 years old (OR > 1)
Fig. 2
Fig. 2
Risk of death and interaction between age, severity of illness and dexmedetomidine treatment. APACHE II Acute Physiology and Chronic Health Evaluation II, CrI credible interval. The effect estimates, odds ratio (OR) for the interaction between dexmedetomidine allocation, age category and six different cut-offs of APACHE II are presented. OR < 1.0 represents a favorable outcome and > 1.0 represents unfavorable outcome with the use of dexmedetomidine. a Odd ratios according to age category, age group > 65 years depicts a high probability of OR < 1.0 with increased APACHEII. b Probability of benefit with the allocation to dexmedetomidine was higher in older age group. c Probability of > 10% benefit with the allocation to dexmedetomidine was higher in patients > 65 years but declined with increasing APACHEII. d Probability of > 10% harm with the allocation to dexmedetomidine was higher in patients ≤ 65 years and increased with rising APACHEII
Fig. 3
Fig. 3
Risk of death and interaction between clusters, age and dexmedetomidine treatment. CrI credible interval. The effect estimates, odds ratio (OR) for the interaction between dexmedetomidine allocation, cluster assignment and six different cut-offs of age categories are presented. OR < 1.0 represents a favorable outcome and > 1.0 represents unfavorable outcome with the use of dexmedetomidine. a Odd ratios according to cluster, operative cluster 1 depicts a high probability of benefit with increased age. b Probability of benefit with the allocation to dexmedetomidine was higher in cluster 1 but mainly in those > 50 years old. c Probability of > 10% benefit with the allocation to dexmedetomidine was higher in cluster 1 but mainly in those > 60 years. d Probability of > 10% harm with the allocation to dexmedetomidine was higher in cluster 2, non-operative, mainly in patients younger than 50 years
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