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A Dark Side of Dexmedetomidine? Another Look at SPICE-III

November 18, 2022

Written by Jason Lesnick

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An increasing propofol dose, combined with a fixed dexmedetomidine infusion, was associated with decreased 90-day mortality in patients ≤ 65 years. An increasing dexmedetomidine dose, combined with a relatively fixed propofol dose, was associated with increased mortality in patients ≤65. Both associations were absent in patients > 65 years old.

Why does this matter?
Dexmedetomidine is a popular sedative option in our mechanically ventilated patients, with major advantages over benzodiazepines: less delirium, shorter duration of mechanical ventilation, and analgesic properties. However, early sedation with dexmedetomidine showed higher 90-day mortality in patients ≤ 65 years and lower mortality in patients > 65 in the SPICE III trial. Propofol was often co-administered with dexmedetomidine. How did this combination influence 90-day mortality?

Prece-fol? Propo-dex? I swear I had something for this…
This secondary analysis of the SPICE-III open label RCT included 1,177 ICU patients who were randomized to receive dexmedetomidine and were given supplemental propofol and were then stratified by age > 65 or ≤ 65. 

Using a double stratification resampling technique, they separated patients into subgroups with similar infusion rates of propofol, then stratified those into quartiles of progressively higher dexmedetomidine dose; this was then repeated in reverse. This allowed the authors to analyze subgroups of patients with steady mean infusion rates of one drug while escalating the rate for another sedative and vice versa. 

There was an association with reduced adjusted mortality in patients ≤ 65 receiving escalating propofol infusions with a fixed dexmedetomidine infusion rate (0.54 mcg/kg/hr). This was consistent with multivariable regression modeling, HR 0.59 (95%CI 0.43-0.78, p <0.0001). Interestingly, in younger patients receiving escalating dexmedetomidine infusion rates, with steady propofol infusions, there was an association with increased adjusted mortality, HR 1.30 (95%CI 1.03-1.65, p = 0.029). No association between sedatives, infusion rates and mortality were identified in patients > 65. Notably, younger patients did receive a significantly higher dose of both sedatives relative to older patients.

Despite using advanced statistics, the associations seen in this post hoc analysis cannot be interpreted as cause and effect and require further investigation. In the meantime, I will keep this association in mind in my sedated patients ≤ 65. 

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. 2022 Oct 10. doi: 10.1164/rccm.202206-1208OC. Online ahead of print.