Sedation with dexmedetomidine, increasing propofol dose lowers mortality in younger adults
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Key takeaways:
- Altering the combined doses of dexmedetomidine and propofol impacts mortality risk in patients aged 65 years or younger.
- No link was found between different doses and mortality in those aged older than 65 years.
A constant dexmedetomidine dose paired with an increasing propofol dose lowered the risk for mortality in ICU patients aged 65 years or younger, according to results published in American Journal of Respiratory and Critical Care Medicine.
However, increasing dexmedetomidine doses may be associated with greater mortality risk, results also showed.
“In ventilated critically ill younger adults sedated with a combination of dexmedetomidine and propofol infusions to achieve targeted deep sedation, the preferential use of incremental doses of propofol or dexmedetomidine was associated with divergent (reduced and increased, respectively) 90-day mortality,” Yahya Shehabi, PhD, MBBS, professor in the department of surgery in the School of Clinical Sciences at Monash Health, Melbourne, Australia, and colleagues wrote.
“In interpreting these findings, it is imperative to consider the inherent uncertainty of secondary analyses and the observed associations with mortality,” Shehabi and colleagues added. “Specifically, inference of causation and explanation for these association[s] are speculative.”
In a secondary cohort analysis of the Sedation Practice in Intensive Care Evaluation (SPICE III) trial, Shehabi and colleagues evaluated 1,177 ventilated patients (mean age, 64.7 years; 38.9% women) who received dexmedetomidine and supplemental propofol in the initial trial to understand how different doses of the sedatives together impacted the risk for mortality and whether this risk differed based on age (> 65 years or 65 years).
As Healio previously reported, the SPICE III trial found that patients undergoing mechanical ventilation in the ICU who received early sedation with dexmedetomidine as the primary agent had comparable 90-day mortality rates to patients who used propofol or midazolam.
In the current trial, researchers conducted a double stratification analysis to compare patients who received an unchanged dose of dexmedetomidine combined with an increasing dose of propofol with patients who received an unchanged dose of propofol combined with an increasing dose of dexmedetomidine.
Researchers then assessed how the two sedative dosing regimens were related to mortality at 90 days through clinical variable-adjusted Cox proportional hazard and multivariable regression models.
Of the total cohort, 579 patients (mean age, 73.7 years; 39.9% women) were aged older than 65 years, whereas 598 patients (mean age, 53.7 years; 38% women) were aged 65 years or younger. Researchers observed significantly increased infusion rates of both sedatives among the younger cohort vs. the older cohort (dexmedetomidine median dose, 0.54 μg/kg per hour vs. 0.44 μg/kg per hour; propofol median dose, 0.5 mg/kg per hour vs. 0.33 mg/kg per hour; P < .001 for both).
90-day mortality risk
After accounting for confounding variables, younger patients had a lower risk for 90-day mortality with an unchanged 0.54 μg/kg mean dose of dexmedetomidine per hour combined with a rising mean dose of propofol from 0.2 mg/kg to 1.27 mg/kg per hour. Researchers did not observe any association to mortality with this dosing dynamic among older patients.
After accounting for baseline risk and interaction with dexmedetomidine dose in multivariable regression, researchers continued to find a lower risk for mortality among younger patients (HR = 0.59; 95% CI, 0.43-0.78).
When assessing the opposite dosing of unchanged propofol combined with increasing dexmedetomidine in double stratification, no link was found to 90-day mortality in both age cohorts, according to researchers.
However, multivariable regression demonstrated that when the mean dexmedetomidine dose was raised from 0.28 μg/kg to 0.82 μg/kg per hour, the younger cohort faced a heightened risk for mortality (aHR = 1.3; 95% CI, 1.03-1.65).
When eliminating 8.1% of the total study population to only assess patients who remained in the ICU at the 48-hour mark, researchers again found a decreased risk for mortality with rising propofol in the younger cohort.
“These observations, although exploratory and hypothesis generating in nature, provide a pharmacodynamically plausible explanation of the age-related heterogeneity of treatment effect observed in the SPICE III trial,” Shehabi and colleagues wrote.
Considerations for future studies
Clinicians should interpret this study by Shehabi and colleagues with caution due to limitations such as possible additional confounders, according to an accompanying editorial by Lisa Burry, PharmD, PhD, assistant professor in the Leslie Dan Faculty of Pharmacy at University of Toronto, and Audrey De Jong, MD, PhD, doctor in the anesthesia and critical care department at Centre Hospitalier Universitaire Montpellier in France.
“There are potentially unmeasured confounders related to the clinician’s decision to initiate and titrate the supplemental sedative and in relation to dexmedetomidine titration because of the open-label study design (eg, dose adjustments or addition of supplemental sedative in anticipation of side effects with advancing doses, biases related to dose titration on the basis of age and perceived risk of adverse effects, and management of side effects with fluids and vasopressors),” Burry and De Jong wrote. “Likely, confounders related to the art of sedative titration are missing.”
Another notable limitation was the use of mean hourly infusion rates, Burry and De Jong wrote.
“Although the mean hourly infusion rate for the study period is correctly calculated as the total dose given divided by hours of infusion divided by the patient’s weight, this calculation loses the granularity to examine adverse effects known to be dose-dependent,” Burry and De Jong wrote. “Could drug exposure be oversimplified when presented as the mean? The mean infusion rate may be the same numerically, but the exposure over the time course is different.”
Reference:
Editor’s note: On Aug. 10, this article was updated to correct the dosing measurements for dexmedetomidine. The editors regret the error.