1. Patients in the intensive care unit (ICU) randomized to continue sedation for ventilation with dexmedetomidine often required use of supplementary propofol, midazolam, or both to achieve the prescribed level of sedation.
2. The rate of death from any cause at 90 days after randomization was similar between patients assigned to the dexmedetomidine group or those undergoing traditional sedation with propofol, midazolam, or other sedatives.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Sedation of critically ill patients on ventilation is a part of their medical care, though the best choice of sedative is not definitively known. Dexmedetomidine, an adrenergic agonist of the alpha-2 receptor, may provide benefit as a sedative compared to traditional propofol or midazolam agents. Prior studies have shown an association between dexmedetomidine use and shorter times to extubation, reduced delirium, and lower mortality compared to other sedatives. The SPICE III trial (Sedation Practice in Intensive Care Evaluation) evaluated dexmedetomidine versus traditional sedative agents and found patients randomized to either group had similar rates of all-cause mortality at 90 days. Most patients in the dexmedetomidine group also required use of additional sedative agents to maintain a desired state of sedation.
This large randomized trial provides evidence that mortality among patients sedated with dexmedetomidine compared to traditional agents is generally equivocal, and that dexmedetomidine is often not an agent that can be used alone. The study’s strengths include the randomized design, large number of patients recruited, and thorough subgroup analysis. Limitations include lack of assessment of other ICU associated treatment in the groups, such as vasopressor use, fluid administration, etc.
In-Depth [randomized controlled trial]: This international, open-label, randomized controlled trial enrolled patients between 2013 and 2018. Eligible patients were receiving endotracheal tube ventilation, were expected to continue this treatment for one or more days, and were receiving sedatives. Exclusion criteria included age less than 18 years old, intubation in the ICU more than 12 hours prior to enrollment, and suspected or proven primary brain injury. The sedation target for patients as defined by the Richmond Agitation and Sedation Scale (RASS) was between -2 and 1 (lightly sedated to restless). Patients were randomized to a dexmedetomidine (n=1954) or usual-care (n=1964) group, which included use of propofol, midazolam, or other agents as prescribed by the treating clinician. In a modified intention-to-treat analysis, the primary outcome of rate of all-cause death at 90 days after enrollment was 29.1% in both treatment groups (adjusted risk difference, 0.0 percentage points; 95% confidence interval [CI], −2.9 to 2.8; P=0.98). For patients with proven or suspected sepsis, there was also no difference between groups in 90-day mortality rates. To achieve the desired level of sedation in the first two days, over 70% of patients in the dexmedetomidine group required use of additional sedatives. Approximately 80% of patients in both groups also received fentanyl. Adverse and severe adverse events were more commonly reported in the dexmedetomidine group (0.7% vs 0.1%, P=0.003). The most common adverse events were bradycardia and hypotension.
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