SPICE III trial: Early sedation with dexmedetomidine in critically ill patients

Dexmedetomidine was not superior to propofol or midazolam for intensive care unit (ICU) sedation, led to more bradycardia and hypotension, and often required additional sedation. Prof. Yahya Shehabi (Monash Health, Australia) presented these data, which were simultaneously published in the New England Journal of Medicine [1,2].

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 with traditional propofol or midazolam agents. Prior studies have shown an association between dexmedetomidine use and shorter time to extubation, reduced delirium, and lower mortality compared with other sedatives. The SPICE III trial (Sedation Practice in Intensive Care Evaluation) evaluated dexmedetomidine vs traditional sedative agents and found patients randomised 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 international, open-label, randomised controlled trial enrolled patients between 2013 and 2018. Eligible patients were receiving endotracheal tube ventilation, were expected to continue this treatment for 1 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 enrolment, 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 randomised to dexmedetomidine (n=1,954) or usual care (n=1,964), which included use of propofol, midazolam, or other agents as prescribed by the attending clinician. In a modified intention-to-treat analysis, the primary outcome of all-cause mortality rate at 90 days after enrolment was 29.1% in both treatment groups (adjusted risk difference 0.0 percentage points; 95% 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 2 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.

Other secondary outcomes, including mortality at 180 days, institutional dependence at 180 days, Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) score, and European Quality of Life 5-Dimensions 3-Level (EQ-5D-3L) questionnaire, revealed no difference between the groups.

This large randomised trial provides evidence that mortality among patients sedated with dexmedetomidine compared with traditional agents is generally equivocal, and that dexmedetomidine is often not an agent that can be used alone.

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   1. Shehabi Y, et al. ATS 2019, 17-22 May, Dallas, USA.
   2. Shehabi Y, et al. N Engl J Med. 2019;380(26):2506-2517. 

Posted on 23 July, 201923 March, 2021