PURPOSE: To compare the efficacy, safety, and pharmacokinetics of prolonged sedation with the alpha-2 agonist dexmedetomidine versus the GABA-agonist midazolam for mechanically ventilated patients.
METHODS: A prospective, double-blind, randomized, multinational trial of 366 medical/surgical ICU patients with expected requirement for mechanical ventilation of more than 24 hours. Sedation level and delirium were assessed using the Richmond Agitation-Sedation Scale (RASS) and Confusion Assessment Method for the ICU (CAM-ICU). Dexmedetomidine (0.2–1.4 mcg/kg/hr, n=244) or midazolam (0.02–0.1 mg/kg/hr, n=122) was titrated to achieve light sedation (RASS scores between −2 and +1) from enrollment until extubation or 30 days. Plasma samples were collected 2 and 4 hours after starting infusion and 0, 4, and 8 hours after terminating drug infusion.
RESULTS: Patients were maintained within the target sedation range at similar rates (77.3% dexmedetomidine vs 75.1% midazolam, 95%CI −3.2%–7.5%, p=0.45). Patients managed with dexmedetomidine had a shorter median time to extubation by 1.9 days [3.7; 95%CI 3.1–4.0 vs 5.6; 95%CI, 4.6–5.9; p=0.005] and similar ICU length of stay (5.9 days; 95%CI, 5.7–7.0 vs 7.6; 95%CI, 6.7–8.6; p=0.12). Dexmedetomidine-treated patients had a 22.6% lower incidence of delirium (95%CI, 14–33; p<0.001), approximately one more day free of delirium (2.5 vs. 1.7; p=0.002), and fewer infections (10.2% vs. 19.7%; p=0.02). Dexmedetomidine increased bradycardia requiring treatment (4.9% vs. 0.8%; p=0.07) but decreased tachycardia (25.4% vs. 44.3%; p<0.001) and hypertension requiring treatment (18.9% vs. 29.5%; p=0.02). Samples from 65 patients were included in the PK analysis. Median dexmedetomidine infusion duration was 86h (26–280h). A one-compartment model provided the best fit, with clearance of 39.4 L/hr, half-life of 2.7 hr and volume of distribution of 152 L.
CONCLUSION: At comparable sedation levels, dexmedetomidine reduces the duration of mechanical ventilation and the incidence of delirium and infection compared to midazolam during prolonged ICU sedation. Pharmacokinetics and cardiovascular changes are similar with prolonged use compared to short-term dexmedetomidine data.
CLINICAL IMPLICATIONS: The choice of dexmedetomidine for prolonged ICU sedation provides improved outcomes beyond sedation compared to midazolam.
DISCLOSURE: Richard Riker, Shareholder Own stock options in Hospira, Inc; Employee Employee of Hospira, Inc; No Product/Research Disclosure Information