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We conducted a randomized trial to evaluate the efficacy and safety of dexmedetomidine for prophylactic analgesia and sedation in patients with delayed extubation after craniotomy.From June 2012 to July 2014, 150 patients with delayed extubation after craniotomy were randomized 1:1 and were assigned to the dexmedetomidine group that received a continuous infusion of 0.6 μg/kg/h (10 μg/mL) or the control group that received a maintenance infusion of 0.9% sodium chloride for injection. The mean percentage of time under optimal sedation (SAS3-4), the percentage of patients who required rescue with propofol/fentanyl, and the total dose of propofol/fentanyl required throughout the course of drug infusion, as well as VAS, HR, MAP, and SpO2 were recorded.The percentage of time under optimal sedation was significantly higher in the dexmedetomidine group than in the control group (98.4%±6.7% vs. 93.0%±16.2%, P=0.008). The VAS was significantly lower in the dexmedetomidine group than in the control group (1.0 vs. 4.0, P=0.000). The HR and mean BP were significantly lower in the dexmedetomidine group than in the control group at all 3 time points (before endotracheal suctioning, immediately after extubation, and 30 min after extubation). No significant difference in SpO2 was observed between the 2 groups. For hemodynamic adverse events, patients in the dexmedetomidine group were more likely to develop bradycardia (5.3% vs. 0%, P=0.043) but had a lower likelihood of tachycardia (2.7% vs. 18.7%, P=0.002).Dexmedetomidine may be an effective prophylactic agent to induce sedation and analgesia in patients with delayed extubation after craniotomy. The use of dexmedetomidine (0.6 μg/kg/h) infusion does not produce respiratory depression, but may increase the incidence of bradycardia.