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Procedural sedation for painful procedures in the emergency department (ED) can be accomplished with various pharmacological agents. The choice of the sedative used is highly dependent on procedure- and patient characteristics and on personal- or local preferences.We conducted a multicenter retrospective cohort study of procedural sedations performed in the EDs of 5 hospitals in the Netherlands over a 4 year period to evaluate the efficacy- (success rate of the intended procedure) and safety (incidence of sedation (adverse) events) of propofol sedations compared to midazolam sedations.A total of 592 ED sedations were included in our study. Patients sedated with propofol (n = 284, median dose 75 mg) achieved a deeper level of sedation (45% vs. 25% deep sedation, p < 0.001), had a higher procedure success rate (92% vs. 81%, p < 0.001) and shorter median sedation duration (10 vs. 17 min, p < 0.001) compared to patients receiving midazolam (n = 308, median dose 4 mg). A total of 112 sedation events were registered for 99 patients. Transient apnea was the most prevalent event (n = 73), followed by oxygen desaturation (n = 18) airway obstruction responsive to simple maneuvers (n = 13) and hypotension (n = 6). Propofol sedations were more often associated with the occurrence of apnea's (20% vs. 10%, p = 0.004), whereas clinically relevant oxygen desaturations (< 90%) were found more often in patients sedated with midazolam (8% vs. 1%, p = 0.001). No sedation adverse events were registeredPropofol is more effective and at least as safe as midazolam for procedural sedation in the ED.