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The primary objective of the present study was to compare the required dose of intravenous (IV) propofol between group A (synergistic sedation with an oral dose of midazolam combined with IV propofol) and group B (IV propofol alone), in diagnostic upper gastrointestinal endoscopy (UGIE) in pediatric patients. The secondary objective was to compare the safety, the efficacy, the ease of IV line placement and the ease of separation from parents between the 2 groups.Fifty-four consecutive children (aged 3 y or older) who underwent UGIE were randomly assigned to 1 of the 2 medication regimens. Patients in group A (n = 26, mean age: 8.1 y) received midazolam (0.5 mg/kg) orally. Thirty minutes after the midazolam dose was given, repeated IV doses of propofol 0.5 mg/kg were administered titrated to achieve the level of deep sedation. Patients in group B (n = 28, mean age: 9 y) received IV propofol alone with the same methodology and sedation end point.The mean dose (1.8 ± 0.7 mg/kg) of propofol administered in group A patients was remarkably lower compared with that (2.9 ± 0.9 mg/kg) of group B. Multivariate stepwise logistic regression analysis revealed that among sex, age, ASA grade and the type of sedation, the synergistic sedation was the only factor associated with the ease of IV line placement (χ2 = 16.3, P < 0.001) and the ease of separation from parents (χ2 = 41.6, P < 0.001). Additional multivariate stepwise logistic regression analysis revealed that among sex, age, ASA grade and the type of sedation, synergistic sedation was the only factor associated with a higher level of patient comfort (χ2 = 35.5, P < 0.001). The recovery time was significantly shorter in group B patients (7.7 ± 3.6 min) compared with that of group A (25.9 ± 4.1 minutes) (P < 0.01). The 2 regimens were equally safe.Our data suggest that synergistic sedation with an oral dose of midazolam combined with propofol may benefit the children who undergo UGIE with regard to lower mean dose of propofol used, easier IV line placement, easier separation from the parents, less pain induced by the IV line placement and greater patient comfort.