A New Method for Comprehensive Analysis of Benzodiazepine, Opioid, and Propofol Interactions and Dose Selection Rationales in Gastrointestinal Endoscopy Sedation

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BACKGROUND: The aim of this study was to explore a new method for determining optimal dosing regimens for combinations of propofol, midazolam, and an opioid to achieve rapid on- and off-set of deep sedation. METHODS: We simulated 16 published dosing regimens using a well-validated pharmacodynamic model. The study was divided into 2 parts. First, the regimen that best provided deep sedation and rapid recovery was selected. A deep sedation-time area-under-the-curve (AUC) method was used to compare published dosing regimens; a higher AUC indicated better sedation and faster recovery. Second, subgroup analysis of the best-performing dosing regimen was undertaken better to understand how each drug affected patient recovery. RESULTS: The AUC method identified a combination of midazolam 1 mg, alfentanil 500 µg, and propofol target infusion effect-site concentration (Ce) 2 µg mL -1 as the optimal regimen ( P < .01). Propofol correlated with high probability of sedation and increased AUC (R 2 = 0.53), whereas midazolam had a significant impact on time to return of consciousness (R 2 = 0.86). Subgroup analysis indicated that regimens consisting of a fixed dose of alfentanil and either 5 µg mL -1 Ce propofol, or 1 mg midazolam with 3-5 µg mL -1 Ce of propofol, or 2 mg midazolam with 2 µg mL -1 Ce propofol provided adequate sedation and rapid recovery. Midazolam >3 mg greatly prolonged recovery. CONCLUSIONS: This study used a clinically relevant method and model simulation to determine suitable sedation regimens for use in gastrointestinal endoscopy. A balanced propofol, midazolam, and an opioid should be used. The AUC method was capable of providing objective assessments for model selection.