Dose-Finding of Alfentanil for Hysteroscopy Under Remimazolam Sedation in Obese and Normal-Weight Patients: An Up-and-Down Trial

Abstract

Background Hysteroscopy is a minimally invasive procedure with rapid recovery. However, obesity may alter opioid pharmacokinetics and pharmacodynamics, and optimal alfentanil dosing remains uncertain. This study estimated the median effective dose (ED50) and explored the 95% effective dose (ED95) of alfentanil for suppressing predefined procedural responses during hysteroscopy under remimazolam sedation in obese and normal-weight patients. Methods This was an up-and-down sequential allocation trial. Patients were classified as obese or normal-weight according to body mass index (BMI). Recruitment and dose allocation were conducted independently within each group until seven crossover pairs were obtained. Alfentanil was administered initially at 10 μg/kg, with subsequent doses adjusted using a 1 μg/kg step size according to the preceding patient’s response. Remimazolam was administered as a 0.4 mg/kg bolus followed by infusion at 1 mg/kg/h, titrated to maintain a bispectral index (BIS) of 40–60. The ED50 was initially estimated using the modified Dixon up-and-down method, followed by probit regression to estimate model-derived ED50 and exploratory ED95. Results Sixty patients (31 normal-weight, 29 obese) were enrolled. Probit regression estimated an ED50 of 9.71 μg/kg (95% confidence interval [CI], 7.81–12.26) in obese patients and 13.67 μg/kg (95% CI, 12.77–15.07) in normal-weight patients (P = 0.001). The corresponding ED95 estimates were 12.57 μg/kg (95% CI, 10.92–28.28) and 16.24 μg/kg (95% CI, 14.92–21.48), respectively. The wider confidence interval for ED95 in obese patients indicated limited precision. Conclusion The total-body-weight (TBW)-normalized ED50 of alfentanil was significantly lower in obese than in normal-weight patients (P = 0.001). The ED95 estimates are model-based and carry substantial uncertainty; no formal hypothesis test was performed for ED95 comparisons. Close respiratory monitoring and individualized titration remain necessary.