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

Abstract

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. 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. 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. 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.