Determining the effective dose of esketamine for mitigating pain during propofol injection in children by Dixon's up-and-down method: a single-center, double-blind, prospective clinical study of drug dose-response

Abstract

Abstract Background Short pediatric surgeries and exams use propofol, a widely used intravenous (IV) anesthetic. However, a significant drawback of propofol is the high incidence of injection pain during intravenous administration. This type of pain often causes fear, screams, agitation, and other adverse reactions in children. The younger the age, the higher the incidence and severity of injection pain. We determined the half-effective dose (ED50), 95% effective dose (ED95), and 99% effective dose (ED99) of esketamine for attenuating propofol injection pain in children of different ages using Dixon's up-and-down method in our study, to provide a reference for clinical medication programs for children. Methods Seventy outpatient endoscopic examinations (gastroscopy, colonoscopy, fiber bronchoscopy, etc.) were divided into preschool (3–6 years old) and juvenile (7–17 years old) groups of 35 children each. Esketamine combined with propofol was used to induce anesthesia in children according to Dixon's up-and-down method The target dose of esketamine was injected over 60 s through the left-hand dorsal venous access, followed by propofol (2–3 mg/kg [1 mL/s]) intravenously. During the propofol infusion, intravenous injection pain was assessed every 5 s until the children fell asleep. The pain response was scored using the "four-point method" after propofol infusion. Patient pain response determined the dosage of esketamine. Esketamine was initially 0.3 mg/kg, and the gradient of the adjacent dose was 0.05 mg/kg. The next child's esketamine dose was increased or decreased by 0.05 mg/kg depending on the upper child's pain response assessment. The tests were performed sequentially, with the pain response changing from + to - or from - to +, stopped after at least six crossover points, and the effective dose of esketamine was calculated using probit probability regression analysis. Results In the preschool group, the ED50, ED90, and ED95 of esketamine for mitigating propofol injection pain were 0.315 (0.276, 0.356), 0.405 (0.362, 0.523), and 0.430 (0.381, 0.576) mg/kg, respectively. In the juvenile group, they were 0.221 (0.184, 0.256), 0.308 (0.371, 0.383), and 0.333 (0.290, 0.423). Operation time, recovery time, PAED agitation score during recovery, and Aono's anesthesia recovery score did not differ significantly between groups (P > 0.05). The children's hemodynamics were stable during the study and there were no adverse reactions such as hypotension, bradycardia, nausea, vomiting, or postoperative agitation. Conclusions Low-dose esketamine combined with propofol can be safely and effectively used for outpatient endoscopy. Pre-injection of esketamine at 0.4 mg/kg or 0.3 mg/kg during intravenous propofol induction in children aged 3–6 and 7–17, respectively, alleviated pain caused by propofol with an efficacy greater than 90%. Trial registration Chinese Clinical Trial Registry, ChiCTR2100048951, 19/07/2021. Website: https://www.chictr.org.cn/abouten.aspx.