Maximum tolerated dose of fentanyl in children with spontaneous ventilation

Abstract:

Objective：To estimate the maximum tolerated dose（MTD） of fentanyl for sedations in pediatric caudal block anesthesia us－ing the continual reassessment method（CRM）. Methods：This is a double-blind and prospective study. Six dose levels of fentanyl were chosen before the study started，with the probability of respiratory depression associated with each：1.0 μg/kg（10%）、1.2 μg/kg（20%）、1.4 μg/kg（30%）、1.6 μg/kg（40%）、1.8 μg/kg（50%） and 2.0 μg/kg（60%）. Recruited children were allocated to the same dose of fentanyl by a cohort，each containing 3 individuals. The dose of fentanyl received in each cohort was determined by the responses of all previous patients. MTD was defined as 10% incidence of respiratory depression. Respiratory depression was determined as the respi－ratory rate≤10 b/min，the duration of apnea＞5 s，SpO2＜94% and PETCO2＞70 mmHg. Results：Twenty-seven children were enrolled when it reached to the stopping point according to the principal of CRM. The first decision was to stop the trial when the predetermined fixed sample size was reached. The second stopping decision was due to no change in administered dose level among the next patients（rule 3 above 0.95）. The third decision of stopping based on a sufficient level of reliability in the predictive mean and maximum gain from further patients inclusions on the probability of respiratory depression and width of the associated credibility interval（rule 4 and 6 below 0.05）. The estimated MTD of fentanyl was 1.8 μg/kg with a final estimated probability of respiratory depression of 8.7%（95%CI=1.5% to 26.2%）. Conclusion：CRM can be used to ensure the MTD of fentanyl with limited sample size. The estimated MTD of fentanyl is 1.8 μg/kg.