小儿自主呼吸时对芬太尼最大耐受剂量的研究

Maximum tolerated dose of fentanyl in children with spontaneous ventilation

摘要:

目的：用持续重复评估方案（continual reassessment method，CRM）确定芬太尼复合咪达唑仑用于患儿骶管阻滞静脉注射镇静时，患儿在保留自主呼吸情况下对芬太尼的最大耐受剂量（maximum tolerated dose，MTD）。方法：本研究为前瞻性队列研究，选择骶管阻滞的择期手术患儿：2~6岁、ASA Ⅰ级或Ⅱ级。根据临床经验，在1.0～2.0 mg/kg设定6个芬太尼剂量，并预先估计各剂量可能引起患儿呼吸抑制的发生率（先验概率）分别为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%）和2.0 μg/kg（60%）。以最接近10%呼吸抑制发生率的剂量作为患儿的试验剂量。每3例患儿为一组，组内患儿给予相同剂量的芬太尼，观察3例中发生呼吸抑制的情况。根据观察结果，结合先验概率，对各剂量的芬太尼可能引起患儿发生呼吸抑制的概率进行重新评估，得到后验概率。重复该过程，直至满足试验停止的标准时结束试验。当出现呼吸频率≤10次/min、呼吸停止的时间＞5 s、SpO2＜94%或PETCO2＞70 mmHg中任何一种情况时，即认为发生呼吸抑制。结果：当满足试验终止条件，即达到规定样本量（>24例），下一组患儿分配的试验剂量保持不变的预测概率>0.95，以及下一组患儿MTD的呼吸抑制发生率及其95%CI宽度的平均预测增益<0.05时，共纳入研究对象27例。最终结果1.8 μg/kg芬太尼所引起的患儿呼吸抑制发生率为8.7%（95%CI=1.5%~26.2%），最接近靶概率10%。结论：CRM用有限的样本量即可确定芬太尼的MTD，芬太尼复合咪达唑仑用于患儿骶管阻滞静脉注射镇静时，1.8 μg/kg芬太尼引起呼吸抑制的发生率为8.7%。

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.