上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2021 , Vol. 41 >Issue 10: 1313 - 1317

DOI: https://doi.org/10.3969/j.issn.1674-8115.2021.10.007

论著 · 临床研究

非线性混合效应模型基于异速生长方程拟合上下法实验数据确定儿童右美托咪定半数有效量

  • 许文音 ,
  • 黄贞玲 ,
  • 黄咏磊 ,
  • 张瑞冬 ,
  • 王璐 ,
  • 张莺 ,
  • 白洁 ,
  • 郑吉建
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  • 1.上海交通大学医学院附属上海儿童医学中心麻醉科，上海 200127
    2.上海交通大学医学院附属仁济医院麻醉科，上海 200001
许文音（1972—），女，主治医师，学士；电子信箱：xwy8@sina.com。
黄咏磊，电子信箱：8771@renji.com。

网络出版日期: 2021-09-22

基金资助

上海市科学技术委员会医学引导类（中、西医）科技支撑项目(17411965500)

收起

Half effective bolus dose of dexmedetomidine of children derived from the up-and-down experimental data based on the analysis of nonlinear mixed effects model with allometric equation

  • Wen-yin XU ,
  • Zhen-ling HUANG ,
  • Yong-lei HUANG ,
  • Rui-dong ZHANG ,
  • Lu WANG ,
  • Ying ZHANG ,
  • Jie BAI ,
  • Ji-jian ZHENG
Expand
  • 1.Department of Anesthesiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
    2.Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200001, China
HUANG Yong-lei, E-mail: 8771@renji.com.

Online published: 2021-09-22

Supported by

Shanghai Science and Technology Commission Medical Guidance;Science and Technology Support Project(17411965500)

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摘要

目的·探索采用非线性混合效应模型基于异速生长方程拟合上下法临床实验数据，以确定儿童半数有效量（median effective dose，ED50）的可行性。方法·对22例2~12岁阻塞型睡眠呼吸暂停（obstructive sleep apnea，OSA）患儿采用右美托咪定复合艾司氯胺酮诱导睡眠并实施气道镜检查（drug-induced sleep endoscopy，DISE）。患儿静注艾司氯胺酮0.5 mg/kg，同时开始静脉输注预设剂量右美托咪定10 min，如置入内镜时无体动和/或呛咳并完成DISE检查视为镇静成功，反之为镇静失败。根据上下法确定右美托咪定剂量，初始剂量1.0 μg/kg（剂量间隔1.2倍）。10 min后开始DISE检查。Dixon-Massey公式和非线性混合效应模型拟合用于计算ED50。结果·9例OSA患儿镇静成功，13例患儿失败。Dixon-Massey公式计算的右美托咪定ED50值1.9 μg/kg与非线性混合效应模型拟合值2.0 μg/kg相似。引入异速生长方程模型拟合效果显著改善（P<0.05），将成人体质量标准化为70 kg后，儿童ED50和ED95值分别为5.76×（体质量/70） μg/kg和11.5×（体质量/70） μg/kg，量效关系的斜率为4.25。结论·上下法实验数据可采用非线性混合效应模型基于异速生长方程拟合。相比Dixon-Massey公式的优点是可同时确定药物ED50、ED95以及量效关系的斜率，且这种方法有助于确定协变量的影响。

关键词： 儿童; 右美托咪定; 非线性混合效应; 异速生长; 上下法

本文引用格式

许文音 , 黄贞玲 , 黄咏磊 , 张瑞冬 , 王璐 , 张莺 , 白洁 , 郑吉建 . 非线性混合效应模型基于异速生长方程拟合上下法实验数据确定儿童右美托咪定半数有效量[J]. 上海交通大学学报（医学版）, 2021 , 41(10) : 1313 -1317 . DOI: 10.3969/j.issn.1674-8115.2021.10.007

Abstract

Objective

·To explore the application of nonlinear mixed effects model based on the allometric equation on up-and-down data to determine the half effective dose (ED50) in pediatric patients.

Methods

·Twenty-two pediatric patients aged 2 to 12 years with obstructive sleep apnea (OSA) who were undergoing drug-induced sleep endoscopy (DISE) were enrolled. All patients received intravenous bolus S+-ketamine 0.5 mg/kg. At the same time, a predetermined bolus dose of dexmedetomidine was infused continuously over 10 min for anesthesia induction. The bolus dose of dexmedetomidine was calculated according to the Dixon up-and-down method with initial dose 1.0 μg/kg and step size 1.2 times. DISE was conducted 10 min after dexmedetomidine infusion, and the response of the patients to the procedure was recorded. Dixon-Massey formula and nonlinear mixed effects model fitting are used to calculate ED50.

Results

·There were 9 and 13 children with successful and failed sedation. The value of dexmedetomidine ED50, 1.9 μg/kg, calculated by Dixon-Massey formula was similar to the fitting value, 2.0 μg/kg, of nonlinear mixed effects model. The introduction of allometric equation significantly improved the model (P<0.05). After normalizing adults' body weight to 70 kg, the ED50 and ED95 were 5.76×(body weight/70) μg/kg and 11.5×(body weight/70) μg/kg, and the slope (γ) of the dose-response relationship of dexmedetomidine is 4.25.

Conclusion

·The experimental data from the up-and-down method can be fitted with a nonlinear mixed effects model based on the allometric equation. Compared with the Massey formula, the advantage is that the ED50, ED95 and γ can be determined at the same time, and this method helps to determine the possible effect of covariates.

Key words： children; dexmedetomidine; nonlinear mixed effects; allometric; up-and-down method

参考文献

1 Peltoniemi MA, Hagelberg NM, Olkkola KT, et al. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy[J]. Clin Pharmacokinet, 2016, 55(9): 1059-1077.
2 张剑蔚,宋蕴安,张瑞冬,等.右美托咪定复合氯胺酮用于阻塞型睡眠呼吸暂停综合征患儿行药物诱导睡眠气道镜检查的可行性研究[J].国际麻醉学与复苏杂志,2021,42(02):151-154.
3 Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology--drug disposition, action, and therapy in infants and children[J]. N Engl J Med, 2003, 349(12): 1157-1167.
4 Allen SM, Madrio ME. Ramsay sedation scale project: small, easy changes for a big effect on patient safety[J]. Crit Care Nurse, 2019, 39(4): 64-66.
5 Bush B, Tobias JD, Lin C, et al. Postoperative bradycardia following adenotonsillectomy in children: does intraoperative administration of dexmedetomidine play a role?[J]. Int J Pediatr Otorhinolaryngol, 2018, 104: 210-215.
6 Dixon WJ. The up-and-down method for small samples[J]. J Am Stat Assoc, 1965, 60(312): 967-978.
7 Beal SL, Sheiner LB. NONMEM user's guide[M]. San Francisco: NONMEM Project Group, University of California, 1992.
8 Ehsan Z, Mahmoud M, Shott SR, et al. The effects of anesthesia and opioids on the upper airway: a systematic review[J]. Laryngoscope, 2016, 126(1): 270-284.
9 Mahmoud M, Mason KP. Dexmedetomidine: review, update, and future considerations of paediatric perioperative and periprocedural applications and limitations[J]. Br J Anaesth, 2015, 115(2): 171-182.
10 Koinig H, Marhofer P. S+-ketamine in paediatric anaesthesia[J]. Paediatr Anaesth, 2003, 13(3): 185-187.
11 Pérez-Guillé MG, Toledo-López A, Rivera-Espinosa L, et al. Population pharmacokinetics and pharmacodynamics of dexmedetomidine in children undergoing ambulatory surgery[J]. Anesth Analg, 2018, 127(3): 716-723.
12 Kazama T, Ikeda K, Morita K, et al. Comparison of the effect-site keOs of propofol for blood pressure and EEG bispectral index in elderly and younger patients[J]. Anesthesiology, 1999, 90(6): 1517-1527.
13 陈怡绮,张马忠,王璐,等.口服水合氯醛用于先天性心脏病患儿心脏彩超检查镇静的药效学[J].中华麻醉学杂志,2014,34(2):199-202.
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