Chalkiadis George A, Abdullah Farah, Bjorksten Andrew R, Clarke Alexander, Cortinez Luis I, Udayasiri Sonal, Anderson Brian J
Department of Paediatric Anaesthesia and Pain Management, Royal Children's Hospital, Parkville, Victoria, Australia.
Paediatr Anaesth. 2013 Jan;23(1):58-67. doi: 10.1111/pan.12074. Epub 2012 Nov 20.
To determine if the addition of adrenaline, clonidine, or their combination altered the pharmacokinetic profile of levobupivacaine administered via the caudal epidural route in children.
Children aged <18 years old scheduled to undergo sub-umbilical surgery were administered caudal levobupivacaine plain 2.5 mg · ml(-1) or with adjuvants adrenaline 5 mcg · ml(-1) or clonidine 2 mcg · ml(-1) or their combination. Covariate analysis included weight and postnatal age (PNA). Time-concentration profile analysis was undertaken using nonlinear mixed effects models. A one-compartment linear disposition model with first-order input and first-order elimination was used to describe the data. The effect of either clonidine or adrenaline on absorption was investigated using a scaling parameter (Fabs(CLON), Fabs(ADR)) applied to the absorption half-life (Tabs).
There were 240 children (median weight 11.0, range 1.9-56.1 kg; median postnatal age 16.7, range 0.6-167.6 months). Absorption of levobupivacaine was faster when mixed with clonidine (Fabs(CLON) 0.60; 95%CI 0.44, 0.83) but slower when mixed with adrenaline (Fabs(ADR) 2.12; 95%CI 1.45, 3.08). The addition of adrenaline to levobupivacaine resulted in a bifid absorption pattern. While initial absorption was unchanged (Tabs 0.15 h 95%CI 0.12, 0.18 h), there was a late absorption peak characterized by a Tabs(LATE) 2.34 h (95%CI 1.44, 4.97 h). The additional use of clonidine with adrenaline had minimal effect on the bifid absorption profile observed with adrenaline alone. Neither clonidine nor adrenaline had any effect on clearance. The population parameter estimate for volume of distribution was 157 l 70 kg(-1). Clearance was 6.5 l · h(-1) 70 kg(-1) at 1-month PNA and increased with a maturation half-time of 1.6 months to reach 90% of the mature value (18.5 l · h(-1) 70 kg(-1)) by 5 months PNA.
The addition of adrenaline decreases the rate of levobupivacaine systemic absorption, reducing peak concentration by half. Levobupivacaine concentrations with adrenaline adjuvant were reduced compared to plain levobupivacaine for up to 3.5 hours. Clonidine as an adjuvant results in faster systemic absorption of levobupivacaine and similar concentration time profile to levobupivacaine alone. Adding adrenaline with clonidine does not alter the concentration profile observed with adrenaline alone.
确定加入肾上腺素、可乐定或二者联合使用是否会改变通过骶管硬膜外途径给药的左旋布比卡因在儿童体内的药代动力学特征。
计划接受脐下手术的18岁以下儿童接受骶管注射2.5mg·ml⁻¹的单纯左旋布比卡因，或与5μg·ml⁻¹肾上腺素、2μg·ml⁻¹可乐定或二者联合使用。协变量分析包括体重和出生后年龄（PNA）。使用非线性混合效应模型进行时间-浓度曲线分析。采用具有一级输入和一级消除的单室线性处置模型来描述数据。使用应用于吸收半衰期（Tabs）的标度参数（Fabs(CLON)，Fabs(ADR)）研究可乐定或肾上腺素对吸收的影响。
共有240名儿童（体重中位数11.0，范围1.9 - 56.1kg；出生后年龄中位数16.7，范围0.6 - 167.6个月）。左旋布比卡因与可乐定混合时吸收更快（Fabs(CLON) 0.60；95%CI 0.44，0.83），但与肾上腺素混合时吸收较慢（Fabs(ADR) 2.12；95%CI 1.45，3.08）。左旋布比卡因中加入肾上腺素会导致双峰吸收模式。虽然初始吸收未改变（Tabs 0.15h，95%CI 0.12，0.18h），但存在一个晚期吸收峰，其特征为Tabs(LATE) 2.34h（95%CI 1.44，4.97h）。可乐定与肾上腺素联合使用对单独使用肾上腺素时观察到的双峰吸收曲线影响最小。可乐定和肾上腺素对清除率均无影响。分布容积的群体参数估计值为157l·70kg⁻¹。在出生后1个月时清除率为6.5l·h⁻¹·70kg⁻¹，并以1.6个月的成熟半衰期增加，到出生后5个月时达到成熟值（18.5l·h⁻¹·70kg⁻¹）的90%。
加入肾上腺素可降低左旋布比卡因全身吸收速率，使峰值浓度降低一半。与单纯左旋布比卡因相比，含肾上腺素佐剂的左旋布比卡因浓度在长达3.5小时内降低。可乐定作为佐剂可使左旋布比卡因全身吸收更快，且浓度-时间曲线与单独使用左旋布比卡因相似。将肾上腺素与可乐定联合使用不会改变单独使用肾上腺素时观察到的浓度曲线。
