Bartkowska-Śniatkowska Alicja, Bienert Agnieszka, Wiczling Paweł, Owczarek Marcin, Rosada-Kurasińska Jowita, Grześkowiak Małgorzata, Matysiak Jan, Kokot Zenon J, Kaliszan Roman, Grześkowiak Edmund
Department of Pediatric Anesthesiology and Intensive Therapy, Poznań University of Medical Sciences, Poznań, Poland.
Department of Clinical Pharmacy and Biopharmacy, Poznań University of Medical Sciences, Poznań, Poland.
Pharmacol Rep. 2014 Oct;66(5):821-9. doi: 10.1016/j.pharep.2014.04.012. Epub 2014 May 10.
Propofol is a commonly used agent in total intravenous anesthesia (TIVA). However, the link between its pharmacokinetics and pharmacodynamics has not been fully characterized in children yet. Our aim was to determine the quantitative relationship between the venous plasma concentration and bispectral index (BIS) effect in a heterogeneous group of pediatric patients undergoing various surgical procedures (ASA status I-III).
Nine male and nine female patients were anesthetized with propofol-fentanyl TIVA. Sparse venous samples for propofol concentrations assay and dense BIS measurements were collected during and after the end of infusion. Nonlinear mixed-effect modeling in NONMEM was used for data analysis.
A three-compartment model was linked with a classical Emax model through a biophase compartment to describe the available data. All clearance and volume terms were allometrically scaled to account for the body mass difference among the patients under study. A typical patient had their PK parameters observed within the range of literature values for children. The pharmacodynamic parameters were highly variable. The EC50 of 2.80 mg/L and the biophase distribution rate constant of 3.33 min(-1) were found for a typical patient.
The BIS values in children are highly correlated with the propofol effect compartment concentrations according to the classical Emax concentration-response relationship. Children had slightly lower sensitivity to propofol and slightly higher clearance, as compared with the adult data available in literature. The intra-patient variations in the BIS require the anesthesiologist's attention in using BIS values alone to evaluate the depth of anesthesia in children.
丙泊酚是全静脉麻醉（TIVA）中常用的药物。然而，其药代动力学和药效学之间的联系在儿童中尚未得到充分表征。我们的目的是确定接受各种外科手术（ASA分级I - III级）的异质儿科患者群体中静脉血浆浓度与脑电双频指数（BIS）效应之间的定量关系。
18例患者（9例男性和9例女性）接受丙泊酚 - 芬太尼全静脉麻醉。在输注期间和结束后采集用于丙泊酚浓度测定的稀疏静脉血样以及密集的BIS测量值。使用NONMEM中的非线性混合效应模型进行数据分析。
通过一个双相室将三室模型与经典的Emax模型相联系，以描述现有数据。所有清除率和容积项均进行了异速标度，以考虑所研究患者之间的体重差异。典型患者的药代动力学参数在儿童文献值范围内。药效学参数高度可变。发现典型患者的半数有效浓度（EC50）为2.80 mg/L，双相分布速率常数为3.33 min⁻¹。
根据经典的Emax浓度 - 反应关系，儿童的BIS值与丙泊酚效应室浓度高度相关。与文献中可用的成人数据相比，儿童对丙泊酚的敏感性略低，清除率略高。在仅使用BIS值评估儿童麻醉深度时，患者体内BIS值的变化需要麻醉医生予以关注。
