Cortínez Luis I, De la Fuente Natalia, Eleveld Douglas J, Oliveros Ana, Crovari Fernando, Sepulveda Pablo, Ibacache Mauricio, Solari Sandra
From the Departmento de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Departmento de Cirugía, Escuela de Medicina, Pontificia Universidad Católica de Chile; Departamento de Anestesiología, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo; and Departmento de Laboratorio Clínico, Escuela de Medicina, Pontificia, Universidad Católica de Chile, Santiago, Chile.
Anesth Analg. 2014 Aug;119(2):302-310. doi: 10.1213/ANE.0000000000000317.
Obesity is associated with important physiologic changes that can potentially affect the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anesthetic drugs. We designed this study to assess the predictive performance of 5 currently available propofol PK models in morbidly obese patients and to characterize the Bispectral Index (BIS) response in this population.
Twenty obese patients (body mass index >35 kg/m), aged 20 to 60 years, scheduled for laparoscopic bariatric surgery, were studied. Anesthesia was administered using propofol by target-controlled infusion and remifentanil by manually controlled infusion. BIS data and propofol infusion schemes were recorded. Arterial blood samples to measure propofol were collected during induction, maintenance, and the first 2 postoperative hours. Median performance errors (MDPEs) and median absolute performance errors (MDAPEs) were calculated to measure model performance. A PKPD model was developed using NONMEM to characterize the propofol concentration-BIS dynamic relationship in the presence of remifentanil.
We studied 20 obese adults (mean weight: 106 kg, range: 85-141 kg; mean age: 33.7 years, range: 21-53 years; mean body mass index: 41.4 kg/m, range: 35-52 kg/m). We obtained 294 arterial samples and analyzed 1431 measured BIS values. When total body weight (TBW) was used as input of patient weight, the Eleveld allometric model showed the best (P < 0.0001) performance with MDPE = 18.2% and MDAPE = 27.5%. The 5 tested PK models, however, showed a tendency to underestimate propofol concentrations. The use of an adjusted body weight with the Schnider and Marsh models improved the performance of both models achieving the lowest predictive errors (MDPE = <10% and MDAPE = <25%; all P < 0.0001). A 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (ke0) adequately described the propofol concentration-BIS data. A lag time parameter of 0.44 minutes (SE = 0.04 minutes) to account for the delay in BIS response improved the fit. A simulated effect-site target of 3.2 μg/mL (SE = 0.17 μg/mL) was estimated to obtain BIS of 50, in the presence of remifentanil, for a typical patient in our study.
The Eleveld allometric PK model proved to be superior to all other tested models using TBW. All models, however, showed a trend to underestimate propofol concentrations. The use of adjusted body weight instead of TBW with the traditional Schnider and Marsh models markedly improved their performance achieving the lowest predictive errors of all tested models. Our results suggest no relevant effect of obesity on both the time profile of BIS response and the propofol concentration-BIS relationship.
肥胖与重要的生理变化相关，这些变化可能会影响麻醉药物的药代动力学（PK）和药效动力学（PD）特征。我们设计了这项研究，以评估5种目前可用的丙泊酚PK模型在病态肥胖患者中的预测性能，并描述该人群中的脑电双频指数（BIS）反应。
研究了20例年龄在20至60岁之间、计划进行腹腔镜减肥手术的肥胖患者（体重指数>35kg/m²）。使用丙泊酚靶控输注和瑞芬太尼手动控制输注进行麻醉。记录BIS数据和丙泊酚输注方案。在诱导期、维持期以及术后前2小时采集动脉血样以测量丙泊酚浓度。计算中位性能误差（MDPE）和中位绝对性能误差（MDAPE）以评估模型性能。使用NONMEM开发了一个PKPD模型，以描述在瑞芬太尼存在的情况下丙泊酚浓度与BIS的动态关系。
我们研究了20例肥胖成年人（平均体重：106kg，范围：85 - 141kg；平均年龄：33.7岁，范围：21 - 53岁；平均体重指数：41.4kg/m²，范围：35 - 52kg/m²）。我们获得了294份动脉血样并分析了1431个测量的BIS值。当使用总体重（TBW）作为患者体重输入时，Eleveld异速生长模型表现最佳（P < 0.0001），MDPE = 18.2%，MDAPE = 27.5%。然而，5个测试的PK模型均显示出低估丙泊酚浓度的趋势。使用调整体重结合Schnider和Marsh模型可改善这两个模型的性能，使其达到最低预测误差（MDPE = <10%，MDAPE = <25%；所有P < 0.0001）。一个通过一阶速率常数（ke0）与S形抑制性Emax PD模型相连的三室PK模型充分描述了丙泊酚浓度 - BIS数据。一个0.44分钟（SE = 0.04分钟）的延迟时间参数用于解释BIS反应的延迟，改善了拟合效果。在我们的研究中，对于典型患者，在有瑞芬太尼存在的情况下，估计效应室靶浓度为3.2μg/mL（SE = 0.17μg/mL）时可使BIS达到50。
Eleveld异速生长PK模型在使用TBW时被证明优于所有其他测试模型。然而，所有模型均显示出低估丙泊酚浓度的趋势。使用调整体重而非TBW结合传统的Schnider和Marsh模型显著改善了它们的性能，使其达到所有测试模型中的最低预测误差。我们的结果表明肥胖对BIS反应的时间过程以及丙泊酚浓度 - BIS关系均无显著影响。
