TGA疾病状态下依托咪酯和瑞芬太尼的群体药代学及两药相互作用对体肺循环阻力和脑氧摄取率的影响

Based on population pharmacokinetic modeling methods, we found that the pharmacokinetics of etomidate was best estimated using a three-compartment model with allometric scaling of weight on volumes and clearances. Age was a significant covariate of systemic clearance with increasing age having decreasing clearance in children over 6 months. Our further study suggested that central distribution volume in the children with left to right shunt was increased, and to lesser extent, systemic clearance was decreased, compared with health children. Complex congenital heart disease, e.g., TGA (Transposition of the Great Arteries) children's survival is dependent on arterial-venous blood mixed from the atrioventricular defect and/or patent ductus arteriosus (PDA), which is in turn dependent on the balance of systemic-pulmonary vascular resistance before anesthesia. This anatomical feature means that only part of the drug can reach the systemic circulation and target organs after intravenous administration. We thus suspect that the pharmacokinetics and/or pharmacodynamics might be more complex in the pediatric patients with this type of congenital heart disease. In addition, whether anesthetics and analgesics alone or in combination might affect the balance of systemic-pulmonary vascular resistance, and further affect the balance of cerebral oxygen supply/demand in TGA children, all of these are concerned in clinical. However, the related information has been very limited. The aims of this project are designed to characterize firstly the population pharmacokinetics of etomidate and remifentanil in the disease state of TGA, then to investigate the effect of the drug interaction on the function of central nervous system, systemic and pulmonary vascular resistance, and cerebral extraction ratio based on pharmacodynamic response surface model. Based on the above findings, the ultimate goal is to improve the safety and reduce adverse effects of anesthesia induction and maintenance in the disease state of TGA.

我们基于群体建模方法发现大于6月龄小儿依托咪酯药代学表现为异速生长特性且清除率随年龄增加而降低。随后又证实先心左向右分流增加了该药中央室容积，清除率也在一定程度上降低。复杂先心完全性大动脉错位（TGA）患儿的存活依赖源于房室缺或动脉导管未闭的动静脉血混合，后者又依赖于体肺循环阻力平衡。这种解剖特点意味着静脉给药后仅部分药物可进入体循环和靶器官。我们因而猜想这类先心病患儿的麻醉药药代药效学可能更为复杂，此外，麻醉药和镇痛药单用或联合应用是否影响TGA患儿体肺循环阻力平衡，并进而影响脑氧供需平衡同样值得关注，相关研究资料有限。本课题试图以依托咪酯和瑞芬太尼作为静脉麻醉药和镇痛药的代表，首先阐明在TGA疾病状态下两药的群体药代学特点，随后借助药效学相互作用反应曲面模型探索两药对中枢神经系统功能、体肺循环阻力和脑氧摄取率的影响。以期提高TGA疾病状态下患儿麻醉诱导和维持的的安全性。

课题以依托咪酯和瑞芬太尼为工具药，通过基于贝叶斯估计和广义相加模型构建依托咪酯和瑞芬太尼的群体药代动力学（药代学）模型，并阐明药代学在复杂先心病疾病状态下的特点；随后利用建立的模型靶控输注（TCI）不同组合的药物浓度以建立两药对BIS、体肺循环阻力和脑氧代谢影响的反应曲面模型。本课题基于上述模型，完成了以下内容：⑴、探索儿童单次注射依托咪酯麻醉诱导后的药代动力学特点及影响因素，并建立群体药代动力学模型。年龄不影响依托咪酯的药代动力学，提示其代谢途径出生后即已成熟；体质量以异速生长方式影响依托咪酯的药代动力学，提示较小体质量的儿童单位体质量需要更高的输注剂量和速度。⑵、开展了先心病患儿依托咪酯和瑞芬太尼的群体药代动力学研究（短期输注）。先心病患儿依托咪酯的药代动力学适合用三室模型进行描述；异速生长模型进一步改善了模型的拟合优度，也就是说，不管是否存在心脏畸形，儿童两药的药代学特点符合异速生长的规律；与心脏解剖正常的患儿相比，先天性心脏病患儿依托咪酯的中央室清除率（系统清除率）显著降低，后者清除率为前者的73%；但是瑞芬太尼患儿的清除率不受影响。⑶、探索了右美托嘧啶鼻腔滴注用于术前用药对患儿气管插管反应的影响。麻醉诱导前用2μg/kg的右美托咪啶滴鼻可以减轻气管插管引起的平均动脉压（MAP）上升；心率（HR）和脑电双频谱指数（BIS）的变化也提示这种术前给药方式可以有效的减轻插管反应；小儿术前2μg/kg的右美托嘧啶可以产生镇静作用，有利于麻醉诱导。⑷、以脑电双频谱指数(BIS)为效应指标，建立患儿七氟醚药效学模型。儿童需要较高的七氟醚浓度抑制脑电活动，小儿七氟醚药效学模型的特点决定了药物起效与消除较成人更加迅速。⑸、依托咪酯、瑞芬太尼相互作用对TGA患儿脑氧摄取率的影响：研究也评价了不同剂量氢吗啡酮用于小儿先天性心脏病开胸术后静脉镇痛的效果。先心手术患儿术后合用咪达唑仑镇静机械通气时，氢吗啡酮背景剂量3μg/kg/h，NCA剂量3μg/kg静脉镇痛剂量方案可为小儿先心术后患儿提供良好的镇痛且不良反应较少。课题研究结果是对以前药代学研究的补充和进一步思考，对结果的进一步模拟、推论有助于临床建立更为合理的给药方案，并优化麻醉药物的应用。