Morse James Denzil, Cortinez Luis Ignacio, Anderson Brian Joseph
Department of Anaesthesiology, University of Auckland, Park Road, Auckland 1023, New Zealand.
División Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
J Clin Med. 2023 Feb 18;12(4):1642. doi: 10.3390/jcm12041642.
The intravenous induction or loading dose in children is commonly prescribed per kilogram. That dose recognizes the linear relationship between volume of distribution and total body weight. Total body weight comprises both fat and fat-free mass. Fat mass influences the volume of distribution and the use of total body weight fails to recognize the impact of fat mass on pharmacokinetics in children. Size metrics alternative to total body mass (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale pharmacokinetic parameters (clearance, volume of distribution) for size. Clearance is the key parameter used to calculate infusion rates or maintenance dosing at steady state. Dosing schedules recognize the curvilinear relationship, described using allometric theory, between clearance and size. Fat mass also has an indirect influence on clearance through both metabolic and renal function that is independent of its effects due to increased body mass. Fat-free mass, lean body mass and ideal body mass are not drug specific and fail to recognize the variable impact of fat mass contributing to body composition in children, both lean and obese. Normal fat mass, used in conjunction with allometry, may prove a useful size metric but computation by clinicians for the individual child is not facile. Dosing is further complicated by the need for multicompartment models to describe intravenous drug pharmacokinetics and the concentration effect relationship, both beneficial and adverse, is often poorly understood. Obesity is also associated with other morbidity that may also influence pharmacokinetics. Dose is best determined using pharmacokinetic-pharmacodynamic (PKPD) models that account for these varied factors. These models, along with covariates (age, weight, body composition), can be incorporated into programmable target-controlled infusion pumps. The use of target-controlled infusion pumps, assuming practitioners have a sound understanding of the PKPD within programs, provide the best available guide to intravenous dose in obese children.
儿童静脉诱导剂量或负荷剂量通常按每千克体重来开具。该剂量考虑到了分布容积与总体重之间的线性关系。总体重包括脂肪和去脂体重。脂肪量会影响分布容积，而使用总体重来计算剂量未能认识到脂肪量对儿童药代动力学的影响。已有人提出用替代总体重的尺寸指标（如去脂体重和正常脂肪量、理想体重和瘦体重）来根据尺寸调整药代动力学参数（清除率、分布容积）。清除率是用于计算输注速率或稳态维持剂量的关键参数。给药方案考虑到了清除率与尺寸之间的曲线关系，这种关系可用异速生长理论来描述。脂肪量还通过代谢和肾功能对清除率产生间接影响，这种影响独立于其因体重增加而产生的作用。去脂体重、瘦体重和理想体重并非药物特异性指标，未能认识到脂肪量对儿童（包括瘦儿童和肥胖儿童）身体组成的不同影响。正常脂肪量与异速生长理论结合使用，可能是一个有用的尺寸指标，但临床医生为个体儿童进行计算并不容易。由于需要多室模型来描述静脉药物的药代动力学，且浓度效应关系（包括有益和有害关系）往往难以理解，给药变得更加复杂。肥胖还与其他可能影响药代动力学的疾病相关。最好使用考虑了这些不同因素的药代动力学 - 药效学（PKPD）模型来确定剂量。这些模型以及协变量（年龄、体重、身体组成）可纳入可编程的靶控输注泵中。假设从业者对程序中的PKPD有充分理解，使用靶控输注泵可为肥胖儿童的静脉给药提供最佳指导。
