Anderson Brian Joseph, Cortinez Luis Ignacio
Department of Anaesthesiology, University of Auckland, Park Road, Auckland 1023, New Zealand.
División Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago de Chile 8331150, Chile.
Children (Basel). 2023 Mar 27;10(4):625. doi: 10.3390/children10040625.
Acetaminophen is a commonly used perioperative analgesic drug in children. The use of a preoperative loading dose achieves a target concentration of 10 mg/L associated with a target analgesic effect that is 2.6 pain units (visual analogue scale 1-10). Postoperative maintenance dosing is used to keep this effect at a steady-state concentration. The loading dose in children is commonly prescribed per kilogram. That dose is consistent with the linear relationship between the volume of distribution and total body weight. Total body weight is made up of both fat and fat-free mass. The fat mass has little influence on the volume of distribution of acetaminophen but fat mass should be considered for maintenance dosing that is determined by clearance. The relationship between the pharmacokinetic parameter, clearance, and size is not linear. A number of size metrics (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale clearance and all consequent dosing schedules recognize curvilinear relationships between clearance and size. This relationship can be described using allometric theory. Fat mass also has an indirect influence on clearance that is independent of its effects due to increased body mass. Normal fat mass, used in conjunction with allometry, has proven a useful size metric for acetaminophen; it is calculated using fat-free mass and a fraction (Ffat) of the additional mass contributing to total body weight. However, the Ffat for acetaminophen is large (Ffat = 0.82), pharmacokinetic and pharmacodynamic parameter variability high, and the concentration-response slope gentle at the target concentration. Consequently, total body weight with allometry is acceptable for the calculation of maintenance dose. The dose of acetaminophen is tempered by concerns about adverse effects, notably hepatotoxicity associated with use after 2-3 days at doses greater than 90 mg/kg/day.
对乙酰氨基酚是儿童围手术期常用的镇痛药物。术前给予负荷剂量可使血药浓度达到10 mg/L的目标值，产生相当于2.6个疼痛单位（视觉模拟评分1 - 10）的目标镇痛效果。术后维持给药用于使该效果维持在稳态浓度。儿童的负荷剂量通常按每千克体重来开具。该剂量与分布容积和总体重之间的线性关系一致。总体重由脂肪和去脂体重组成。脂肪量对乙酰氨基酚的分布容积影响较小，但在根据清除率确定维持剂量时应考虑脂肪量。药代动力学参数清除率与体型之间的关系并非线性。已提出多种体型指标（如去脂体重和正常脂肪量、理想体重和瘦体重）来调整清除率，所有后续给药方案都认识到清除率与体型之间的曲线关系。这种关系可用异速生长理论来描述。脂肪量对清除率也有间接影响，这种影响独立于其因体重增加而产生的影响。已证明，将正常脂肪量与异速生长理论结合使用，对于乙酰氨基酚来说是一种有用的体型指标；它是根据去脂体重和对总体重有贡献的额外体重的一部分（Ffat）来计算的。然而，乙酰氨基酚的Ffat值较大（Ffat = 0.82），药代动力学和药效学参数变异性较高，且在目标浓度下浓度 - 反应斜率较平缓。因此，结合异速生长理论使用总体重来计算维持剂量是可以接受的。对乙酰氨基酚的剂量会因对不良反应的担忧而有所调整，尤其是担心连续2 - 3天使用剂量大于90 mg/kg/天会导致肝毒性。
