Pokorna P, Wildschut E D, Vobruba V, van den Anker John N, Tibboel D
Intensive Care and Dept. of Pediatric Surgery, Erasmus MC - Sophia Children's Hospital, Dr. Molewaterplein 60, 3015 GJ The Netherlands.
Curr Pharm Des. 2015;21(39):5705-24. doi: 10.2174/1381612821666150901110929.
Therapeutic hypothermia (HT) is frequently used in neonates with hypoxic-ischemic encephalopathy and young infants during cardiopulmonary bypass (CPB). Hypothermia and CPB result in physiological changes contributing to pharmacokinetic (PK) and pharmacodynamic (PD) changes. Changes in the absorption, the volume of distribution (Vd) and the total body clearance (CL) of drugs used during hypothermia and CPB might lead to the interindividual PK variability resulting in either insufficient or toxic plasma concentrations and have an impact on the biodisposition and action of drugs. Both under- or overdosing of medicines in these critically ill patients may contribute to a worse overall outcome. Overall, hypothermia decreases CL but may decrease or increase Vd by changing intravascular blood volume, organ perfusion and enzymatic metabolic processes. In addition, maturational as well as organ specific changes may occur during hypothermia superimposed on the underlying disease and/or procedures such as extracorporeal membrane oxygenation (ECMO) or CPB. This paper will provide an overview of variables and potential covariates (e.g., asphyxia, sepsis, multiorgan dysfunction syndrome, cardiac arrest) determining the PK of frequently used drugs. In addition, the effects of hypothermia on individual drugs are described as well as alternative ways for future study designs such as the use of population PK-PD and opportunistic sampling. Ultimately, these investigations are warranted to obtain specific dosing nomograms of medicines for use in clinical practice and to improve the treatment results of this vulnerable group of pediatric patients.
治疗性低温（HT）常用于患有缺氧缺血性脑病的新生儿以及体外循环（CPB）期间的幼儿。低温和CPB会导致生理变化，进而引起药代动力学（PK）和药效动力学（PD）的改变。低温和CPB期间所用药物的吸收、分布容积（Vd）和总体清除率（CL）的变化可能导致个体间PK变异性，从而导致血浆浓度不足或中毒，并对药物的生物处置和作用产生影响。在这些重症患者中，药物剂量不足或过量都可能导致更差的总体预后。总体而言，低温会降低CL，但可能通过改变血管内血容量、器官灌注和酶促代谢过程而降低或增加Vd。此外，在低温期间，除了潜在疾病和/或诸如体外膜肺氧合（ECMO）或CPB等操作外，还可能发生成熟以及器官特异性变化。本文将概述决定常用药物PK的变量和潜在协变量（例如，窒息、败血症、多器官功能障碍综合征、心脏骤停）。此外，还描述了低温对个别药物的影响以及未来研究设计的替代方法，例如使用群体PK-PD和机会性抽样。最终，有必要进行这些研究以获得用于临床实践的特定药物剂量图，并改善这一脆弱儿科患者群体的治疗效果。
