School of Pharmacy, University of Waterloo, 10 Victoria St S. Kitchener, Waterloo, ON, N2G 1C5, Canada.
Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.
Clin Pharmacokinet. 2022 Feb;61(2):189-229. doi: 10.1007/s40262-021-01085-z. Epub 2021 Nov 30.
The use of continuous renal replacement therapy (CRRT) for renal support has increased substantially in critically ill children compared with intermittent modalities owing to its preferential effects on hemodynamic stability. With the expanding role of CRRT, the quantification of extracorporeal clearance and the effect on primary pharmacokinetic parameters is of the utmost importance. Within this review, we aimed to summarize the current state of the literature and compare published pharmacokinetic analyses of commonly used medications in children receiving CRRT to those who are not.
A systematic search of the literature within electronic databases PubMed, EMBASE, Cochrane Library, and Web of Science was conducted. Published studies that were included contained relevant information on the use of commonly administered medications to children, from neonates to adolescents, receiving CRRT. Pharmacokinetic parameters that were analyzed included volume of distribution, total clearance, extracorporeal clearance, area under the curve, and elimination half-life. Information regarding CRRT circuit, flow rates, and membrane components was analyzed to investigate differences in pharmacokinetics between each modality.
Forty-five studies met the final inclusion criteria within this systematic review, totaling 833 pediatric patients, with 586 receiving CRRT. Antimicrobials were the most common pharmacological class represented within the literature, representing 81% (35/43) of studies analyzed. Children receiving CRRT largely had similar volume of distribution and total clearance to critically ill children not receiving CRRT, suggesting reno-protective dose adjustments may lead to subtherapeutic dosing regimens in these patients. Overall, there was a tendency for hydrophilic agents, with a low protein binding to undergo elevated total clearance in these children. However, results should be interpreted with caution because of the large variability amongst patient populations and heterogeneity with CRRT modalities, flow rates, and use of extracorporeal membrane oxygenation within studies. This review was able to identify that variation in solute removal, or CRRT modalities, properties (i.e., flow rates), and membrane composition, may have differing effects on the pharmacokinetics of commonly administered medications.
The current state of the literature regarding medications administered to children receiving CRRT largely focuses on antimicrobials. Significant gaps remain with other commonly used medications such as sedatives and analgesics. Overall reporting of patient clinical characteristics, CRRT settings, and circuit composition was poor, with only 10% of articles including all relevant information to assess the impact of CRRT on total clearance. Changes in pharmacokinetics because of CRRT often required higher than labeled doses, suggesting renally adjusted or reno-protective doses may lead to subtherapeutic dosing regimens. A thorough understanding of the interplay between patient, drug, and CRRT-circuit factors are required to ensure adequate delivery of dosing regimens to this vulnerable population.
与间歇性方式相比，连续肾脏替代疗法（CRRT）在危重病儿童中的肾支持作用大大增加，这是因为它对血流动力学稳定性具有更好的效果。随着 CRRT 作用的不断扩大，对外科清除率的量化及其对主要药代动力学参数的影响至关重要。在本次综述中，我们旨在总结文献现状，并比较接受 CRRT 治疗的儿童与未接受 CRRT 治疗的儿童常用药物的已发表药代动力学分析。
我们在电子数据库 PubMed、EMBASE、Cochrane 图书馆和 Web of Science 中进行了文献系统搜索。纳入的研究包含有关接受 CRRT 治疗的儿童（从新生儿到青少年）常用药物使用的相关信息。分析的药代动力学参数包括分布容积、总清除率、体外清除率、曲线下面积和消除半衰期。还分析了 CRRT 回路、流速和膜成分的信息，以研究每种方式之间的药代动力学差异。
这项系统综述共纳入 45 项研究，最终符合纳入标准的患者总数为 833 例，其中 586 例接受了 CRRT 治疗。抗生素是文献中最常见的药物类别，占分析的 35/43 项研究。接受 CRRT 的儿童与未接受 CRRT 的危重病儿童的分布容积和总清除率大致相似，这表明肾保护剂量调整可能导致这些患者的治疗剂量不足。总体而言，亲水性药物、蛋白结合率低的药物，在这些儿童中总清除率较高。但是，由于患者人群的变异性很大，并且研究中 CRRT 方式、流速以及体外膜氧合的异质性，结果应谨慎解释。本综述能够确定溶质清除率或 CRRT 方式、特性（即流速）和膜组成的变化，可能对常用药物的药代动力学产生不同的影响。
目前有关接受 CRRT 治疗的儿童用药的文献主要集中在抗生素上。关于镇静剂和镇痛药等其他常用药物，仍存在很大差距。总体而言，患者临床特征、CRRT 设置和回路组成的报告很少，只有 10%的文章包含评估 CRRT 对总清除率影响的所有相关信息。由于 CRRT 导致的药代动力学变化通常需要高于标签剂量的药物，这表明肾调整或肾保护剂量可能导致治疗剂量不足。为了确保为这一脆弱人群提供足够的剂量方案，需要全面了解患者、药物和 CRRT 回路因素之间的相互作用。
