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Pharmacokinetics of Commonly Used Medications in Children Receiving Continuous Renal Replacement Therapy: A Systematic Review of Current Literature

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Abstract

Background and Objective

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.

Methods

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.

Results

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.

Conclusions

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.

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Correspondence to Andrea Edginton.

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Dr. Watt receives support for pediatric research from the National Institute of Child Health and Human Development (R01HD097775, R21HD104412).

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SD, KW, and AE conceptualized the idea and topic of this systematic review. SD with guidance of KW and AE designed the framework for conducting this review and analysis. With the help of CC in building the search strategy, SD, SB, and BA performed the initial literature search and first-level and second-level screening of the applicable studies. SD was the third reviewer to resolve any discrepancies in SB and BA’s independent screen. SD, SB, and BA conducted the qualitative assessment using the ClinPK tool. Preparation of final manuscript was conducted by SD. CY was consulted for assistance with methodology and review of the final manuscript. The final version of the manuscript was reviewed by all authors.

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Dubinsky, S., Watt, K., Saleeb, S. et al. Pharmacokinetics of Commonly Used Medications in Children Receiving Continuous Renal Replacement Therapy: A Systematic Review of Current Literature. Clin Pharmacokinet 61, 189–229 (2022). https://doi.org/10.1007/s40262-021-01085-z

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