164 C . C . Honeycutt et al .: J Extra Corpor Technol 2023 , 55 , 159 – 166
by fluid removal rate . In order to determine optimal dosing , future experiments that evaluate multiple fluid removal rates are necessary . Lastly , the results of ex vivo experiments , while modeling physiological conditions , do not recapitulate the physiological complexity of critically ill patients and are insufficient to guide optimal drug dosing recommendations . Factors including increased volume of distribution , altered drug clearance due to inflammation and other processes , and rapid changes in clinical condition ( either improvements or deteriorations ) contribute to the challenging problem of optimizing drug dosing in critically ill patients [ 43 ].
To address this , in the future , these data from ex vivo ECMO and CRRT circuits can be incorporated into physiologically based pharmacokinetic ( PBPK ) models , which integrate pharmacological and physiological data from critically ill patients to predict drug dosing requirements more accurately [ 44 , 45 ]. In this manner , the data presented here concerning meropenem recovery and extraction can be utilized as a parameter to inform and improve PBPK models for critically ill patients concurrently on meropenem and ECLS . Follow-up clinical studies should additionally be conducted to confirm our ex vivo findings .
Acknowledgements . We are grateful to Mike Lowe for technical support during the experiments and to the American Red Cross for the supply of expired blood products .
Conflict of interest The authors declare no conflict of interest .
Funding
This work was supported by the National Institutes of Health ( 1R01HD097775 ). In addition , JH receives support from the Thrasher Research Fund . AM receives support from the National Institute of Diabetes and Digestive and Kidney Diseases ( F31DK130542 ) and the American Foundation for Pharmaceutical Education Pre-Doctoral Research Fellowship in Pharmaceutical Sciences . DG receives support from the National Heart , Lung , and Blood Institute ( 2T32HL105321 ). AW receives support from The Indiana University-Ohio State University Maternal and Pediatric Precision in Therapeutics Data , Model , Knowledge , and Research Coordination Center ( IU-OSU MPRINT DMKRCC ), in part by Grant Number P30HD106451 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) Obstetrics and Pediatric Pharmacology and Therapeutics Branch ( OPPTB ).
Data availability
The research data associated with this article are included within the article .
Ethics
The ECMO experiments were performed at Duke University and the CRRT experiments were performed at the
University of Utah . Both institutions ’ Institutional Review Boards provided waivers of review because the protocol met the definition of research not involving human subjects .
Author contributions
K . M . W . designed the studies . C . C . H , C . G . M ., A . M ., J . P . H ., A . W ., D . J . G ., and K . M . W . performed the research and analyzed the data . C . C . H and K . M . W . wrote the manuscript , and all authors contributed to the final version .
Supplementary material
The supplementary material of this article is available at https :// ject . edpsciences . org / 10.1051 / ject / 2023035 / olm
Supplemental Table 1 . Raw data from ECMO and CRRT circuits and controls .
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