The Journal of ExtraCorporeal Technology No 56-4 | Page 33

A . J . Whelan et al .: J Extra Corpor Technol 2024 , 56 , 167 – 173 171

Table 2 . Milrinone CRRT clearance effluent concentrations ( ng / mL ).

only slightly lipophilic ( LogP 0.3 – 1 ) and moderately protein bound ( 70 %) [ 19 ]. Therefore , these results are concordant with our hypothesis that the physicochemical properties of milrinone would result in minimal circuit-drug adsorption .

In contrast , milrinone was rapidly cleared by CRRT with concentrations below the lower limit of quantitation by 3 h . In a CRRT system , drugs can be extracted via adsorption to circuit components and / or clearance across the dialysis membrane . For milrinone , the sieving coefficient of 0.7 suggests that most of this loss was due to transmembrane clearance . While additional extraction via adsorption is possible , it is less likely given our findings in the ECMO system . Published pediatric PK literature reports milrinone clearance ranging from 2.91 – 17.6 L / h / 70 kg [ 5 , 38 , 39 ]. The average clearance of milrinone calculated from these three ex vivo circuits was 9.45 L / h / 70 kg and falls within the lower end of the reported range .

These results provide additional insight regarding two published studies describing milrinone exposure in a small cohort of adults ( n = 6 )[ 40 ] and children ( n = 3 )[ 38 ] supported with CRRT . Both studies reported that milrinone clearance was lower in individuals on CRRT compared to those with normal renal function , this is expected as milrinone is renally cleared and total clearance depends on both clearance by CRRT and native renal function . Additionally , clearance due to continuous venovenous hemofiltration estimated in the adult study was lower than the clearance determined through this work . This suggests that the CVVHDF modality results in greater drug clearance than the CVVH modality . These observations confirm that native renal function and CRRT modality , as well as filter type and dialysis prescription , should be incorporated when dosing milrinone in patients on CRRT [ 29 , 30 ].

There are limitations to this work . Milrinone is frequently used as an infusion in patients in the intensive care unit ( ICU ) and this study only included a single bolus dose . Infusion dosing can have an impact on ECLS by saturating adsorption sites . Given that minimal adsorption was observed , this is unlikely to have a substantial impact on our results . Additionally , these experiments were carried out with only one type of ECMO and CRRT circuit components , hemofilters , and surface coatings making it difficult to generalize to circuits using different materials . Another limitation of this study is that milrinone CRRT circuits were all run at the same flow rates that are comparable to flow rates used clinically but do not encompass the heterogeneity seen in clinical practice . Based on our results , flow rates that reflect more aggressive dialysis will increase drug clearance by CRRT [ 31 ]. Finally , optimal milrinone dosing on ECLS cannot be confirmed using ex vivo experiments in isolation as these studies fail to account for patient factors such as organ function , edema , variations in plasma proteins , and patient-circuit factors like increased volume of distribution .

Nevertheless , these results demonstrate that optimal dosing of milrinone in patients on CRRT must account for clearance by the CRRT circuit as well as residual renal function . Future studies that consider important patient pathophysiology are needed to better predict milrinone exposure . We have developed an approach that uses physiologically based pharmacokinetic ( PBPK ) modelling to translate results from ex vivo experiments into optimal dosing recommendations [ 41 ]. PBPK models are structured in a physiologically relevant manner with virtual organ compartments connected by blood flow . Each virtual “ organ ” is parameterized with mass-balance differential equations characterizing the disposition of the drug within the compartment . In order to model drug exposure in patients on ECLS , an ECLS “ organ ” can be linked to the PBPK model and parameterized using data from ex vivo studies [ 32 – 38 ]. Model predictions can then be evaluated by comparing with observed data from patients on ECLS and the drug of interest .

Conclusion

Milrinone is rapidly cleared by CRRT circuits and may require altered dosing in critically ill patients being supported by this therapy . Clinical studies that incorporate patient pathophysiology are needed to inform optimal drug dosing . By contrast , milrinone is not measurably adsorbed to components of an ECMO circuit , thus dosing adjustments to account for adsorption to the ECMO circuit are likely unnecessary . These results will inform clinical studies of optimal dosing in patients requiring ECMO and CRRT and improve the safety and efficacy of milrinone in these vulnerable populations . Funding

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 ). JH receives support from the Thrasher Research Fund . AM receives support from the National Institute of Diabetes and Digestive and Kidney Diseases ( F31DK130542 ). DG receives support from the National Heart , Lung , and Blood Institute ( 2T32HL105321 ). KW receives research support from the National Institute of Child Health and Human Development ( R01HD097775 , R21HD104412 ).

Conflicts of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .

Data availability statement

The research data associated with this article are included in the article .

Author contributions statement

JH , AM , DG , and CI performed the experiments . JM guided and oversaw the analytical aspects of the study . AW , SH , JH , AM , DG , and