J Extra Corpor Technol 2024 , 56 , 167 – 173 Ó The Author ( s ), published by EDP Sciences , 2024 https :// doi . org / 10.1051 / ject / 2024014
Available online at : ject . edpsciences . org
ORIGINAL ARTICLE
Interaction of milrinone with extracorporeal life support
Aviva J . Whelan ( MD ) 1 , 2 , Sabiha Mim ( MSc ) 3 , J . Porter Hunt ( PhD ) 1 , Autumn M . McKnite ( PhD ) 4 , Danielle J . Green ( MD , MSCI ) 1 , 2 , Carina E . Imburgia ( BSc ) 1 , Jeremiah D . Momper ( Pharm . D ., PhD ) 5 , Gideon Stitt ( Pharm . D ., BCPPS , BCCCP ) 1 , and Kevin M . Watt ( MD , PhD ) 1 , 2 ,*
1 Division of Clinical Pharmacology , Department of Pediatrics , University of Utah , 295 Chipeta Way , Salt Lake City , UT 84108 , USA 2 Division of Pediatric Critical Care , Department of Pediatrics , University of Utah , 295 Chipeta Way , Salt Lake City , UT 84108 , USA 3 Pharmacometric Research Group , Department of Pharmacy , Uppsala University , Husargatan , Uppsala 752 37 , Sweden 4 Department of Pharmacology and Toxicology , University of Utah , 295 Chipeta Way , Salt Lake City , UT 84108 , USA 5 Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California San Diego , 9255 Pharmacy Lane , MC 0657 ,
La Jolla , CA 92093 , USA Received 2 February 2024 , Accepted 12 June 2024
Abstract – Background : Milrinone is commonly prescribed to critically ill patients who need extracorporeal life support such as extracorporeal membrane oxygenation ( ECMO ) and continuous renal replacement therapy ( CRRT ). Currently , the effect of ECMO and CRRT on the disposition of milrinone is unknown . Methods : Ex vivo ECMO and CRRT circuits were primed with human blood and then dosed with milrinone to study drug extraction by the circuits . Milrinone percent recovery over time was calculated to determine circuit component interaction with milrinone . Results : Milrinone did not exhibit measurable interactions with the ECMO circuit , however , CRRT cleared 99 % of milrinone from the experimental circuit within the first 2 hours . Conclusion : Milrinone dosing adjustments are likely required in patients who are supported with CRRT while dosing adjustments for ECMO based on these ex-vivo results are likely unnecessary . These results will help improve the safety and efficacy of milrinone in patients requiring ECMO and CRRT . Due to the limitations of ex-vivo experiments , future studies of milrinone exposure with ECLS should include patient circuit interactions as well as the physiology of critical illness .
Key words : Milrinone , Extracorporeal life support ( ECLS ), Extracorporeal membrane oxygenation ( ECMO ), Continuous renal replacement therapy ( CRRT ).
Introduction
Patients undergoing cardiopulmonary bypass ( CPB ) are at risk of low cardiac output syndrome ( LCOS ). LCOS and heart failure are conditions that frequently require support with extracorporeal life-support ( ECLS ) such as extracorporeal membrane oxygenation ( ECMO ) and continuous renal replacement therapy ( CRRT ) [ 1 , 2 ]. Milrinone is frequently used in critically ill patients supported on ECLS and has been shown to reduce the risk of LCOS in children with heart failure or those who have undergone CPB [ 3 – 10 ].
ECLS is an important life-saving technology , however , patients supported with ECMO and / or CRRT are at high risk of mortality [ 1 , 11 – 13 ]. The increased mortality risk may be in part due to altered drug disposition in patients on ECLS [ 14 , 15 ]. ECLS can alter drug disposition in several ways : 1 ) adsorption of the drug to ECLS circuit components ; 2 ) hemofilter clearance of the drug in CRRT ; 3 ) exogenous fluids used in priming the circuit increase the volume of distribution [ 16 ].
* Corresponding author : kevin . watt @ hsc . utah . edu
Additionally , other factors such as edema , inflammation , and altered protein binding can affect drug disposition in the population of critically ill patients supported on ECLS . The degree of drug extraction by ECLS depends on the circuit components as well as drug physicochemical properties ( e . g ., protein binding , molecular weight , lipophilicity ). Hydrophilic drugs with low protein binding are likely to be cleared by a hemofilter , while lipophilic and highly protein-bound drugs more frequently adsorb to circuit components [ 17 , 18 ].
Milrinone is a type 3 phosphodiesterase inhibitor that provides inotropic , lusitropic , and vasodilatory effects , making it an important agent in treating patients with heart failure and LCOS . It increases cyclic adenosine monophosphate levels which in turn increases intracellular calcium concentrations . Calcium can then be used by troponin I and phospholamban which impact inotropy and lusitropy , respectively [ 19 – 21 ]. In adults , plasma milrinone concentrations ranging from 100 to 300 ng / mL are associated with therapeutic effects [ 22 , 23 ]. Toxicities like systemic hypotension from excessive vasodilation , arrhythmias , and thrombocytopenias are associated with higher concentrations (> 500 ng / mL ) [ 23 , 24 ]. Since little is known about
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