Milrinone, a phosphodiesterase type 3 inhibitor, is frequently used in critically ill patients to improve cardiac output and vasodilation, particularly for conditions like low cardiac output syndrome (LCOS) or heart failure. Many of these patients require extracorporeal life support (ECLS), which includes extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). While these systems are life-saving, they can alter drug pharmacokinetics due to factors such as adsorption to circuit components, hemofiltration clearance, and increased fluid volumes from circuit priming. This study aimed to evaluate how milrinone interacts with ECMO and CRRT circuits, providing insights for optimizing dosing strategies.
The study used ex vivo setups to simulate ECMO and CRRT systems. Both circuits were primed with human blood solutions, and milrinone was administered to achieve therapeutic concentrations. Concentrations were monitored over six hours to measure drug recovery and clearance. The ECMO circuit included components like oxygenators, reservoirs, and pumps, while the CRRT circuit used hemofilters and dialysis solutions. Control samples were included to evaluate milrinone degradation in the absence of ECLS circuits.
Results showed that milrinone interacted minimally with ECMO circuits. Drug recovery in ECMO experiments was nearly 100%, indicating negligible adsorption to circuit components. This aligns with milrinone’s physicochemical properties, which include moderate protein binding and low lipophilicity. These properties reduce the likelihood of drug adsorption, a problem often seen with more lipophilic or highly protein-bound drugs. The stability of milrinone in ECMO circuits suggests that no significant dosing adjustments are needed for patients on ECMO.
In contrast, milrinone was rapidly cleared by CRRT circuits. Within the first two hours, 99% of the drug was removed from the circuit. This rapid clearance is attributed to transmembrane clearance through the hemofiltration process rather than adsorption to circuit components. The mean transmembrane clearance was measured at 119 mL/min, significantly impacting drug levels. These findings highlight the need for tailored dosing strategies for patients receiving CRRT to ensure therapeutic drug concentrations are maintained.
While the results are promising for understanding drug behavior in ECLS systems, the study has limitations. The experiments used a single bolus dose of milrinone, whereas patients in clinical settings often receive continuous infusions. Infusion dosing could potentially saturate adsorption sites, though this is unlikely to significantly affect results given the minimal adsorption observed. The study also tested only one type of ECMO and CRRT circuit configuration, limiting its applicability to other setups with different materials, coatings, or flow rates. Additionally, patient-specific factors such as organ function, edema, and altered protein binding were not accounted for, as these variables cannot be replicated in ex vivo systems.
Future studies should incorporate physiologically based pharmacokinetic (PBPK) modeling to address these limitations. PBPK models use virtual organ compartments and blood flow parameters to simulate drug behavior, allowing for the inclusion of patient-specific variables such as renal function and plasma protein levels. These models could help bridge the gap between ex vivo findings and clinical applications, providing more accurate dosing recommendations for patients on ECMO or CRRT.
From a clinical perspective, the findings suggest that milrinone dosing adjustments are not necessary for ECMO, as the drug exhibits stable concentrations and minimal interaction with circuit components. However, patients on CRRT require careful consideration of the modality, flow rates, and residual renal function, as these factors significantly influence milrinone clearance. For example, the study found that CVVHDF, the mode used in the experiments, results in higher clearance rates compared to other modalities like CVVH. This insight is critical for tailoring milrinone therapy to individual patient needs.
In conclusion, the study provides valuable data on milrinone’s interaction with ECLS systems, emphasizing the importance of CRRT-specific dosing adjustments while confirming the stability of the drug in ECMO circuits. These findings are essential for improving the safety and efficacy of milrinone therapy in critically ill patients reliant on ECLS. Future research incorporating patient physiology and real-world variables will further enhance dosing precision, ultimately benefiting this vulnerable patient population.
