Pharmacokinetic Modeling Using Real‐World Data to Optimize Unfractionated Heparin Dosing in Pediatric Patients on Extracorporeal Membrane Oxygenation and Evaluate Target Achievement–Clinical Outcomes Relationship

Abstract

Unfractionated heparin (UFH) is a commonly used anticoagulant for pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) but evidence is lacking on the ideal dosing. We aimed to: (i) develop a population pharmacokinetic (PK) model for UFH, measured through anti‐factor Xa assay, (ii) optimize UFH starting infusions and dose titrations through simulations, and (iii) explore UFH exposure‐clinical outcomes relationship. Data from 218 patients admitted to Utah's Primary Children's Hospital were retrospectively collected. A one‐compartment PK model with time‐varying clearance (CL) adequately described UFH PK. Weight on CL and volume of distribution and, ECMO circuit change on CL were significant covariates. The typical estimates for initial CL and first‐order rate constant to reach steady‐state CL were 0.57 L/(h·10 kg) and 0.02 h−1. Comparable to non‐ECMO patients, the typical steady‐state CL was 0.81 L/(h·10 kg). Simulations showed that a 75 IU/kg UFH bolus dose followed by starting infusions of 25 & 20 IU/h/kg for patients < 6 & ≥ 6 years, respectively, achieved the therapeutic target in 56.6% of all patients while only 3.1% exceeded the target. The proposed UFH titration schemes achieved the target in > 90% of patients while < 0.63% were above the target after 24 and 48 hours of treatment. The median intensive care unit survival time in patients within and below the target at 24 hours was 136 and 66 hours, respectively. In conclusion, PK model of UFH was developed for pediatric patients on ECMO. The proposed UFH dosing scheme attained the anti‐factor Xa target rapidly and safely.This article is protected by copyright. All rights reserved

Heparin Dosing Regimen Optimization in Veno-Arterial Extracorporeal Membrane Oxygenation: A Pharmacokinetic Analysis

“…Secondly, the UFH administration pattern with prolonged continuous infusion and few boluses was challenging for V estimation. However, interpatient variability for V and CL in our final model was lower than in Salem’s study [ 23 ] (75.3 versus 262.9% and 52.4 versus 58.9%, respectively). The residual variability could also be explained by unidentified factors or those known to interact with UFH, among which are antithrombin [ 11 ] or Von Willebrand factor [ 31 ].…”

“…In the current study, several covariates were identified to explain UFH PK variability. Firstly, baseline BW was acknowledged to explain interpatient variability for V, confirming existing literature describing the need to individualize the UFH loading dose according to BW in CPB or ECMO [ 22 , 23 ]. Secondly, SCr, a surrogate of glomerular filtration capabilities or CRRT filtration performance, influenced UFH exposure.…”

“…To our knowledge, this is the first study to perform a PK analysis of UFH in adult VA-ECMO patients using a nonlinear mixed-effects modeling approach. Among the previous studies that investigated UFH PK [ 18 , 19 , 20 , 21 , 22 , 23 ], only a few focused on cardiopulmonary bypass (CPB) [ 21 , 22 ] or ECMO [ 23 ]. Similar analyses were performed in adult patients undergoing CPB for cardiac surgery, using either anti-activated factor II (anti-IIa) [ 21 ] or anti-Xa [ 22 ] assays.…”

“…The single study available on ECMO before our research included exclusively pediatric patients and was undermined by the heterogeneity of the population characteristics, which consisted in both veno-venous (VV) and VA-ECMO [ 23 ]. This study was performed using real-world data collected retrospectively, with anti-Xa routinely measured to describe UFH PK.…”