Objective: 

Unfractionated heparin (UFH) is the most widely used anticoagulant during extracorporeal membrane oxygenation (ECMO). Optimal dosing of UFH for children undergoing ECMO is unknown, leading to suboptimal exposure. We aimed to develop a population pharmacokinetic (PK) model for UFH in children undergoing venoarterial (VA) ECMO, using anti-Xa activity, to improve the initial dosing regimen.

Design: 

A retrospective observational study (March 2015 to May 2021) using nonlinear, mixed-effect modeling software (Monolix) and Monte Carlo simulations to optimize the dosing.

Setting: 

Single-center study in a PICU in Paris, France.

Patients: 

All children under 18 years old who needed VA-ECMO and received continuous UFH.

Interventions: 

None.

Measurements and Main Results: 

We included 59 children and 1305 anti-Xa activity results, 13% of which were outside the limits of quantification. Median (range) initial UFH bolus and infusion rate were 50 international units/kg (20–100) and 20 international units/kg/hr (9–40), respectively. Among the 1305 anti-Xa activity results, 875 (67%) were in the therapeutic range (0.3–0.7 international units/mL), whereas 263 (20%) and 167 (13%) were below and above the PK target, respectively. A one-compartment model with first-order elimination and time-varying clearance best fitted the data. Body weight according to allometric scale on clearance and volume of distribution was the selected covariate. Initial clearance was low and increased until steady state was reached after 16 hours. Simulations showed that initial bolus of 40 international units/kg followed by continuous infusion of 25, 20, and 15 international units/kg/hr for patients under 10, between 10 and 15 and above 15 kg, respectively, improved exposure.

Conclusions: 

In children undergoing VA-ECMO, body weight, and time-varying clearance explained the variability for UFH between subjects. This model can be used to optimize initial UFH dosing.