316 - Evaluation of Pharmacokinetics and Dosing Strategies of Antithrombin III in Neonatal Patients Undergoing Extracorporeal Membrane Oxygenation

Poster Number: 316
Publication Number: 316.444

Gabriella Philipson, Nicklaus Children’s Hospital, Miami, FL, United States; Gustavo R. Alvira-Arill, University of Tennessee Health Science Center College of Medicine, Memphis, TN, United States; Jennifer M. Ryder, Nicklaus Children’s Hospital, Doral, FL, United States; Balagangadhar R. Totapally, Nicklaus Children’s Hospital, Miami, FL, United States

Background: Due to naturally low levels and acquired deficiency of antithrombin III (AT3) in neonates on ECMO, replacement is provided with AT3 concentrate (human plasma-derived, Thrombate 3®) to achieve adequate anticoagulation. Unfortunately, current lab-directed dosing recommendations for AT3 concentrate often underestimate the needs of critically ill neonates and the pharmacokinetics of AT3 concentrate in neonates on ECMO is not well described.

Objective: The objective of our retrospective study is to describe the pharmacokinetics of AT3 concentrate in neonates on ECMO and propose new dosing recommendations based on our experience.

Design/Methods: We retrospectively reviewed charts of all neonates on ECMO who received AT3 concentrate over 18 months. We collected demographic details, AT3 concentrate dose and time of administration, AT3 levels before, after, and lowest level within 24 hours after AT3 concentrate administration, and level collection times. AT3 half-life was calculated by pairing levels after dose administration and volume of distribution (Vd) was calculated based on a single-compartment model. A regression equation was generated for the AT3 concentrate dose required per kg of body weight to achieve a desired AT3 level from any given baseline.

Results: A total of 135 doses of AT3 concentrate from 18 neonates on ECMO were included. The median age and weight of the neonates were, 2.5 (IQR: 1-4.25) days and 3.04 (IQR: 2.7-3.36) kgs, respectively. The mean (SD) AT3 levels (%) before AT3 administration, after AT3 administration, and lowest AT3 level within 24 hours were 58.6 (13.9), 76.5 (13.8), and 66.2 (11.5), respectively (p < 0.001, Repeated ANOVA). The mean AT3 dose given was 44.8 (17.2) IU/kg. The median (IQR) values of half-life and Vd calculated from 97 episodes were 48.1 (29.6-77.3) hours and 23.5 (18.5-30.6) liters/kg, respectively. The half-life of AT3 showed a quadratic distribution with a decrease early and prolongation later during ECMO (R2 = 0.19, p < 0.001). The regression equation for AT3 dose (IU/kg) required was = (Z-20.899-(0.665*Y))/ 0.346, where Z is desired AT3 level and Y is the baseline AT3 level.Conclusion(s): The manufacturer recommended lab-directed dosing for AT3 concentrate is inadequate to achieve desired AT3 levels in neonates on ECMO, most likely due to increased Vd. The half-life of AT3 in neonates on ECMO is similar to published values. Dosing estimates from this study may achieve therapeutic AT3 levels and reduce the number of additional doses required to maintain adequate AT3 levels. Dosing guidelines derived from this study should be further evaluated prospectively.