Neonates on ECMO Clinical Trial
Official title:
Pharmacokinetics of Recombinant Antithrombin III in Neonates Undergoing Extracorporeal Membrane Oxygenation
Maintenance of adequate anticoagulation or blood thinning is of critical importance when patients are placed on extracorporeal life support, such as extracorporeal membrane oxygenation (ECMO). During ECMO, a patient's entire blood volume is constantly exposed to the artificial surfaces of the ECMO circuit. This exposure activates the clotting cascade, and not only is the circuit at risk for clot formation, but the patient is also at risk for clotting within the body. Hence anticoagulation is vital in allowing the ECMO circuit to support a patient for an extended period of time. Anticoagulation on ECMO is achieved primarily by the use of a blood thinning agent called heparin. Heparin's main mechanism of action is to activate an enzyme called antithrombin III (AT III). AT III deficiency has been shown to be a common finding in pediatric patients requiring ECMO. This deficiency may then result in ineffective blood thinning by heparin. The purpose of this study is to determine how a neonate on ECMO, processes and eliminates a medication called ATryn® from their body. ATryn® is a form ATIII that is made from goat's milk. This will ultimately aid in establishing standardized dosing for the use of ATryn® in this patient population.
Maintenance of adequate anticoagulation is of critical importance when patients are placed
on extracorporeal life support, such as ECMO. During ECMO, a patient's entire blood volume
is constantly exposed to the artificial surfaces of the ECMO circuit. This exposure
activates the clotting cascade, and not only is the circuit at risk for clot formation, but
the patient is also at risk for thromboembolic events. Hence anticoagulation is vital in
allowing the ECMO circuit to support a patient's entire cardiopulmonary system for an
extended period of time. Anticoagulation on ECMO is achieved primarily by the use of a
heparin continuous infusion. Heparin's main mechanism of action is to bind to and activate
an enzyme called antithrombin III (AT III). AT III is the principal inhibitor of the blood
coagulation serine proteases - Thrombin and Factor Xa. In the presence of, and when bound to
heparin, the inhibitory activity of AT III is greatly enhanced. AT III deficiency has been
shown to be a common finding in pediatric patients requiring ECMO. Our center has reported
that most neonatal patients requiring ECMO also have a significant degree of ATIII
deficiency prior to, and during ECMO bypass. This deficiency may lead to challenges in
achieving adequate anticoagulation while on ECMO. For this reason, our institution already
supplements antithrombin during pre-ECMO circuit priming and for maintaining AT III levels
above 70% during the entire length of ECMO support. Optimizing AT III levels may then
improve anticoagulation while on ECMO. This study aims to determine the pharmacokinetics of
recombinant antithrombin (ATryn®) supplementation. To date, the use of ATryn® has primarily
been studied in adults. There is no published data to date, and no current studies on the
pharmacokinetics of antithrombin III in neonates, and hence no published data on the
pharmacokinetics of antithrombin III in the neonatal ECMO population. Since the use of
antithrombin III in the neonatal ECMO patient population has not been thoroughly studied,
the use of antithrombin III supplementation varies greatly among different neonatal
intensive care units. Therefore, studies that aim at determining the pharmacokinetics of
antithrombin III, particularly in ECMO patients, are important because of the lack of data
and published studies in this patient population. By determining the pharmacokinetics of
ATryn® in our neonatal ECMO patient population, we will aid in establishing standardized
dosing and administration protocols for the supplementation of antithrombin in this specific
patient population.
Summary of Risks and Benefits: ATryn® is FDA approved for use in the prevention of
peri-operative and peri-partum thromboembolic events in hereditary antithrombin III
deficient patients. ATryn® is a transgenically produced recombinant antithrombin concentrate
from goat milk that is preservative free. It has an identical amino acid structure with
minor glycosylation differences to endogenous human AT IIII. When assayed in the presence of
excess heparin, the potency and efficacy of ATryn® is not different from that of
plasma-derived AT III concentrates.5 ATryn® is administered as a continuous intravenous
infusion, with weight-adjusted loading and maintenance dosing regimens as recommended by the
medication's package insert. As dosing is specific to a patient's weight, this theoretically
minimizes the risk for overdosing. In addition, as dosing is administered as a continuous
infusion that is titrated to maintain stable AT III levels, there is the additional
potential for less fluctuations in a patient's AT III levels. Not only will anticoagulation
be optimized throughout the duration of ECMO support, but theoretically there may be a
decreased need for, or less fluctuations in a patient's heparin requirements. This may
furthermore minimize the risk for thromboembolic events within the ECMO circuit and the
patient. Additionally, ATryn® is preservative free and because it is a recombinant product,
it should be free from the risk of viral infection or prion transmission.
;
Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment