Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery

• Published in: British journal of clinical pharmacology 2017-08, Vol.83 (8), p.1745-1757
• Main Authors: Gertler, Ralph, Gruber, Michael, Grassin‐Delyle, Stanislas, Urien, Saïk, Martin, Klaus, Tassani‐Prell, Peter, Braun, Siegmund, Burg, Simon, Wiesner, Gunther
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; antifibrinolytic agents; Antifibrinolytic Agents - pharmacokinetics; Antifibrinolytic Agents - therapeutic use; Blood Loss, Surgical - prevention & control; cardiac surgical procedures; Cardiac Surgical Procedures - adverse effects; Cardiopulmonary Bypass - adverse effects; congenital heart defects; Drug Administration Schedule; Female; Gas Chromatography-Mass Spectrometry; Humans; Infant; Infant, Newborn; Male; Models, Biological; Nonlinear Dynamics; Pharmacokinetics; Seizures - chemically induced; Seizures - epidemiology; Thrombosis - chemically induced; Thrombosis - epidemiology; tranexamic acid; Tranexamic Acid - pharmacokinetics; Tranexamic Acid - therapeutic use
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13274

Aim Tranexamic acid (TXA) continues to be one of the antifibrinolytics of choice during paediatric cardiac surgery. However, in infants less than 1 year of age, the optimal dosing based on pharmacokinetic (PK) considerations is still under discussion. Methods Forty‐three children less than 1 year of age were enrolled, of whom 37 required the use of cardiopulmonary bypass (CPB) and six were operated on without CPB. Administration of 50 mg kg–1 TXA intravenously at the induction of anaesthesia was followed by 50 mg kg–1 into the CPB prime in the CPB group. Plasma concentrations of TXA were analysed by gas chromatography–mass spectrometry. PK data were investigated using nonlinear mixed‐effect models. Results A two‐compartment model was fitted, with the main covariates being allometrically scaled bodyweight, CPB, postmenstrual age (PMA). Intercompartmental clearance (Q), peripheral volume (V2), systemic clearance, (CL) and the central volume (V1) were calculated. Typical values of the PK parameter estimates were as follows: CL = 3.78 [95 % confidence interval (CI) 2.52, 5.05] l h–1; central volume of distribution = 13.6 (CI 11.7, 15.5) l; Q = 16.3 (CI 13.5, 19.2) l h–1; V2 = 18.0 (CI 16.1, 19.9) l. Independently of age, 10 mg kg–1 TXA as a bolus, a subsequent infusion of 10 mg kg–1 h–1, then a 4 mg kg−1 bolus into the prime and a reduced infusion of 4 mg kg–1 h–1 after the start of CPB are required to maintain TXA concentrations continuously above 20 μg ml–1, the threshold value for an effective inhibition of fibrinolysis and far lower than the usual peak concentrations (the ‘10‐10‐4‐4 rule’). Conclusions The introduction of a modified dosing regimen using a starting bolus followed by an infusion and a CPB prime bolus would prohibit the potential risk of seizures caused by high peak concentrations and also maintain therapeutic plasma concentration above 20 μg ml–1.