title: Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery.
abstract: 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.
  
  
  
  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-1TXA intravenously at the induction of anaesthesia was followed by 50 mg kg-1into 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.
  
  
  
  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-1TXA as a bolus, a subsequent infusion of 10 mg kg-1h-1, then a 4 mg kg-1bolus into the prime and a reduced infusion of 4 mg kg-1h-1after 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').
  
  
  
  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.
authors.affiliation: Klinik für Anaesthesie, operative und allgemeine Intensivmedizin, Notfallmedizin, Klinikum Links der Weser, University Medical Center Hamburg-Eppendorf, Bremen, Germany.|Institute of Anaesthesiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Gertler
authors.affiliation: Department of Anesthesia, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gruber
authors.affiliation: Département des Maladies des Voies Respiratoires, Hôpital Foch, Université Versailles Saint Quentin en Yvelines, Université Paris Saclay, F-92150, Suresnes, France.|Plateforme de spectrométrie de masse et INSERM UMR1173, UFR Sciences de la Santé Simone Veil, Université Versailles Saint Quentin en Yvelines, Université Paris Saclay, F-78180, Montigny-le-Bretonneux, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Grassin-Delyle
authors.affiliation: CIC1419 Inserm Necker-Cochin, URC Paris Descartes Necker Cochin, AP-HP, Paris, France.|EAU7323, Université Paris Descartes, Sorbonne Paris Cité, France.
authors.forename: Saïk
authors.initials: S
authors.lastname: Urien
authors.affiliation: Institute of Anaesthesiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Martin
authors.affiliation: Institute of Anaesthesiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Tassani-Prell
authors.affiliation: Institute of Laboratory Medicine, German Heart Centre Munich, Technical University Munich, Munich, Germany.
authors.forename: Siegmund
authors.initials: S
authors.lastname: Braun
authors.affiliation: Institute of Anaesthesiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Burg
authors.affiliation: Institute of Anaesthesiology, German Heart Centre Munich, Technical University Munich, Munich, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Wiesner
mesh_terms: D061605:Administration, Intravenous; D000933:Antifibrinolytic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016063:Blood Loss, Surgical / Q000517:prevention & control*; D006348:Cardiac Surgical Procedures / Q000009:adverse effects*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D004334:Drug Administration Schedule; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012640:Seizures / Q000139:chemically induced / Q000453:epidemiology; D013927:Thrombosis / Q000139:chemically induced / Q000453:epidemiology; D014148:Tranexamic Acid / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid
keywords: antifibrinolytic agents; cardiac surgical procedures; congenital heart defects; pharmacokinetics; tranexamic acid