Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery

TY - JOUR

T1 - Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery

AU - Gertler, Ralph

AU - Gruber, Michael

AU - Grassin-Delyle, Stanislas

AU - Urien, Saïk

AU - Martin, Klaus

AU - Tassani-Prell, Peter

AU - Braun, Siegmund

AU - Burg, Simon

AU - Wiesner, Gunther

N1 - © 2017 The British Pharmacological Society.

PY - 2017/8

Y1 - 2017/8

N2 - 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 .

AB - 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 .

KW - Administration, Intravenous

KW - Antifibrinolytic Agents

KW - Blood Loss, Surgical

KW - Cardiac Surgical Procedures

KW - Cardiopulmonary Bypass

KW - Drug Administration Schedule

KW - Female

KW - Gas Chromatography-Mass Spectrometry

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Male

KW - Models, Biological

KW - Nonlinear Dynamics

KW - Seizures

KW - Thrombosis

KW - Tranexamic Acid

KW - Clinical Trial

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1111/bcp.13274

DO - 10.1111/bcp.13274

M3 - SCORING: Journal article

C2 - 28245519

VL - 83

SP - 1745

EP - 1757

JO - BRIT J CLIN PHARMACO

JF - BRIT J CLIN PHARMACO

SN - 0306-5251

IS - 8

ER -