Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery
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Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery. / Gertler, Ralph; Gruber, Michael; Grassin-Delyle, Stanislas; Urien, Saïk; Martin, Klaus; Tassani-Prell, Peter; Braun, Siegmund; Burg, Simon; Wiesner, Gunther.
In: BRIT J CLIN PHARMACO, Vol. 83, No. 8, 08.2017, p. 1745-1757.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -