S4A-02 SESSION 4A: GENERALITIES IN CRANIOSYNOSTOSIS – PART I EFFICACY OF TWO TRANEXAMIC ACID DOSAGE REGIMES FOR CRANIOSYNOSTOSIS SURGERY; A RANDOMIZED CONTROLLED EQUIVALENCY TRIAL.

Abstract

Introduction: Tranexamic acid (TXA) in a dose of 50 mg/kg loading dose followed by 5 mg/kg/h maintenance infusion has been shown to significantly reduce blood loss and blood transfusion in pediatric open craniosynostosis surgery compared with placebo. TXA plasma concentrations with this dosing regimen were shown to exceed the accepted therapeutic level by over 10 fold. From pharmacokinetic modeling, we predicted that reducing the loading dose to 10 mg/kg is adequate to maintain plasma concentrations above the presumed accepted therapeutic level of 20 mcg/mL. This may be safer in terms of side effect profile. The hypothesis of this study is to validate our TXA pharmacokinetic model and determine if the lower dosage scheme is as effective as the higher dosage scheme in decreasing blood loss and transfusion requirements in pediatric craniosynostosis surgery. Methods: With IRB (P00008434) and Ethic (2013-001056-35) approval, patients were consented and enrolled in a two-center, prospective, double-blind equivalence randomized controlled trial to compare high TXA dose (50mg/kg/15min and 5mg/kg/h) vs a lower TXA dose (10 mg/kg/15min and 5 mg/kg/h) regime. Standardized anesthetic, fluid, blood and blood product management protocols were followed. TXA analysis was performed by the Boston Children’s Hospital Pharmacokinetic Laboratory using liquid chromatography with mass spectrometry detection (LC/MS). An a priori non-inferiority margin of -20 mL/kg and -10 mL/kg was set in the analysis of blood loss and transfusion respectively. The two participating hospitals were: Boston Children’s Hospital, Boston USA, and Istituto Gaslini, Genoa, Italy. ClinicalTrials.gov identifier: NCT02188576. Results: Sixty-eight children, 3 months to 2 years scheduled for open craniosynostosis surgery were included. Demographics were comparable between groups. There was no significant difference in blood loss (39.4 vs 40.3 mL/kg) or blood transfusion (PRBC 23.3 vs 29.9 mL/kg) between the high and lower dose groups respectively. TXA plasma levels at steady state averaged 50 mcg/mL in the high dose vs 25 mcg/mL the lower dose group; both above the presumed therapeutic threshold. Blood loss and blood transfusion were also less than our previous study by two-fold. No adverse events such as seizures or thromboembolic events were observed in either group. Conclusion: A tranexamic acid dose regimen of 10 mg/kg loading dose and 5 mg/kg/h maintenance dose is as effective (non-inferior) as a higher dose regime of 50 mg/kg loading dose and 5 mg/kg/h maintenance infusion rate in reducing blood loss and transfusion requirements in pediatric craniosynostosis reconstruction surgery.