Pharmacokinetics of Tranexamic Acid in Neonates, Infants, and Children Undergoing Cardiac Surgery With Cardiopulmonary Bypass

Abstract

T ranexamic acid (TXA) is often used to reduce blood loss and need for transfusion in children undergoing cardiac surgery. However, analysis of TXA in young children who need cardiac surgery that includes cardiopulmonary bypass (CPB), hypothermia, circulatory arrest, and ultrafiltration has not been conducted.The present study included 55 pediatric patients separated into 3 groups: children younger than 2 months, infants 2 months to 1 year old, and children older than 1 year and weighing up to 20 kg. Tranexamic acid was administered at 100 mg/kg followed by a 10 mg/kg per hour throughout the surgery, and a dose of 100 mg/kg was placed in the CPB prime. High-performance liquid chromatography was used to measure concentrations of TXA in the blood. Results of the first examination of TXA in young pediatric patients provide dose guidelines for use of TXA. A safe and effective TXA concentration range for young cardiac surgery patients needs to be better defined. COMMENTAlthough the use of antifibrinolytics to prevent bleeding after CPB is well established, there are scant data on TXA in neonates and young infants undergoing complex cardiac operations. Drug disposition pharmacokinetics in neonatal populations is often substantially altered because of immature organ development with liver metabolism, biliary conjugation, and renal excretion taking months and sometimes years to fully develop. For this reason, the covariate age better predicts drug pharmacokinetics than body weight because of age-related organ and enzyme system development. Here, Wesley et al publish the first comprehensive pharmacokinetic investigation of TXA in neonates, young infants, and children undergoing complex cardiac surgery. The authors find that age is a much better covariate than body weight and that in neonates and young infants, interestingly, the bolus dose of TXA required to maintain a given plasma level decreases with age. Although CPB alters the disposition pharmacokinetics of TXA in children, the use of modified ultrafiltrate had no impact on TXA concentrations. Instead, patient age was the dominant factor in predicting TXA pharmacokinetics. That is, older children required lower doses.Wesley et al recruited 55 pediatric patients undergoing openheart surgery and divided them into 3 groups; children younger than 2 months, infants 2 months to 1 year, and children older than 1 year weighing up to 20 kg. Tranexamic acid 100 mg/kg was administered after anesthetic induction followed by 10 mg/kg per hour, and an additional 100 mg/kg was added to the CPB prime. A total of 889 concentration-time observations were obtained from these 55 patients, and CBP bypass management included ultrafiltration in all patients, modified ultrafiltration in select cases, and circulatory arrest in a few cases. Temperature on CPB ranged from 17.4°C to 34°C, with a median temperature of 28.1°C. Pharmacokinetic analysis was performed using a 2-compartment model and NONMEM (nonlinear mixed-effects model), with age being the most relevant covariate. Although the opti...

Pharmacokinetics of tranexamic acid in neonates and infants undergoing cardiac surgery

“…In contrast to Wesley et al . , we did not find a different TXA dose requirement in the neonatal group.…”

“…to Wesley et al [8], we did not find a different TXA dose requirement in the neonatal group. Any dosing recommendation in our investigation is aiming at target plasma TXA concentration of 20 mg l -1 .…”

“…Our study was an extension of the previous work by Grassin-Delyle et al [7] that investigated children with a mean age of 5 years and only showed an effect of CPB on Q. By contrast, Wesley et al [8], in children less than 4 years of age, found an effect of CPB on volume and clearance parameters. Our results did not reveal an effect of CPB on V1.…”

“…This is in agreement with the study by Wesley et al . where neither MUF nor hypothermia were found to be influential factors.…”

“…By contrast, Wesley et al . , in children less than 4 years of age, found an effect of CPB on volume and clearance parameters. Our results did not reveal an effect of CPB on V1.…”