Tranexamic Dosing for Major Joint Arthroplasty in Adult Patients with Chronic Kidney Disease: A Pharmacokinetic Study and New Dosing Regimen.

BACKGROUND

Tranexamic acid is an antifibrinolytic agent routinely used during hip and knee joint replacement surgery to minimize bleeding. Chronic kidney disease is a common chronic health problem seen among adults requiring major arthroplasty surgery. Tranexamic acid is renally cleared and may accumulate in chronic kidney disease. Optimal tranexamic acid dosing and dose adjustment for chronic kidney disease patients needing major arthroplasty is unknown. The objective of this study was to serially measure plasma tranexamic acid concentrations in patients with varied kidney function undergoing hip or knee replacement surgery for population pharmacokinetic modeling and to guide new dosing recommendations.

METHODS

A prospective cohort study enrolled 21 adults undergoing hip or knee replacement surgery between June 2020 and September 2022. Based on estimated glomerular filtration rate, the patients were stratified into good (greater than or equal to 60 ml · min -1 · 1.73 m -2 ) and poor (less than 60 ml · min -1 · 1.73 m -2 ) renal function. Serial blood samples were taken to measure plasma tranexamic acid concentration levels (primary outcome) after an intravenous tranexamic acid 20-mg/kg bolus dose after anesthesia induction. Secondary clinical outcomes included adverse events (thromboembolic events, seizures), red cell transfusion, mortality, and length of hospital stay. Analyses used curve stripping and population pharmacokinetic modeling and simulation.

RESULTS

Plasma tranexamic acid concentration levels were higher in patients with poor renal function and clearance compared to those with good renal function. Population pharmacokinetic modeling tested various tranexamic acid bolus and maintenance infusion regimens. Simulations revealed that single-bolus tranexamic acid administration leads to rapid rise and decline in plasma concentrations. This study identified that plasma tranexamic acid levels of 50 to 75 mg/l were maintained for approximately 4 h using a tranexamic acid bolus infusion of 15 mg/kg over a 15-min duration together with a maintenance infusion of 7.5 or 5 mg · kg -1 · h -1 for 2 h for the good and poor renal function groups, respectively. There was no difference in secondary outcomes.

CONCLUSIONS

Population pharmacokinetic modeling and simulation resulted in recommendations for a new dosing regimen to optimize the antifibrinolytic effect of tranexamic acid and avoid excessive dosing.