• Br J Anaesth · Jan 2025

    A pharmacokinetic/pharmacodynamic analysis of intravenous tranexamic acid in adult patients undergoing elective total hip arthroplasty (ORACLE).

    • Usha Gurunathan, Robert L Medcalf, Lily Chiang, Zikou Liu, Xin Liu, Charithani B Keragala, Maria Patricia Hernandez-Mitre, Paul Brady, Steven C Wallis, Jason A Roberts, Daniel Mullany, Harshal Nandurkar, Victoria Eley, and Suzanne L Parker.
    • Department of Anaesthesia and Perfusion Services, The Prince Charles Hospital, Brisbane, Australia; Faculty of Medicine, The University of Queensland, Brisbane, Australia. Electronic address: usha.gurunathan@health.qld.gov.au.
    • Br J Anaesth. 2025 Jan 22.

    BackgroundUncertainty about optimal tranexamic acid (TXA) dosage has led to significant practice variation in hip arthroplasty. We aimed to identify the optimal i.v. dosage of TXA using a population pharmacokinetic/pharmacodynamic (PK/PD) approach in adults undergoing primary elective hip arthroplasty.MethodsParticipants received an i.v. TXA bolus dose of 15 mg kg-1 of total body weight, 30 min before skin incision (maximum dose 1500 mg). Blood samples were collected at baseline, 5 min post-TXA, skin incision, skin closure, and 3, 6, and 24 h post-TXA administration. TXA activity was measured ex vivo using a tissue plasminogen activator-induced clot lysis assay, targeted to achieve 90% maximal antifibrinolysis, based on maximum lysis rate. A nonlinear mixed-effects population PK/PD model was developed. Monte Carlo simulations (n=1000) identified the dosing regimens to achieve the PK/PD target over 24 h.ResultsThere were 24 participants (18 females, 6 males), with a median (range) age of 62 (56.5-72) yr and BMI of 31.1 (23.0-41.8) kg m-2. A three-compartment model best described the 24-h data. The 15 mg kg-1 of i.v. bolus maintained TXA concentrations above the PK/PD target of 10 mg L-1 for a median duration of 4.94 h (IQR: 3.76-8.21 h). Of the various simulated regimens, only 30 mg kg-1 of i.v. TXA infusion after this bolus achieved the 24-h PK/PD target in 76-100% of patients, varying with their estimated glomerular function rates.ConclusionsThe PK/PD modelling indicated that 15 mg kg-1 of i.v. TXA bolus followed by a continuous i.v. infusion achieves the 24-h antifibrinolytic target.Clinical Trial Registrationhttps://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377339&isClinicalTrial=False (ACTRN12619000670178); registered on May 6, 2019.Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

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