Tranexamic Acid Dosing for Cardiac Surgical Patients With Chronic Renal Dysfunction: A New Dosing Regimen

Angela Jerath, FRCPC, FANZCA, MBBS, BSc; Qi Joy Yang, MSc; K. Sandy Pang, PhD; Nikita Looby, MSc; Nathaly Reyes-Garces, MSc; Tijana Vasiljevic, BSc; Barbara Bojko, PhD; Janusz Pawliszyn, PhD; Duminda Wijeysundera, PhD, FRCPC; W. Scott Beattie, PhD, FRCPC; Terrence M. Yau, PhD, FRCSC, MD, MSc, BA; Marcin Wąsowicz, FRCPC, PhD, MD

Disclosures

Anesth Analg. 2018;127(6):1323-1332. 

In This Article

Abstract and Introduction

Abstract

Background: Tranexamic acid (TXA) is a common antifibrinolytic agent used to minimize bleeding in cardiac surgery. Up to 50% cardiac surgical patients have chronic renal dysfunction (CRD). Optimal dosing of TXA in CRD remains poorly investigated. This is important as TXA is renally eliminated with accumulation in CRD. High TXA doses are associated with postoperative seizures. This study measures plasma TXA concentrations in CRD cardiac surgical patients for pharmacokinetic modeling and dose adjustment recommendations.

Methods: This prospective cohort study enrolled 48 patients with stages 1–5 CRD, classified by Kidney Disease Outcome Quality Initiative. Patients were separated into 2 treatment groups. A "low-risk" group underwent simple aortocoronary bypass or single-valve repair/replacement and received a 50 mg/kg TXA bolus. A "high-risk" group underwent redo, aortic, multiple valve or combination surgery and received the Blood Conservation Using Anti-fibrinolytics Trial dosing regimen (loading dose 30 mg/kg, infusion 16 mg/kg/h with 2 mg/kg in pump prime). Primary outcome identified changes in TXA clearance and distribution volume, which provided the rationale for dose adjustment. Descriptive clinical outcomes assessed postoperative seizures, blood loss, ischemic-thrombotic complications, in-hospital mortality, and length of hospital stay.

Results: TXA concentrations were elevated and sustained above the therapeutic threshold for approximately 12 hours in high-risk stages 3–5 groups, in accordance to CRD severity.

Conclusions: Using a pharmacokinetic model, we propose a simple new TXA dosing regimen that optimizes maximal antifibrinolysis and avoids excessive drug dosing.

Introduction

More than 1 million cardiac surgical procedures are performed worldwide each year.[1] The Thoracic Surgeons National Adult Cardiac Database identified up to 50% of cardiac surgical patients suffer from preoperative chronic renal dysfunction (CRD).[2] CRD is an important comorbidity that accelerates the risk of developing cardiovascular disease and incurs greater postsurgical complications (17%–77%) and mortality (7%–18%) in comparison to patients with normal renal function.[3–6] A common complication of cardiac surgery with cardiopulmonary bypass (CPB) is postoperative bleeding and chest reexploration, which affect 20% and 5% patients, respectively.[1,7] CRD is associated with an even higher risk of massive blood loss and transfusion secondary to chronic anemia and uremia-induced platelet dysfunction.

Tranexamic acid (TXA) is a commonly used antifibrinolytic agent with class 1A recommendations to minimize bleeding during CPB surgery.[8] Recent results from the Aspirin and Tranexamic Acid for Cardiac Surgery (ATACAS) trial further strengthened this indication with clear evidence showing that TXA reduces blood loss and transfusion in cardiac surgery.[9] The ATACAS trial was a multicenter double-blinded randomized controlled trial aiming to assess the safety and efficacy of aspirin and TXA in 4631 aortocoronary bypass patients. TXA inhibits clot breakdown by predominantly binding to plasminogen with maximal antifibrinolysis achieved at a plasma concentration of 100 mg/L.[10,11] Rising evidence questions the safety of TXA, with high doses linked to postoperative seizures.[9,12,13] Additional risk factors for seizures include preoperative CRD and long CPB times.[13,14] TXA is primarily cleared (>90%) unchanged by glomerular filtration with a half-life of 1.5–2 hours.[15,16] Elevated plasma TXA concentration levels have been observed in proportion to the severity of CRD in nonsurgical patients.[17] However, data in cardiac surgical patients are scarce, and there are no guidelines regarding TXA dosing for CRD patients. Using a computer-assisted simulation based on the 2-compartment model, we previously demonstrated that plasma TXA concentrations in CRD were high and potentially at toxic levels using current dosing regimens.[18] Optimizing TXA dosing for this patient subgroup is vital to achieve therapeutic antifibrinolysis while avoiding unnecessary large doses, which may promote postoperative seizure activity. The objective of this study was to conduct TXA pharmacokinetic profiling in cardiac surgical patients with varying CRD severity and recommend optimal dose adjustment.

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