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Hemostasis and Thrombosis: Original Clinical Research Report

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

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

Author Information
doi: 10.1213/ANE.0000000000002724

Abstract

KEY POINTS

  • Question: What is the pharmacokinetic profile of tranexamic acid among cardiac surgical patients with varying levels of preoperative chronic renal dysfunction?
  • Findings: Plasma tranexamic acid levels are raised in accordance with severity of chronic renal dysfunction in patients undergoing cardiopulmonary bypass surgery.
  • Meaning: Dosing of tranexamic acid should be lowered in patients with chronic renal dysfunction presenting for cardiac surgery.

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.

METHODS

Study Design

This single-center prospective cohort study enrolled patients undergoing cardiac surgery with CPB from August 2011 to April 2015. The article adheres to the appropriate Enhancing the QUAlity and Transparency Of health Research (EQUATOR) guidelines. We received Health Canada, Institutional Ethics Board approval and written patient consent. Study eligibility was adult patients (>18 years of age) with stages 1–5 CRD defined by the Kidney Disease Outcome Quality Initiative classification (KDOQI).19 Exclusion criteria were TXA allergy, preexisting coagulopathy, pregnancy, renal transplant recipients, advanced liver disease (2-fold or greater elevation in liver enzymes), and taking contraceptives or tretinoin (thrombotic risks are raised with TXA). In keeping with our institutional practice, we defined 2 study populations based on the postoperative bleeding risk that received separate dosing regimens. A “low-risk” group underwent aortocoronary bypass or single-valve repair/replacement. A “high-risk” group underwent complex redo, multiple valve and combined aortocoronary bypass with valve repair/replacement or aortic procedures. We aimed to recruit up to 6 patients in each CRD stage for both study groups. Given that we previously conducted and reported the pharmacokinetic analysis in high-risk stage 1 CRD patients, we therefore recruited stages 2–5 CRD high-risk patients during this study.10

Study Conduct

As per our institutional practice, the low-risk group received a single 50 mg/kg TXA bolus after induction of anesthesia. The high-risk group received Blood Conservation Using Anti-fibrinolytics Trial (BART) TXA regimen, consisting of 30 mg/kg bolus infused over 15 minutes after induction, followed by 16 mg/kg/h infusion until chest closure with a 2 mg/kg load within the pump prime. The BART TXA infusion regimen was developed in 2002 by Dowd et al.15 This study assessed 3 TXA dosing regimens and subsequently developed a TXA dosing infusion regimen to achieve a plasma TXA concentration of 100 mg/L and maximal antifibrinolysis. This dosing regimen was generated using a computer-simulated algorithm that was never tested in vivo. This TXA dosing regimen was subsequently used in the BART in 2008, which was designed to compare the safety and efficacy of TXA, aprotinin, and ε-aminocaproic acid.1 This study resulted in Food and Drug Administration removal of aprotinin for cardiac surgical patients. Perioperative care was standardized for all patients. Anesthesia was induced by using fentanyl (10–20 µg/kg), midazolam (0.05–0.1 mg/kg), rocuronium (0.6–1 mg/kg), and propofol (<1 mg/kg) and maintained with sevoflurane or isoflurane (0.6–1 minimum alveolar concentration [MAC]) and propofol infusion at 50 µg/kg/min during CPB. Patients were anticoagulated by using heparin (400 U/kg) to achieve an activated clotting time >480. CPB circuit was primed using 1.1 L Ringer’s lactate with 50 mL of 20% mannitol. Standard CPB management included hypothermia drift to 34°C, mean arterial pressures between 50 and 70 mm Hg, hematocrit >0.24, and α-pH stat. Post-CPB, anticoagulation was reversed with 1-mg protamine per 100 U of heparin. Patients with severe (stage 4 or 5) CRD received dialysis on bypass and the intensive care unit (ICU) to manage hyperkalemia and/or volume excess.

Serial blood samples were drawn at defined time points for measuring plasma TXA concentrations to facilitate pharmacokinetic modeling (see below for details). Samples were collected in standard citrate tubes and blinded to the analytical laboratory. The citrate tubes were placed on ice, centrifuged at 2000g for 15 minutes at 4°C, and the supernatant stored at −70°C until analysis. TXA was extracted and measured using solid-phase microextraction and liquid chromatography-tandem mass spectroscopy/tandem mass spectroscopy. This methodology was previously described and validated.11

Outcomes

Primary outcome measured serial plasma TXA concentrations to enable construction of pharmacokinetic profiles for all 5 CRD stages in low- and high-risk groups. Previous data identified that plasma concentration of 100 mg/L provides near 100% inhibition and maximal antifibrinolysis.10,11 This level constituted the therapeutic threshold for TXA dose adjustment.

Descriptive clinical outcomes were postoperative seizures, blood loss, bleeding requiring chest reexploration or tamponade release, transfusion, ischemic-thrombotic complications (deep venous thrombosis, pulmonary embolism, myocardial ischemia, and stroke), ventilation duration, in-hospital mortality, and length of ICU and hospital stay. Routine electroencephalography (EEG) is not performed in our institution to monitor subclinical seizure activity and was not the study’s primary focus. All clinical seizure activity was documented, followed by a neurological assessment, brain computed tomography scan, and EEG at the discretion of the specialist team. Blood hematological and renal (glomerular filtration rate, creatinine) markers were measured plus postoperative creatinine clearance (CL) using 24-hour urine collections when permissible. Patients were followed until hospital discharge.

Pharmacokinetic and Statistical Analysis

To assess the pharmacokinetic profile of TXA in cardiac surgical patients, serial blood samples were drawn at baseline (pre-TXA administration) and then in 5 distinct phases of the cardiac surgical procedure, which matched the pharmacokinetic analysis. Phase I reflects the loading dose, phase II is sternotomy to pre-CPB, phase III is on-CPB period, phase IV is post-CPB to chest closure, and phase V reflects the washout period (samples taken up to 12 hours, for details, please refer to Yang et al,18 2015). Blood samples were taken for a total of 12 hours, spanning the post chest closure duration that more than doubled the half-life of TXA.

Compartment Model Fitting to Data.

Pharmacokinetic analysis, estimation of CLs, and volumes of distribution were performed using the previously developed 2-compartment model (see Supplemental Digital Content, Figure 1, https://links.lww.com/AA/C174). The extracorporeal (CPB) compartment was turned on during CPB (phase III) only, with the assumption that fluid in the extracorporeal compartment (1.1 L) was returned to patients at the end of CPB. The flow rate between the CPB circuit and the central compartment was assigned as 5 L/min.18 Data from each CRD stage (stages 1–5) and risk group (low versus high risk) were fitted individually using ADAPT5 (BMSR version 5; USC, Los Angeles, CA); mass balance equations were previously reported to examine whether pharmacokinetic parameter estimates are different for various CRD stages and risk groups.18 The computational algorithm used was the maximum likelihood solution via the expectation/maximization algorithm (MLEM), and the error variance (VAR) function used was , where and are the intercept and slope of standard deviation of variance function, respectively. The difference in the estimates was compared using 5 × 2 two-way analysis of variance, with main effects defined as CRD stages 1–5 and risk groups (low versus high). Additionally, the correlation between total TXA plasma CL and estimated glomerular filtration rate (eGFR) was studied, and the coefficient of determination (r2) and the corresponding P value were calculated by Sigma Plots (Systat Software, San Jose, CA).

Simulations.

T1
Table 1.:
Pharmacokinetic Parameter Estimates Using ADAPT5
T2
Table 2.:
KDOQI Classification of Chronic Renal Dysfunction and Tranexamic Acid Dosing Recommendation

A series of simulations were performed for each CRD stage and dosing groups according to our developed 2-compartmental model and reported pharmacokinetic parameters.18 The simulated profiles were based on the fitted parameters (Table 1) and suggested bolus loading dose and maintenance infusion rate (Table 2) for the high-risk patient group among stages 2–5. The 2-compartmental model was used, and the area under the curve to time infinity (AUC) was calculated using trapezoidal rule and added to the extrapolated area (Clast/terminal slope). The plasma CL (dose/AUC) was plotted against the baseline eGFR using scatterplot. The coefficient of determination (r2) and the corresponding P value were calculated by Sigma Plots.

NONMEM Population Modeling and Covariates.

The composite data (with all 5 CRD stages in the 2 risk groups) were used for population analysis to evaluate the important covariate that can explain the between-subject variability (BSV) using NONMEMVII (version 7.3; ICON Development Solution, Ellicott City, MD). The base population model was obtained from a previous study.18 The baseline eGFR was assigned as a continuous covariate and expressed in the form of , where is the median value.18 The risk group (low versus high), as a binary or dichotomous covariate, was assigned to be either 1 (high-risk group) or 0 (low-risk group) and can be expressed in form of CLi or , where CLiL or ViL and CLiH or ViH represent pharmacokinetic parameters for the low- and high-risk group, respectively. Because the weight-normalized dose was used, body weight was not considered as a covariate. Model I is the basic model with consideration of covariates, then eGFR on CL, or CL and V1, or CL and CL12 (same as CL21), then eGFR on CL and risk category (low versus high) on V1, or eGFR on CL and risk category on V1 and CL12, and finally, eGFR on CL and risk category on V1, CL12, and V2. Improvement of the fit was examined after the incorporation of each covariate combination to certain pharmacokinetic parameters. Decrease in the objective function values was compared using −2 times the log-likelihood ratio test with a stringent α level of .005 for significance. The model with the best improvement in goodness of fit was selected as the final model. The model fit was examined with diagnostic plots (observation versus prediction), and unexplained variability (ETAs) in CLi or Vi versus covariates (baseline eGFR and risk groups) plots were used to guide the covariate model-building process.

Descriptive clinical data were reported using median (interquartile range) for continuous variables. Clinical categorical variables were reported as frequencies (percentages). In keeping with other pharmacokinetic studies, the sample size was deemed sufficient for modeling.15,20–22 Analyses were conducted using SAS v9.4 (SAS Institute Inc, Cary, NC). To control for 5 comparisons, a P value <.01 (conventional P value .05 divided by 5) was considered statistically significant after Bonferroni correction.

RESULTS

T3
Table 3.:
Perioperative Patient and Surgical Characteristics in the Low- and High-Risk Study Groups

We recruited 26 low-risk and 22 high-risk patients. Stage 4 and low-risk stage 2 CRD patients were more difficult to recruit; thus, patient numbers were lower in these categories. Perioperative patient characteristics are reported in Table 3 and Supplemental Digital Content, Table 1, https://links.lww.com/AA/C174.

Clinical Outcomes

Four patients (8%) suffered postoperative seizures in CRD stages 5 (3 patients) and 3 (1 patient) in the high-risk group (Supplemental Digital Content, Table 2, https://links.lww.com/AA/C174). Brain computed tomography scans revealed no new focal mass lesion in any of these patients. There were 5 (10%) postoperative deaths in low-risk stage 3 (1 patient), high-risk stage 3 (1 patient), and stage 5 (3 patients) CRD, which included 2 patients who suffered a seizure. There was no significant difference in postoperative bleeding, chest reexploration, transfusion, ischemic-thrombotic complications, or length of stay.

Pharmacokinetic Modeling and Simulations

F1
Figure 1.:
Fitted (lines) and observed (symbols) plasma TXA concentration–time profiles in low- and high-risk study groups for each stage of CRD. The different colors represent different stages of CRD (1–5). Red dashed lines indicate the TXA threshold level of 100 mg/L that allows 100% antifibrinolysis.9 , 10 The yellow circles (high-risk group, stages 3 and 5) represent TXA concentration data in the 4 seizure patients. Based on the newly recommended reduction in loading dose and maintenance infusion (Table 2) for the high-risk stages 2–5 CRD groups, simulation of TXA profiles was performed: the dashed and solid turquoise lines represent the pharmacokinetic profile when loading dose is 25 or 30 mg/kg, respectively. For the CRD 3–5 groups, the turquoise solid and the dashed lines represent the loading dose of 30 and 25 mg/L, respectively, with the same upper boundary maintenance infusion rate (shown in Table 2); the brown solid and dashed lines represent the loading dose of 30 and 25 mg/kg, respectively, with the same lower boundary maintenance infusion rate recommended (Table 2). CRD indicates chronic renal dysfunction; TXA, tranexamic acid.
F2
Figure 2.:
Baseline eGFR versus TXA plasma clearance. Different colors represent different stages of CRD. The yellow closed circles represent the data obtained from seizure patients. The measured TXA concentrations of 1 seizure patient were consistently rising; therefore, the AUC of that patient could not be calculated. The dashed and solid black lines denote the regression line and line of identity (y = x), respectively. AUC indicates area under the curve to time infinity; eGFR, estimated glomerular filtration rate; TXA, tranexamic acid.

Pharmacokinetic parameters obtained from fitting are summarized in Table 2 and include data previously obtained on 15 high-risk stage 1 CRD patients.10 The loading or bolus dose was effective at establishing the initial plasma TXA concentration to attain a therapeutic threshold above 100 mg/L. TXA concentration–time profiles demonstrated that plasma levels were elevated with increasing severity of CRD in both study groups (Figure 1). The total body CL (estimated as dose/AUC) values for TXA remain similar for stages 1 and 2 in the low- (0.094 stage 1 vs 0.073 stage 2, L/h/kg) and high-risk (0.110 stage 1 vs 0.092 stage 2, L/h/kg) groups. However, the total body CL reduces markedly with declining renal function between stages 3 and 5 in both the low- and high-risk treatment groups (Table 1). Collectively speaking, the CL progressively decreased among patients who were more renally compromised. A similar trend was observed for V1, volume of the central compartment. While there was no change in low-risk stages 1–5, V1 progressively reduced for high-risk stages 4 and 5 groups, likely due to accompanying dialysis and other procedures that reduced the plasma volume. The intercompartmental CL, CL12 or CL21, was >2-fold higher for the high-risk group versus the low-risk group for each stage. Due to the combined changes in CL, CL12, and V1, plasma levels fell below the therapeutic threshold in 2–4 hours in low-risk group stages 1 and 2 CRD patients, retaining a short t½ of 2.6–3.4 hours. However, the t½values progressively increased to 6.3, 12, and 38 hours (Table 1) in low-risk CRD stages 3–5, with TXA displaying a slower decay and sustained plasma levels near 100 mg/L for approximately 6 hours. By contrast, the high-risk group showed consistently elevated plasma TXA concentrations above 100 mg/L that were sustained for up to 12 hours in stages 3–5. This reduction in CL was consistent with CRD stages (represented by baseline eGFR), with a significant correlation of r2 of 0.67 (Figure 2).

Population Pharmacokinetics

F3
Figure 3.:
Plots of contribution of covariates (including eGFR, CRD stages, and risk groups [low versus high]) to the random effects (ETAs) for CL1, V1, CL12 or CL21, and V2 of tranexamic acid for (A) base and (B) final models. These plots were generated from output of NONMEM using R (R Development Core Team, Vienna, Austria). Risk groups are assigned as 0 (low risk) or 1 (high risk). CL indicates clearance; CRD, chronic renal dysfunction; eGFR, estimated glomerular filtration rate; V1, volume of the central compartment; V2, volume of peripheral compartment.

With population pharmacokinetic modeling, we investigated which covariates influence CL, V1, and CL12. We identified that eGFR and patient risk group (low or high) were important covariates influencing the CL, V1, V2, CL12 and the unexplained intersubject variability (represented by ETAs) associated with the pharmacokinetic parameters were also reduced (Figure 3; Supplemental Digital Content, Table 3, https://links.lww.com/AA/C174). The final model is robust with reasonably good predictions for characterizing TXA pharmacokinetics among CRD patients.

Seizure Versus Nonseizure Patients

We examined the pharmacokinetic profiles of the 4 seizure patients, which are highlighted in yellow symbols for high-risk group stages 3 and 5 (Figure 1, right panel), reflecting the higher area under the curve (AUC) and lower CL. The seizure group showed higher TXA concentrations and prolonged t½ (29.6 vs 3.4 hours; P = .014) and the area above the 100 mg/L mark, or AUC>100 mg/L (AUC − AUC≤100 mg/L) compared to the nonseizure group (Supplemental Digital Content, Table 2, https://links.lww.com/AA/C174). This suggests that higher TXA systemic accumulation and reduced CL may have contributed to seizure development.

Dosing Adjustment for CRD

Given observations of reduced V1 and CL but higher CL12 among high-risk patients, we developed a new proposal for the TXA infusion regimen, aiming to maintain a plasma concentration around 100 mg/L (Table 2). We lowered the loading dose in stages 3–5 CRD (due to reduced V1 but higher CL12) slightly to 25 mg/L and the maintenance infusion rate (corresponding to eGFR) for all CRD stages to bring TXA plasma levels into a safe range. Simulations based on the newly recommended regimen demonstrate this expected pattern for high-risk stages 2–5 CRD patients (Figure 1). Given that TXA exhibits minimal protein binding, any change in protein levels is unlikely to influence TXA plasma levels.

DISCUSSION

This study confirmed that plasma TXA levels were elevated in proportion to the severity of CRD and the reduction in renal CL. This is most pronounced among advanced CRD stages 3–5 when TXA maintenance infusions were used. We have recommended a simple adjustment strategy to the BART dosing regimen to minimize costly drug overdosing, accumulation, and potential toxic effects of TXA. We also identified that single TXA bolus dosing in stages 1 and 2 CRD was associated with a rapid decline in plasma levels to subtherapeutic concentrations, without much risk of toxicity. This is important during prolonged surgeries where repeat dosing may be warranted or an infusion is preferable. Bolus dosing among stages 4 and 5 CRD provided near therapeutic plasma TXA levels with effective antifibrinolysis for several hours.

Although the primary aim was not to assess clinical outcomes, we revealed an alarmingly high seizure rate (8%) in advanced CRD. Postoperative seizures typically affect <1% of cardiac surgical patients and are associated with 10-fold higher incidence of delirium, stroke, mechanical ventilation, and mortality.13 Risk-adjusted analyses demonstrate that independent predictors of early seizures include elderly patients (>75 years of age), preoperative cardiac arrest, preoperative neurological disease (cerebrovascular disease, seizure disorder, alcohol abuse, brain tumor, multiple sclerosis), Acute Physiology And Chronic Health Evaluation II scores >20, redo surgery, peripheral vascular disease, open left heart and aortic operations, long CPB times, preoperative CRD, and high TXA doses.13,14 The recent large multicenter trial reported by Myles et al9 provides further evidence demonstrating a link between TXA and seizures. This trial showed that seizures were 7 times more likely in patients receiving similar TXA bolus doses (50–100 mg/kg) in comparison to placebo. Seizures secondary to dialysis disequilibrium syndrome are unlikely given this is exceedingly rare and commonly occurs after commencing new-onset hemodialysis.23,24 Dialysis disequilibrium syndrome is characterized by neurological changes such as restlessness, acute confusion, headache, and seizures whose etiology remains unknown.25 Animal data have demonstrated that the mechanism of TXA-induced seizures is through central inhibition of glycine and glycine and gamma-aminobutyric acid subtype a receptors.26,27 Although this mechanism is plausible, other factors such as cerebral embolic load from open cardiac procedures, blood–brain barrier leak, cerebral inflammation, and preoperative CRD would likely interplay in raising central TXA levels and inducing seizures.28,29 Currently, we lack human data assessing the correlation between plasma and cerebrospinal fluid TXA levels and seizure induction. However, TXA dosing appears to be an important variable with several studies demonstrating a dose–response relationship.13,27,30

Our data support the higher mortality rate seen among cardiac patients with CRD.4,5 Previous work showed that even mild CRD (creatinine, 130–140 mmol/L) was significantly associated with higher mortality.31,32 Renal function further deteriorates postsurgery secondary to altered hemodynamics, surgical trauma, systemic inflammatory response leading to altered renal vasoreactivity, local hypoxia, and oxidative injury causing medullary congestion.33 This would further reduce the CL of renally excreted drugs such as TXA.

Our findings are supported by Andersson et al17 who administered intravenous TXA to 28 nonsurgical patients with varying CRD levels. They identified that plasma TXA levels were highest in patients with the poorest renal function. This study formed the basis of current licensed Food and Drug Administration dosing recommendations of short-term TXA use among hemophiliacs undergoing dental extraction. The dosing of cardiac surgery patients is very different, given the presence of CPB, altered distribution volumes, transfusion, and intense inflammatory response. Data in cardiac surgery are limited to a single study performed by Fiechtner et al34 who assessed plasma TXA levels in 21 patients where only 4 had preoperative CRD (serum creatinine, 2.3–6.4 g/dL). The TXA regimen consisted of 10 mg/kg bolus dose and 1 mg/kg/h maintenance infusion for up to 2 hours in the ICU. The plasma TXA levels were significantly raised in CRD in comparison to normal renal function patients. Analyses of these 4 CRD patients led to recommending a TXA regimen of 5.4 mg/kg bolus dose, 50 mg in the CPB prime and reduced maintenance infusion by 25% (3.75 mg/kg/h) in patients with serum creatinine 141–291 mmol/L, 50% (2.5 mg/kg/h) serum creatinine 291–583 mmol/L and 75% (1.25 mg/kg/h) when creatinine exceeded 583 mmol/L. Although our findings corroborated elevated plasma TXA levels in CRD patients, we recommend an alternative dosing reduction regime. Our recommendations are based on the pharmacokinetic interpretation of a larger CRD population using the KDOQI classification, studying patients for longer CPB times and assessing 2 different dosing regimens. Our results demonstrated a reduction in the volume of distribution and CL of TXA among CRD patients (Table 1). This resulted in high plasma TXA concentrations in accordance with the severity of CRD. In advanced CRD, plasma levels were 3–4 higher than the threshold required to achieve maximal antifibrinolysis (100 mg/L). There has been no previous work that has clearly shown that plasma TXA levels rise with increasing severity of CRD as defined by the KDOQI guidelines among cardiac surgical patients.

We acknowledge that our study is not without limitations. First, the clinical outcomes are not powered in the sample size. Given that this is primarily a pharmacokinetic study, we did not aim to demonstrate a clinical difference but the data provide a useful trend and foundation for conducting a larger clinical trial. Our sample size is in keeping with other pharmacokinetic studies.15,20–22 Although fewer patients were recruited in certain CRD stages, we believe that valuable information had been ascertained to meet our study objectives. Second, only clinically evident postoperative seizures were documented. Routine EEG monitoring for subclinical seizure activity is not standard practice in ours and many other cardiac centers. Thus, the true incidence of seizures may be even higher. Given our findings, cardiac centers may wish to consider the role of routine EEG monitoring in cardiac surgical patients who are at high risk of postoperative seizures. Third, many centers may use ε-aminocaproic acid for antifibrinolysis, which has also been associated with seizure activity. Although this agent is structurally similar to TXA and undergoes predominant renal elimination, further studies are needed to recommend the optimal dosing regimen. Fourth, we acknowledge that even though the BART dose is a commonly used regimen, our low-risk bolus dose may not be unanimously accepted. However, this bolus dose was used in the recent TXA trial conducted by Myles et al.9 Fifth, we accept that in vivo validation of our dosing scheme has not been performed. However, given that the study findings corroborate our previous work and protein binding of TXA is low, this TXA pharmacokinetic model for CRD and dosing recommendations are likely to be robust.18 Sixth, we acknowledge that the plasma TXA threshold of 100 mg/L used in this study is based on in vitro and theoretical considerations to provide near-maximal antifibrinolysis. There is no sensitive point-of-care test to assess individual patient response to TXA or degree of fibrinolysis. However, our bolus dose was used in the ATACAS study, which remains the largest trial assessing the safety and efficacy of TXA. Last, our model did incorporate CPB priming volume and returned blood volume at the end of CPB. However, we acknowledge that TXA levels may still be affected by sudden blood loss, blood transfusion and use of a cell saver. These factors may impact whether the proposed dosing scheme will achieve therapeutic plasma TXA levels.

This study is the first to formally conduct pharmacokinetic analysis and make simple dosing recommendations specifically for CRD patients undergoing cardiac surgery that can be widely adopted. Further work includes examining TXA dosing for other clinical areas. Off-label TXA is commonly used to manage bleeding in trauma patients (Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage [CRASH] 2 trial), severe menorrhagia, hereditary angioedema, and complex noncardiac surgeries (major orthopedics, maxillofacial, prostate, hepatobiliary).35,36 Despite widespread use, informed kinetic analysis and dosing schemes are lacking in these areas. This study will form a solid basis for further work optimizing dosing regimens beyond cardiac surgical patients.

ACKNOWLEDGMENTS

We thank Humara Poonawala, Ishtiaq Ahmadi, and Justin Chan for assisting in sample and data collection and our colleagues in the Departments of Anesthesia, Cardiac Surgery and Perfusion medicine for their support of this study. We thank the Heart and Stroke Foundation of Canada, Merit Award, Department of Anaesthesia, University of Toronto, and Natural Sciences and Engineering Research Council of Canada who helped to fund this study.

DISCLOSURES

Name: Angela Jerath, FRCPC, FANZCA, MBBS, BSc.

Contribution: This author helped to conceive the study question, design the study, study recruitment, carrying out the study, analyze the data, draft the manuscript, obtain funding, and read and approve the final draft.

Name: Qi Joy Yang, MSc.

Contribution: This author helped to perform the pharmacokinetic analysis and modeling, draft the manuscript, and read and approve the final draft.

Name: K. Sandy Pang, PhD.

Contribution: This author helped to perform the pharmacokinetic analysis and modeling, draft the manuscript, and read and approve the final draft.

Name: Nikita Looby, MSc.

Contribution: This author helped to undertake sample analysis, measure the plasma tranexamic acid levels, and read and approve the final draft.

Name: Nathaly Reyes-Garces, MSc.

Contribution: This author helped to undertake sample analysis, measure the plasma tranexamic acid levels, and read and approve the final draft.

Name: Tijana Vasiljevic, BSc.

Contribution: This author helped to undertake sample analysis, measure the plasma tranexamic acid levels, and read and approve the final draft.

Name: Barbara Bojko, PhD.

Contribution: This author helped to develop the methodology for sample analysis, undertook sample analysis, and read and approve the final draft.

Name: Janusz Pawliszyn, PhD.

Contribution: This author helped to develop the methodology for sample analysis, undertook sample analysis, and read and approve the final draft.

Name: Duminda Wijeysundera, PhD, FRCPC.

Contribution: This author helped to design the study protocol, study recruitment, carrying out the study, and read and approve the final draft.

Name: W. Scott Beattie, PhD, FRCPC.

Contribution: This author helped to design the study protocol, study recruitment, carrying out the study, and read and approve the final draft.

Name: Terrence M. Yau, PhD, FRCSC, MD, MSc, BA.

Contribution: This author helped to design the study protocol, study recruitment, carrying out the study, and read and approve the final draft.

Name: Marcin Wąsowicz, FRCPC, PhD, MD.

Contribution: This author helped to conceive the study question, design the study, study recruitment, carrying out the study, draft the manuscript, and read and approve the final draft.

This manuscript was handled by: Roman M. Sniecinski, MD.

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