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CARDIOVASCULAR ANESTHESIA

Plasma Tranexamic Acid Concentrations During Cardiopulmonary Bypass

Bridget K. Fiechtner, MD^*, Gregory A. Nuttall, MD^*, Michael E. Johnson, MD, PhD^*, Yue Dong, MD^*, Nuntiya Sujirattanawimol, MD^*, William C. Oliver, Jr., MD^*, Rajbir S. Sarpal, MD, Lance J. Oyen, PharmD, BCPS^*, and Mark H. Ereth, MD^*

*Mayo Graduate School of Medicine, Rochester, Minnesota; and Department of Biology, University of Wisconsin Critical Care, Madison, Wisconsin

Address correspondence and reprint requests to Gregory A. Nuttall, MD, Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905. Address e-mail to nuttall.gregory{at}mayo.edu

	Abstract

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Although tranexamic acid is used to reduce bleeding after cardiac surgery, there is large variation in the recommended dose, and few studies of plasma concentrations of the drug during cardiopulmonary bypass (CPB) have been performed. The plasma tranexamic acid concentration reported to inhibit fibrinolysis in vitro is 10 µg/mL. Twenty-one patients received an initial dose of 10 mg/kg given over 20 min followed by an infusion of 1 mg · kg^-1 · h^-1 via a central venous catheter. Two patients were removed from the study secondary to protocol violation. Perioperative plasma tranexamic acid concentrations were measured with high-performance liquid chromatography. Plasma tranexamic acid concentrations (µg/mL; mean ± SD [95% confidence interval]) were 37.4 ± 16.9 (45.5, 29.3) after bolus, 27.6 ± 7.9 (31.4, 23.8) after 5 min on CPB, 31.4 ± 12.1 (37.2, 25.6) after 30 min on CPB, 29.2 ± 9.0 (34.6, 23.8) after 60 min on CPB, 25.6 ± 18.6 (35.1, 16.1) at discontinuation of tranexamic acid infusion, and 17.7 ± 13.1 (24.1, 11.1) 1 h after discontinuation of tranexamic acid infusion. Four patients with renal insufficiency had increased concentrations of tranexamic acid at discontinuation of the drug. Repeated-measures analysis revealed a significant main effect of abnormal creatinine concentration (P = 0.02) and time (P < 0.001) on plasma tranexamic acid concentration and a significant time x creatinine concentration interaction (P < 0.001).

Implications: A 10 mg/kg initial dose of tranexamic acid followed by an infusion of 1 mg·kg^-1·h^-1produced plasma concentrations throughout the cardiopulmonary bypass period sufficient to inhibit fibrinolysis in vitro. The dosing of tranexamic acid may require adjustment for renal insufficiency.

	Introduction

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Excessive bleeding after cardiopulmonary bypass (CPB) is one of the most common complications of cardiac surgery (1). Bleeding has important health and economic consequences (2). Fibrinolysis is thought to be an important cause of excessive bleeding after cardiac surgery. Tran-examic acid (trans-4-aminomethylcyclohexane-1-carboxylic acid), a synthetic lysine analog, is a competitive inhibitor of plasmin and plasminogen (3,4). Prophylactic administration of tranexamic acid decreases blood loss and blood transfusion requirements in cardiac surgery patients (5–16).

Although tranexamic acid has been effective in reducing bleeding after cardiac surgery, there is a large variation in the recommended dose (8,12). No complete studies of plasma concentrations of the drug during cardiac surgery with CPB have been performed.

Therefore, we prospectively measured plasma tranexamic acid concentrations in 21 patients receiving tranexamic acid prophylaxis according to our standard protocol for primary cardiac surgery with CPB. Our goal was to determine whether our dosing protocol resulted in plasma tranexamic acid concentrations sufficient to inhibit fibrinolysis in vitro (10 µg/mL) (3).

	Methods

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After IRB approval and verbal consent, 21 adult cardiac surgical patients were enrolled. The patients were enrolled in the study if they were having any type of cardiac surgical procedure requiring CPB and the anesthesiologist caring for the patient was planning to use prophylactic tranexamic acid on the basis of clinical criteria. Exclusion criteria were age <18 yr, history of allergy to tranexamic acid, history of previous antifibrinolytic or thrombolytic therapy within 7 days of surgery, or history of coagulation disorder.

Patients were administered anesthesia based on moderate dose opioids (fentanyl 20–25 µg/kg) balanced with midazolam 0.1 mg/kg, nondepolarizing muscle relaxants, and isoflurane 0.5%–1.5%. Venous, radial artery, and pulmonary artery catheters were inserted. CPB was accomplished with a Sarns 9000 CPB machine (Sarns Inc., Ann Arbor, MI) and a Univox membrane oxygenator (Bently Inc., Irvine, CA). The CPB priming solution consisted of 1.5 L of plasmalyte with 10 mEq of sodium bicarbonate and 12.5 g of mannitol. The initial dose of porcine heparin was 300 U/kg, with an oxygenator prime of 10,000 U. When necessary, an additional 5000 U of heparin was administered to achieve a celite activated clotting time of more than 450 s before the initiation of CPB. After CPB, heparin was neutralized with protamine sulfate at a dose of 1.3 mg/kg. If this dose of protamine failed to return the activated clotting time to within 10% of the preheparin level, additional doses of 20 to 50 mg were given at the discretion of the anesthesiologist.

The patients received an initial dose of 10 mg/kg tranexamic acid given over 20 min, followed by an infusion of 1 mg · kg^-1 · h^-1 via a central venous catheter (8). The infusion was continued for 2 h after the patient’s arrival in the intensive care unit (ICU). Blood samples were withdrawn from an existing arterial catheter at the following time points: baseline; 5 min after tranexamic acid bolus and institution of tranexamic acid infusion; at 5, 30, and 60 min on CPB; at the time of discontinuation of tranexamic acid infusion; and 1 h after tranexamic acid was discontinued. Each blood sample (900 µL) was placed in a tube with 100 µL of 0.105M buffered sodium citrate. Within 1 h the tubes were centrifuged at 2000g for 15 min, and the platelet-poor supernatants were frozen and stored at -70°C until assayed.

Plasma tranexamic acid concentration was determined by adapting an established high-performance liquid chromatography (HPLC) amino acid assay using ortho-phthalaldehyde derivatization (17–19) and by pretreating the sample with leucine dehydrogenase (20,21) to minimize interfering branched-chain amino acid peaks. Leucine dehydrogenase (Toyobo Co., Ltd., Osaka, Japan) was added to aliquots of plasma samples and incubated 1 h at 37°C. Samples were then deproteinized by addition of acetonitrile and centrifuged at 2000g for 2 min. The supernatant was then filtered by using a 0.45-µm PTFE filter and subsequently derivatized with o-phthalaldehyde for 2.5 min. The derivatized sample was immediately analyzed on a 4.6 x 150.0-mm Microsorb-MV, C18 column (Rainin, Walnut Creek, CA) eluted with 19% acetonitrile and 81% buffer (20mM sodium phosphate pH 6.9, 90% water, 10% acetonitrile) at a flow rate of 1.3 mL/min. The tranexamic acid derivative was detected fluorometrically, and its peak area was determined by electronic integration. HPLC elution of the tranexamic acid derivative occurred at 4.6 min under the aforementioned conditions. Plasma concentrations were determined from a standard curve generated with known quantities of tranexamic acid (Sigma, St. Louis, MO) added to plasma. The standard curve for the HPLC assay was well correlated between peak area and plasma tranexamic acid concentration between 0 and 40 µg/mL (R² = 0.998).

Intraoperative mediastinal blood loss was salvaged and reinfused in all cases. During CPB, a hemoglobin concentration of more than 7 g/dL was maintained, preferentially by reinfusion of salvaged blood, with allogeneic red blood cells (RBCs) used when autologous blood was not available. After CPB, allogeneic RBCs were transfused to achieve a hemoglobin concentration of more than 8 g/dL. The decision to transfuse allogeneic fresh frozen plasma, platelets, and cryoprecipitate was based on clinical evidence of bleeding, such as oozing at the surgical site, as well as laboratory studies. Laboratory-based transfusion algorithms were not used as part of this study.

The primary outcome variable was the concentration of tranexamic acid in the plasma as determined by HPLC. Secondary outcome measures were postoperative blood loss, which was measured and recorded hourly by ICU staff, and transfusion of allogeneic blood products in the operating room and in the first 24 h in the ICU.

	Results

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We studied the plasma concentrations of tranexamic acid in 19 of the 21 enrolled patients. Two patients were excluded from the study secondary to protocol violation. One patient had the tranexamic acid infused into the right ventricular port of the pulmonary artery catheter, and the other patient did not receive the initial dose of tranexamic acid. Preoperative demographics and intraoperative characteristics are shown in Table 1. Patient weight ranged from 59 to 118 kg. Mean duration of CPB was 67 ± 33 min. Thirteen patients had a duration of CPB long enough to measure tranexamic acid plasma concentrations at 60 min duration of CPB.

View larger version (34K): [in this window] [in a new window]   Figure 1. High-pressure liquid chromatograms of a patient’s plasma before and after the administration of tranexamic acid. Tranexamic Acid = tranexamic acid peak.

View larger version (34K): [in this window] [in a new window]   Figure 2. Plasma arterial tranexamic acid concentrations for each patient measured at each of the time points throughout cardiopulmonary bypass (CPB) for patients with normal (A) and impaired (B) renal function. Preload = before initial tranexamic acid load; Load + 5 = 5 min after initial tranexamic load during drug infusion; CPB + 5 = 5 min after initiation of CPB; CPB + 30 = 30 min after initiation of CPB; CPB + 60 = 60 min after initiation of CPB; D/C = discontinuation of tranexamic acid infusion; D/C + 1 h = 1 h after discontinuation of tranexamic acid infusion.

The postoperative mediastinal blood loss over 24 h was 626 ± 377 mL. There was no correlation between blood loss and plasma tranexamic acid concentrations. Four patients received at least one allogeneic RBC transfusion during surgery. One patient received one allogeneic RBC transfusion after surgery, and one patient received a transfusion of six allogeneic platelet units after surgery.

	Discussion

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The dose of tranexamic acid administered prophylactically to prevent excessive bleeding associated with cardiac surgery and CPB varies greatly between institutions. Published dosing schedules for tranexamic acid range between 150 mg/kg initial dose (12) to 10 mg/kg initial dose followed by a 1 mg · kg^-1 · h^-1 infusion (8). The dosing schedule of tranexamic acid used in our study was based on the dose-response study published by Horrow et al. (8), but the plasma tranexamic acid concentrations had not been shown to be adequate during CPB except for a preliminary report in abstract form (22). All patients in our study had plasma tranexamic acid concentrations during CPB more than those needed to reduce tissue plasminogen activator activity by 80% in vitro (10 µg/mL) (3). This is a concentration sufficient to suppress fibrinolytic activity. Tranexamic acid may also abolish plasmin-induced platelet activation in vitro at 16 µg/mL (11). Sixteen of the 19 patients had concentrations above this throughout the CPB period. Pharmacologically, it would be desirable to achieve stable plasma levels throughout the duration of CPB and into the ICU. We are not achieving this with the current regimen, though the concentrations were relatively stable throughout CPB, with a range of 14.3 to 54.4 µg/mL.

The information derived from our study can be combined with that of Dowd et al. (22), Andersson et al. (23), Eriksson et al. (24), Pilbrant et al. (25), and Puigdellivol et al. (26) to design a potentially more pharmacologically rational dosing regimen for tranexamic acid for patients with and without renal insufficiency (Appendix 1). It is rare that a drug is without increasing toxicity at increasing doses, although we cannot prove this point with our study. Given the theoretic advantages of minimal achievable dose for benefit, coupled with the reduced cost of avoiding larger-than-necessary doses, a dosing strategy to efficiently achieve the antifibrinolytic level of >10 µg/mL is attractive. We did not design our study to determine the complex pharmacokinetics of tranexamic acid in CPB patients. Pharmacokinetic studies have been done on healthy volunteers, and these studies suggest that tranexamic acid fits a three-compartment model (23–26). However, Dowd et al. (22) concluded that when the variables of the operating room are considered (CPB, fluids, etc.), tranexamic acid pharmacokinetics follow a simpler two-compartment model. Resolution of these differences in published pharmacokinetic models involves difficult and questionable assumptions (e.g., CPB does not influence drug distribution or clearance), so we did not attempt to extend our analysis to a specific pharmacokinetic model. We believe that the more clinically relevant approach, as reported here, is to study plasma levels achieved with our current dosing and suggest reasonable adjustments, as we have done in Appendix 1.

The small number of patients enrolled limits our study. Our study was designed to assess the concentrations of tranexamic acid achieved with only one dosing regimen of tranexamic acid. Our study is insufficiently powered to determine what level of tranexamic acid is needed to prevent excessive bleeding. The dose-response study published by Horrow et al. (8) suggests that the levels documented in our current study may be adequate. Another limitation of our study is that the amount of tranexamic acid needed to prevent fibrinolysis in vivo is not known. The type of anesthetic administered may also affect the pharmacokinetics of tranexamic acid. Finally, the short duration of CPB in this study limits an analysis of the effect of longer periods of CPB on plasma tranexamic acid concentrations. Many institutions routinely have longer CPB durations for these types of surgery. Further, there is a gradual decrease in plasma tranexamic acid concentrations over time, and longer CPB durations may result in insufficient concentrations of drug in normal renal function patients. An increase in the tranexamic infusion to 5 mg · kg^-1 · h^-1 (Appendix 1) may result in prevention of this decrease in plasma tranexamic acid concentration and maintain a level of 20 µg/mL, though prospective dose-ranging studies are needed to address this.

The variability of tranexamic acid plasma concentrations, despite the use of a weight-based dosing regimen, suggests that other factors may affect the plasma concentration of tranexamic acid. Tranexamic acid is distributed throughout all tissues (3). The elimination half-life of tranexamic acid is 120 minutes, with the majority of tranexamic acid being recovered in the urine (4). Our largest plasma concentrations of tranexamic acid after CPB were found in patients with renal insufficiency. The dosing of tranexamic acid likely needs to be modified in CPB patients with impaired renal function. None of our patients underwent hemofiltration during CPB, but in considering the small size of the tranexamic acid molecule, it is likely that hemofiltration would also affect plasma tranexamic acid concentrations.

In summary, the dosing regimen of 10 mg/kg initial dose followed by an infusion of 1 mg · kg^-1 · h^-1 tranexamic acid resulted in adequate plasma concentrations defined by in vitro studies to prevent fibrinolysis, with relatively stable drug levels throughout CPB. Prospective studies will be required to determine the needed dosing for CPB patients with impaired renal function and to determine the in vivo plasma concentration of tranexamic acid required to reduce bleeding and transfusion requirements.

Appendix 1: Clinical Recommendation for Tranexamic Acid Dosing
Our data can be combined with other published data (22) and recommendations (23) to provide a clinical recommendation for tranexamic acid dosing, designed to maintain plasma levels of 20 µg/mL through the CPB period. Although not yet prospectively validated, it provides a rational approach and is consistent with our current data.

Estimated volume of distribution: 10 mg/kg (load) ÷ 0.037 mg/mL (concentration peak, approximation) = 0.27 L/kg

• Assumes the peak at 5 min after load is without any elimination or distribution to another compartment (both unlikely).
  
• This is similar to the reported volume of distribution (VD) at steady state (0.39 L/kg) but quite different from the central compartment VD (0.18 L/kg). Our value is likely a combination of both, given the time of sampling (after distribution but before steady state), and our value should be and is between those numbers.
  
• This is consistent with graphical interpolation of our Figure 2, A and B, where it appears that roughly half of the loading dose should be required to achieve the 20 mg/L (20 µg/mL) target level.
  

Loading dose needed to achieve only goal concentration of 20 mg/L = 20 mg/L x 0.33 L/kg = 5.4 mg/kg.

Infusion rate needed to yield a steady-state concentration of 20 mg/L is approximately 6 mg · kg^-1 · h^-1, using information from Dowd et al. (22):

• Graphical estimation of plasma concentration after a 10-h infusion is 3–4 mg/L.
  
• Plasma levels are likely to be near or at steady state after a 10-h infusion.
  
• Desired infusion rate = concentration (steady state) x clearance, where clearance is constant. So, at steady state:
     equation
  

  
     Thus, Rate 2 is 5 mg · kg^-1 · h^-1, to yield 20 µg/mL.
  

Recommended regimen to achieve 20 µg/mL:

Loading dose: 5.4 mg/kg.

CPB prime dose: 50 mg for 2.5-L circuit (assuming 1 L/kg VD in prime fluids), 40 mg for 2-L circuit.

Rate of infusion: 5 mg · kg^-1 · h^-1.

Adjustment for renal insufficiency (normal loading dose and prime dose):

Serum creatinine = 1.6–3.3 mg%: reduce infusion to 3.75 mg · kg^-1 · h^-1.

Serum creatinine = 3.3–6.6 mg%: reduce infusion to 2.5 mg · kg^-1 · h^-1.

Serum creatinine > 6.6 mg%: reduce infusion to 1.25 mg · kg^-1 · h^-1.

	Acknowledgments

 
Supported by a grant from the Mayo Foundation for Medical Education and Research.

	Footnotes

 
Presented in part at the International Anesthesiology Research Society Annual Meeting, Honolulu, HI, March 12, 2000.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999