Bleeding and the subsequent need for blood transfusion is a major contributor to postoperative mortality and morbidity in cardiac surgery.1,2 Antifibrinolytic therapy has become a mainstay in complex cardiac surgical procedures to decrease bleeding and minimize transfusion requirements. The recent Society of Cardiovascular Anesthesia and Society of Thoracic Surgery transfusion guidelines specifically recommended the use of antifibrinolytic therapy, namely, ε-aminocaproic acid (EACA), tranexamic acid (TXA), or aprotinin, for patients at increased risk of bleeding during cardiac surgery.3 However, increasing concern regarding the adverse effects of aprotinin4 has led to its worldwide withdrawal.5 Furthermore, in some countries including Canada and New Zealand, EACA is not available for clinical use.6,7 Given the demonstrated efficacy of antifibrinolytic therapy8 and the increased morbidity and mortality associated with postoperative hemorrhage and allogeneic blood transfusion,9,10 many clinicians have chosen to use TXA to minimize the risk of hemorrhage in cardiac surgical patients.
In several dose-ranging studies, TXA doses of up to 100 mg/kg have been recommended.11 However, a significant increase in clinical seizures in the early postoperative period was noted in 2 institutions after introduction of routine TXA infusions for high-risk cardiac surgical patients. The purpose of this investigation was to perform a retrospective review to examine whether there was a relation between the use of TXA and seizures after cardiac surgery.
After withdrawal of aprotinin from clinical use, both Papworth Hospital in Cambridge, United Kingdom, and London Health Sciences Center (LHSC) in London, Ontario, implemented the continuous intraoperative use of TXA in patients at high risk for bleeding undergoing cardiac surgery. This commenced in mid-November 2007 at LHSC and in January 2008 at Papworth. Our clinical observation was drawn from a series of 24 patients at both institutions in whom generalized convulsive seizures were observed in the postoperative period in the absence of significant new ischemic lesions on brain imaging identified over a 5-month (LHSC) and an 11-month (Papworth) period after the initial commencement of this strategy.
In an attempt to determine the etiology of the seizure activity, a comprehensive review of medical records was undertaken in all 24 patients. All patients who experienced seizures had head computerized tomography or magnetic resonance imaging performed. Furthermore, at LHSC, a subset of 11 patients had an electroencephalogram recorded.
Six hundred sixty-nine patients were treated with TXA at both institutions (Papworth 149 patients, LHSC 520 patients) during the time period of this review. The usual initial loading dose was 100 mg/kg at LHSC and 20 to 50 mg/kg at Papworth. The infusion rate varied between 10 and 25 mg · kg−1 · h−1. Because of the novelty of the protocol and the differing nature and duration of the surgical procedures, there was considerable variation in the total dose of TXA ranging from 61 to 259 mg/kg at LHSC and 71 to 258 mg/kg at the Papworth Hospital.
Patient characteristics and procedure details are shown in Table 1. Factors potentially predisposing to seizure activity were not present in any patients. A large proportion had operations requiring opening of cardiac chambers. Seizures occurred on average 4.7 hours postoperatively. In a number of these patients, onset of seizure activity was coincident with weaning of the sedation dose of propofol before tracheal extubation. Two patients had focal seizures, one of which became generalized, whereas the others had generalized convulsions. In the patients in whom electroencephalograms were obtained, spikes or generalized seizures were demonstrated in 7, focal spikes in 1, multifocal spikes in 4, and generalized in 2. Of the 24 identified patients, 3 showed evidence of recent small areas of cerebral infarction on brain imaging, which were not thought to contribute to their seizures. There was no evidence of ischemic injury in 21 patients. All reported patients made an uneventful neurological recovery without subsequent deficits or recurring seizures.
Papworth Hospital had an increase in cases of clinical seizures from 19 in the 11 months preceding the introduction of TXA to 30 cases in the 11 months after its introduction. This reflects an unchanged incidence of seizures with positive brain imaging findings and an additional 11 patients with negative imaging studies.
Since this review, dosing guidelines have been modified to a lower dose of TXA (30 mg/kg load, 15 mg · kg−1 · h−1 infusion, and 2 mg/kg in the cardiopulmonary bypass priming solution) consistent with doses used in the BART (Blood Conservation Using Antifibrinolytics in a Randomized Trial) study.4 Since this dosing change, the incidence of postoperative seizures has returned to the previous baseline of 0 to 2 per month.
Reports of the incidence of seizures after adult cardiac surgery are remarkably rare. In their large multicenter observational study, Roach et al.12 reported seizures in approximately 0.4% of cardiac surgical patients. Before the introduction of TXA, the clinical seizure incidence at LHSC was 1.3% (unpublished data), increasing to 3.8% during the period reported here.
In neither the 770 TXA-treated patients reported in the BART study4 nor the 822 TXA-treated patients reported in an international survey13 was the incidence of perioperative seizures reported. Although this absence could reflect a relative lack of data sensitivity, it may more likely indicate that the frequency of seizures was low because of the lower dosage of TXA used in these population. Recently, however, 2 large series of patients undergoing cardiac surgery have linked the use of TXA with postoperative seizures.14,15
In a nonselective, prospective study of cardiac surgical patients, a significantly higher incidence of seizures was found in patients receiving TXA versus aprotinin (4.6% vs 1.2%, P < 0.001). However, the authors did not analyze for incidence of ischemic or nonischemic seizures in this population.14 Also of note is the recent abstract reported by Jerath in which 15.4% of 39 adult cardiac surgical patients having received median doses of TXA of 109 mg/kg experienced postoperative seizures compared with 4.8% of 103 patients receiving median TXA doses of 67 mg/kg.16 Several case reports describe seizure activity from TXA when inadvertently injected into the spinal and subarachnoid spaces.17–20
Possible mechanisms of TXA-induced seizures include direct cerebral ischemia secondary to decreases in regional or global cerebral blood flow21–23 and blockage of inhibitory cortical γ-aminobutyric acid (GABA)-A receptors.24 Because GABA-A receptors govern opening of neuronal chloride channels resulting in neuronal hyperpolarization and reduced excitability, blockage by TXA results in lowering of the depolarization threshold and enhanced excitotoxicity.24 TXA has been shown to cause hyperexcitability and convulsions when applied directly onto central nervous system tissue.25
Plasma TXA levels after a dose of 100 mg/kg, similar to that given to our patients with seizures, can exceed 4000 μmol/L (600 mg/L).26 Extrapolating from animal studies27 and from cerebrospinal fluid (CSF) concentrations of TXA measured in patients with subarachnoid hemorrhage,28 this may produce CSF concentrations approximating 100 to 200 mg/L. There is evidence for a dose-related toxicity. In a dose-ranging study of topical TXA applied cortically in a rat model, concentrations of topical hemostatic agent containing TXA 0.5, 5, or 47.5 mg/mL produced seizures in progressively more animals, which were of greater severity and duration with increasing TXA dosage.29
Of relevance to the series reported here, cardiac surgery leads to an inflammatory response as well as generation of cerebral emboli, all of which may contribute to altered blood-brain barrier permeability30 and possibly a larger TXA concentration in the CSF and brain compartment than reported in vitro.
Whether another lysine analog antifibrinolytic, EACA, may share the same epileptogenic propensity if administered in a high enough dose remains unclear.31 Regardless, our series should caution physicians from using large doses of TXA during cardiac surgery because of our observation of a link of this dose with clinical seizures.
1. Unsworth-White MJ, Herriot A, Valencia O, Poloniecki J, Smith EE, Murday AJ, Parker DJ, Treasure T. Resternotomy for bleeding after cardiac operation: a marker for increased morbidity and mortality. Ann Thorac Surg 1995;59:664–7
2. Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation 2007;116:2544–52
3. Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Ferraris SP, Saha SP, Hessel EA II, Haan CK, Royston BD, Bridges CR, Higgins RS, Despotis G, Brown JR; Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion, Spiess BD, Shore-Lesserson L, Stafford-Smith M, Mazer CD, Bennett-Guerrero E, Hill SE, Body S. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg 2007;83:S27−86
4. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, Côté D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R; BART Investigators. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319−31
8. Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Anesth Analg 1997;85:1258–67
9. Koch CG, Li L, Duncan AI, Mihaljevic T, Cosgrove DM, Loop FD, Starr NJ, Blackstone EH. Morbidity and mortality risk associated with red blood cell and blood-component transfusion in isolated coronary artery bypass grafting. Crit Care Med 2006;34:1608–16
10. Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, Ghannam M, Yeo E, Djaiani G, Karski J. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion 2004;44:1453–62
11. Karski JM, Dowd NP, Joiner R, Carroll J, Peniston C, Bailey K, Glynn MF, Teasdale SJ, Cheng DC. The effect of three different doses of tranexamic acid on blood loss after cardiac surgery with mild systemic hypothermia (32 degrees C). J Cardiothorac Vasc Anesth 1998;12:642–6
12. Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, Aggarwal A, Marschall K, Graham SH, Ley C. Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 1996;335:1857–63
13. Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353–65
14. Martin K, Wiesner G, Breuer T, Lange R, Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg 2008;107: 1783–90
15. Breuer T, Martin K, Wilhelm M, Wiesner G, Schreiber C, Hess J, Lange R, Tassani P. The blood sparing effect and the safety of aprotinin compared to tranexamic acid in paediatric cardiac surgery. Eur J Cardiothorac Surg 2009;35:167–71
17. Yeh HM, Lau HP, Lin PL, Sun WZ, Mok MS. Convulsions and refractory ventricular fibrillation after intrathecal injection of a massive dose of tranexamic acid. Anesthesiology 2003;98:270–2
18. Wong JO, Yang SF, Tsai MH. [Accidental injection of tranexamic acid (Transamin) during spinal anesthesia]. Ma Zui Xue Za Zhi 1988;26:249–52
19. de Leede-van der Maarl MG, Hilkens P, Bosch F. The epileptogenic effect of tranexamic acid. J Neurol 1999;246:843
20. Garcha PS, Mohan CV, Sharma RM. Death after an inadvertent intrathecal injection of tranexamic acid. Anesth Analg 2007;104:241–2
21. Tsementzis SA, Meyer CH, Hitchcock ER. Cerebral blood flow in patients with a subarachnoid haemorrhage during treatment with tranexamic acid. Neurochirurgia (Stuttg) 1992;35:74–8
22. Tsementzis SA, Hitchcock ER, Meyer CH. Benefits and risks of antifibrinolytic therapy in the management of ruptured intracranial aneurysms. A double-blind placebo-controlled study. Acta Neurochir (Wien) 1990;102:1–10
23. Iplikcioglu AC, Berkman MZ. The effect of short-term antifibrinolytic therapy on experimental vasospasm. Surg Neurol 2003;59:10–6; discussion 16–7
24. Furtmuller R, Schlag MG, Berger M, Hopf R, Huck S, Sieghart W, Redl H. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid(A) receptor antagonistic effect. J Pharmacol Exp Ther 2002; 301:168–73
25. Schlag MG, Hopf R, Redl H. Convulsive seizures following subdural application of fibrin sealant containing tranexamic acid in a rat model. Neurosurgery 2000;47:1463–7
26. Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL, Butterworth J. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology 2002;97:390–9
27. Yamaura A, Nakamura T, Makino H, Hagihara Y. Cerebral complication of antifibrinolytic therapy in the treatment of ruptured intracranial aneurysm: animal experiment and a review of literature. Eur Neurol 1980;19:77–84
28. Fodstad H, Pilbrant A, Schannong M, Strömberg S. Determination of tranexamic acid (AMCA) and fibrin/fibrinogen degradation products in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage. Acta Neurochir (Wien) 1981; 58:1–13
29. Schlag MG, Hopf R, Zifko U, Redl H. Epileptic seizures following cortical application of fibrin sealants containing tranexamic acid in rats. Acta Neurochir (Wien) 2002;144:63–9
30. Cavaglia M, Seshadri SG, Marchand JE, Ochocki CL, Mee RB, Bokesch PM. Increased transcription factor expression and permeability of the blood brain barrier associated with cardiopulmonary bypass in lambs. Ann Thorac Surg 2004;78:1418–25
31. Shinar E, Rabinovici R, Heyman A, Kluger Y. Convulsions induced by aminocaproic acid infusion. DICP 1989;23:780–1