High-dose tranexamic acid is related to increased risk of generalized seizures after aortic valve replacement

Keyl, Cornelius; Uhl, Reiner; Beyersdorf, Friedhelm; Stampf, Susanne; Lehane, Cornelius; Wiesenack, Christoph; Trenk, Dietmar

doi:10.1016/j.ejcts.2010.12.030

Cited by 94 publications

(86 citation statements)

References 24 publications

(34 reference statements)

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“…Tranexamic acid has traditionally been considered a safe drug with a reported low incidence of adverse events. More recently, several investigators have suggested highdose tranexamic acid to be aetiological in postoperative seizures following cardiac surgery especially in patients with renal dysfunction [7][8][9][10][11]. Murkin et al observed an increase in the incidence of postoperative seizures following administration of high-dose tranexamic acid (up to 259 mg.kg ) at centres in Canada and the United Kingdom.…”

Section: Discussionmentioning

confidence: 99%

“…seizures in cardiac surgical patients [7][8][9][10][11]. Following the publication of a randomised controlled trial examining the use of antifibrinolytic agents in high-risk cardiac surgical patients (Blood Conservation Using Antifibrinolytics in a Randomised Trial (BART)), and the subsequent restriction of the use of aprotinin, tranexamic acid is currently a widely used antifibrinolytic agent in cardiac surgery [5].…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass*

et al. 2012

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SummaryWe conducted a study to assess pharmacokinetics of high-dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High-dose tranexamic acid involved a bolus of 30 mg.kg )1 infused over 15 min followed by a 16 mg.kg.h )1 infusion until chest closure with a 2 mg.kg )1 load within the pump prime. Tranexamic acid followed first-order kinetics best described using a two-compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra-operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high-dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high-risk cardiac surgery needs to be refined. Tranexamic acid, a synthetic antifibrinolytic, is a lysine derivative that competitively inhibits the activation of plasminogen, thereby reducing the conversion of plasminogen to plasmin, an enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins, including the procoagulant factors V and VIII [1]. At higher doses, tranexamic acid directly inhibits plasmin activity [2][3][4][5]. Tranexamic acid thus inhibits fibrinolysis, a putative mechanism of bleeding after cardiopulmonary bypass (CPB) [6]. Hence, this compound is routinely used during cardiac surgery procedures involving CPB, to reduce blood loss [1][2][3][4][5]. Tranexamic acid is considered to have a good safety profile. However, this has been challenged recently as several studies have found an association between high-dose tranexamic acid administration and an increased incidence in postoperative

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass*

et al. 2012

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“…TXA-associated seizures occur most frequently as patients emerge from general anesthesia in the early postoperative period (23,24,27,59). Thus, we postulated that the prototypic general anesthetics isoflurane (60) and propofol (39) would attenuate TXA inhibition of glycine receptors.…”

Section: Figurementioning

confidence: 99%

“…More recently, TXA has been associated with an increased incidence of postoperative seizures in cardiac patients (23,24). Historically, postoperative seizures have occurred in about 0.5%-1% of cardiac patients (25,26), but the use of higher doses of TXA has been associated with a higher incidence of seizures (2.7%-7.6%) (27,28), primarily of the grand mal type (23,29).…”

Section: Introductionmentioning

confidence: 99%

Tranexamic acid concentrations associated with human seizures inhibit glycine receptors

Lecker¹,

Wang²,

Romaschin³

et al. 2012

J. Clin. Invest.

162

156

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Antifibrinolytic drugs are widely used to reduce blood loss during surgery. One serious adverse effect of these drugs is convulsive seizures; however, the mechanisms underlying such seizures remain poorly understood. The antifibrinolytic drugs tranexamic acid (TXA) and ε-aminocaproic acid (EACA) are structurally similar to the inhibitory neurotransmitter glycine. Since reduced function of glycine receptors causes seizures, we hypothesized that TXA and EACA inhibit the activity of glycine receptors. Here we demonstrate that TXA and EACA are competitive antagonists of glycine receptors in mice. We also showed that the general anesthetic isoflurane, and to a lesser extent propofol, reverses TXA inhibition of glycine receptor-mediated current, suggesting that these drugs could potentially be used to treat TXA-induced seizures. Finally, we measured the concentration of TXA in the cerebrospinal fluid (CSF) of patients undergoing major cardiovascular surgery. Surprisingly, peak TXA concentration in the CSF occurred after termination of drug infusion and in one patient coincided with the onset of seizures. Collectively, these results show that concentrations of TXA equivalent to those measured in the CSF of patients inhibited glycine receptors. Furthermore, isoflurane or propofol may prevent or reverse TXA-induced seizures.

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“…The reported incidence of seizures after adult cardiac surgery is 0.5-7.6% [1][2][3][4][5][6][7][8]. The aetiology of postoperative seizures is often multifactorial, and causes range from benign metabolic disturbance to cerebrovascular accident.…”

Section: Introductionmentioning

confidence: 99%

The association between tranexamic acid and convulsive seizures after cardiac surgery: a multivariate analysis in 11 529 patients

et al. 2013

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The association between tranexamic acid and convulsive seizures after cardiac surgery: a multivariate analysis in 11 529 patients* SummaryBecause of a lack of contemporary data regarding seizures after cardiac surgery, we undertook a retrospective analysis of prospectively collected data from 11 529 patients in whom cardiopulmonary bypass was used from January 2004 to December 2010. A convulsive seizure was defined as a transient episode of disturbed brain function characterised by abnormal involuntary motor movements. Multivariate regression analysis was performed to identify independent predictors of postoperative seizures. A total of 100 (0.9%) patients developed postoperative convulsive seizures. Generalised and focal seizures were identified in 68 and 32 patients, respectively. The median (IQR [range]) time after surgery when the seizure occurred was 7 (6-12 [1-216]) h and 8 (6-11 [4-18]) h, respectively. Epileptiform findings on electroencephalography were seen in 19 patients. Independent predictors of postoperative seizures included age, female sex, redo cardiac surgery, calcification of ascending aorta, congestive heart failure, deep hypothermic circulatory arrest, duration of aortic cross-clamp and tranexamic acid. When tested in a multivariate regression analysis, tranexamic acid was a strong independent predictor of seizures (OR 14.3, 95% CI 5.5-36.7; p < 0.001). Patients with convulsive seizures had 2.5 times higher in-hospital mortality rates and twice the length of hospital stay compared with patients without convulsive seizures. Mean (IQR [range]) length of stay in the intensive care unit was 115 (49-228 [32-481]) h in patients with convulsive seizures compared with 26 (22-69 [14-1080]) h in patients without seizures (p < 0.001). Convulsive seizures are a serious postoperative complication after cardiac surgery. As tranexamic acid is the only modifiable factor, its administration, particularly in doses exceeding 80 mg.kg

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High-dose tranexamic acid is related to increased risk of generalized seizures after aortic valve replacement

Cited by 94 publications

References 24 publications

Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass*

Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass*

Tranexamic acid concentrations associated with human seizures inhibit glycine receptors

The association between tranexamic acid and convulsive seizures after cardiac surgery: a multivariate analysis in 11 529 patients

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