“Seizing” the opportunity to understand antifibrinolytic drugs

Lecker, Irene; Orser, Beverley A.; Mazer, C. David

doi:10.1007/s12630-011-9621-4

Cited by 13 publications

(8 citation statements)

References 17 publications

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“…Sixty-eight patients experienced generalised and 32 focal seizures. The median (IQR [range]) onset time was 7 (6-12 )h and 8 (6-11 [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]) h for generalised and focal seizures, respectively. Forty out of 100 patients had a single seizure, while the remaining had cluster seizures.…”

Section: Resultsmentioning

confidence: 99%

“…Previously reported risk factors for seizures include older age, pre-operative neurological disease, open-chamber surgery on the heart, prolonged cardiopulmonary bypass (CPB) time, previous cardiac surgery, deep hypothermic circulatory arrest (DHCA), aortic calcification or atheroma, and critical preoperative state [2][3][4]. There is controversy regarding the association of seizures with tranexamic acid [9][10][11]. However, apart from the most recent report, studies were limited to a small number of patients, ranging from 24 to 56 cases [1][2][3][4][5][6]12].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

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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“…Indeed a higher incidence of seizures occurs in patients with preoperative renal failure (91) and those receiving higher doses of TXA (30). Currently, there is no consensus regarding optimum TXA dosing, and studies are urgently needed to determine the minimal effective dose of this drug (92).…”

Section: Discussionmentioning

confidence: 99%

Tranexamic acid concentrations associated with human seizures inhibit glycine receptors

Lecker¹,

Wang²,

Romaschin³

et al. 2012

J. Clin. Invest.

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170

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 postulated mechanism was TXA binding to GABA A receptors, subsequently blocking GABA A -mediated inhibition in the CNS [144,145]. Recently, Lecker et al [145] have demonstrated that TXA is structurally similar to glycine, and competitively inhibits glycine inhibitory receptors in the cortical and spinal cord neurons in rats; TXA also inhibited the GABA A receptors in cortical and spinal cord neurons.…”

Section: Adverse Effects and Dosingmentioning

confidence: 99%

“…Recently, Lecker et al [145] have demonstrated that TXA is structurally similar to glycine, and competitively inhibits glycine inhibitory receptors in the cortical and spinal cord neurons in rats; TXA also inhibited the GABA A receptors in cortical and spinal cord neurons. Both TXA dis-inhibitory pathways cause increased excitatory synaptic drive evidenced by seizure-like events in cortical slices induced at TXA concentrations of 31 μg mL -1 (200 μM), similar to that measured in CSF of patients undergoing CPB.…”

Section: Adverse Effects and Dosingmentioning

confidence: 99%

Tranexamic acid: a clinical review

Jerath

Wąsowicz

2015

Anaesthesiol Intensive Ther

250

151

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Blood loss and subsequent transfusions are associated with major morbidity and mortality. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, liver surgery and solid organ transplantation, obstetrics and gynecology, neurosurgery and non-surgical diseases. The evidence of their efficacy has been mounting for years. Tranexamic acid (TXA), a synthetic lysine-analogue antifibrinolytic, was first patented in 1957 and its use has been increasing in contrast to aprotinin, a serine protease inhibitor antifibrinolytic. This review aims to help acute care physicians navigate through the clinical evidence available for TXA therapy, develop appropriate dose regimens whilst minimizing harm, as well as understand its broadening scope of applications. Many questions remain unanswered regarding other clinical effects of TXA such as anti-inflammatory response to cardiopulmonary bypass, the risk of thromboembolic events, adverse neurological effects such as seizures, and its morbidity and mortality, all of which necessitate further clinical trials on its usage and safety in various clinical settings.

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“Seizing” the opportunity to understand antifibrinolytic drugs

Cited by 13 publications

References 17 publications

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

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

Tranexamic acid concentrations associated with human seizures inhibit glycine receptors

Tranexamic acid: a clinical review

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