Tranexamic acid impairs γ-aminobutyric acid receptor type A-mediated synaptic transmission in the murine amygdala: a potential mechanism for drug-induced seizures?

BACKGROUND: Tranexamic acid (TXA) is commonly used to reduce blood loss in cardiac surgery and in trauma patients. High-dose application of TXA is associated with an increased risk of postoperative seizures. The neuronal mechanisms underlying this proconvulsant action of TXA are not fully understood. In this study, the authors investigated the effects of TXA on neuronal excitability and synaptic transmission in the basolateral amygdala. METHODS: Patch clamp recordings and voltage-sensitive dye imaging were performed in acute murine brain slices. Currents through N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor type A (GABAA) receptors were recorded. GABAA receptor-mediated currents were evoked upon electrical stimulation or upon photolysis of caged GABA. TXA was applied at different concentrations. RESULTS: Voltage-sensitive dye imaging demonstrates that TXA (1 mM) reversibly enhances propagation of neuronal excitation (mean ± SEM, 129 ± 6% of control; n = 5). TXA at concentrations of 0.1, 0.3, 1, 5, or 10 mM led to a dose-dependent reduction of GABAA receptor-mediated currents in patch clamp recordings. There was no difference in the half-maximal inhibitory concentration for electrically (0.76 mM) and photolytically (0.84 mM) evoked currents (n = 5 to 9 for each concentration), and TXA did not affect the paired-pulse ratio of GABAA receptor-mediated currents. TXA did not impact glutamatergic synaptic transmission. CONCLUSIONS: This study clearly demonstrates that TXA enhances neuronal excitation by antagonizing inhibitory GABAergic neurotransmission. The results provide evidence that this effect is mediated via postsynaptic mechanisms. Because GABAA receptor antagonists are known to promote epileptiform activity, this effect might explain the proconvulsant action of TXA.

Hydroxyethyl starch and acute kidney injury in high-risk patients undergoing cardiac surgery: A prospective multicenter study.

BACKGROUND: Hydroxyethyl starch (HES) solutions increase the risk of acute kidney injury (AKI) in critically ill patients admitted to intensive care unit (ICU) for medical indications. We conducted a cohort study to evaluate the renal safety of modern 6% HES solutions in high-risk patients having cardiac surgery. METHOD: In this multicentre prospective cohort study, we recruited 261 consecutive patients at high-risk for developing cardiac surgery-associated AKI, based on a Cleveland score ≥ 4 points, from July to December 2017th in 14 hospitals in Spain and the United Kingdom. Multivariable logistic regression modeling and propensity-score matched-pairs analysis were used to determine the adjusted association between administration of HES and AKI. RESULTS: Of the cohort, 95 patients (36.4%) received 6% HES 130/0.4 either intraoperatively or postoperatively. Postoperative AKI occurred in 145 patients (55.5%). The unadjusted odds of AKI was significantly higher in the HES group, when compared to those not receiving HES (OR 2.22, 95% CI 1.30-3.80, p = 0.003). In multivariable logistic regression models, modern HES was not associated with significantly increased risk of AKI (adjusted OR 0.84, 95% CI 0.41-1.71, p = 0.63). In propensity score match-pairs analysis of 188 patients, the HES group experienced similar adjusted odds of AKI (OR 1.05, CI 95% 0.87-1.27, p = 0.57) and RRT (OR 1.06, CI 95% 0.92-1.22, p = 0.36). CONCLUSIONS: The use of modern hydroxyethyl starch 6% HES 130/0.4 was not associated with an increased risk of AKI nor dialysis in this cohort of patients at elevated risk for developing AKI after cardiac surgery.

The anaesthetic xenon partially restores an amyloid beta-induced impairment in murine hippocampal synaptic plasticity.

BACKGROUND: It is controversially discussed whether general anaesthesia increases the risk of Alzheimer's disease (AD) or accelerates its progression. One important factor in AD pathogenesis is the accumulation of soluble amyloid beta (Aß) oligomers which affect N-methyl-d-aspartate (NMDA) receptor function and abolish hippocampal long-term potentiation (LTP). NMDA receptor antagonists, at concentrations allowing physiological activation, can prevent Aß-induced deficits in LTP. The anaesthetics xenon and S-ketamine both act as NMDA receptor antagonists and have been reported to be neuroprotective. In this study, we investigated the effects of subanaesthetic concentrations of these drugs on LTP deficits induced by different Aß oligomers and compared them to the effects of radiprodil, a NMDA subunit 2B (GluN2B)-selective antagonist. METHODS: We applied different Aß oligomers to murine brain slices and recorded excitatory postsynaptic field potentials before and after high-frequency stimulation in the CA1 region of hippocampus. Radiprodil, xenon and S-ketamine were added and recordings evoked from a second input were measured. RESULTS: Xenon and radiprodil, applied at low concentrations, partially restored the LTP deficit induced by pre-incubated Aß1-42. S-ketamine showed no effect. None of the drugs tested were able to ameliorate Aß1-40-induced LTP-deficits. CONCLUSIONS: Xenon administered at subanaesthetic concentrations partially restored Aß1-42-induced impairment of LTP, presumably via its weak NMDA receptor antagonism. The effects were in a similar range than those obtained with the NMDA-GluN2B antagonist radiprodil. Our results point to protective properties of xenon in the context of pathological distorted synaptic physiology which might be a meaningful alternative for anaesthesia in AD patients.