<div>Title:</div><div>Tranexamic acid-associated fatal status epilepticus in a paediatric
patient</div><div>Author:</div><div>Dr Santosh Patel MD, FRCA, PG Dip (Med Edu)</div><div>Consultant Anaesthetist</div><div>Department of anaesthesia</div><div>Tawam hospital</div><div>Al Ain</div><div>United Arab Emirates</div><div>Correspondence address: as above.</div><div>Email: skpatel@seha.ae</div><div>Funding: No source of funding to declare</div><div>Conflicts of interest: Nothing to declare</div><div>Dear Editor,</div><div>I have read with interest a case report and literature review published
in the British journal of pharmacology on tranexamic acid (TXA)
associated SE in a 4-year child who underwent
tonsillectomy.<sup>1</sup> I would like to congratulate the
authors for reporting the case despite the fatal outcome. Considering
that the use of TXA is expanding to minimise blood loss in a wide range
of surgeries, an evidence-based therapeutic approach for its associated
seizures is of paramount importance.</div><div>The authors described in their report (also mentioned in Table 2) and
concluded that general anaesthetics, propofol and halogenated inhaled
anaesthetics are considered the first line of management of
TXA-associated seizures due to their direct activity at glycine
receptors. In support of their statement, they have quoted three
references (references 35,45,46 in their report). However, in their
articles, the authors did not recommend the use of general anaesthetics
(propofol and halogenated inhalational anaesthetics) as the first line
of treatment for TXA-related seizures. It is valuable to point out to
the readers that their conclusion is not valid and needs clarification
and correction.</div><div>TXA-associated hyperexcitability of neural networks is because it is a
competitive antagonist of glycine and GABAA
receptors.<sup>2</sup> Following IV TXA administration, not all
seizures progress to status epilepticus. Although TXA-related seizures
commonly manifest as generalised tonic-clonic activity, focal seizures
have been reported; which are not an indication for the use of general
anaesthetics. Refractory status epileptics (RSE) and super RSE are
uncommon following IV TXA although this is a common feature following
intrathecal TXA.<sup>3</sup></div><div>Propofol’s anticonvulsant, hypnotic, sedative and anaesthetic effects
are mediated via multiple complex molecular mechanisms, including
modulation of GABAA and glycine receptors. GABAA receptor modulation by
propofol has distinct dose-dependent effects likely involving multiple
sites of action; clinical concentrations of propofol potentiate
GABA-activated currents, increase open channel frequency, and reduce the
rate of desensitization, while intermediate concentrations directly
activate GABAA channels, and even higher concentrations inhibit receptor
function.<sup>4</sup></div><div>Propofol can cause neuroexcitatory effects, including tonic-clonic
seizures, particularly during the start or weaning from propofol
infusion.<sup>5</sup> Among the various mechanisms that have been
proposed for these neuroexcitatory symptoms are antagonism of glycine
and dopamine receptors, hyposensitization of GABAergic pathways and
dysregulated inhibition of NMDA glutamate receptors.<sup>6</sup>Its use is associated with side effects, including hypotension (and the
associated use of vasopressors) and respiratory depression. With
prolonged infusion, propofol infusion syndrome (PIS) may occur, which
may contribute to morbidity and mortality of RSE. Children are more
susceptible to developing this complication. Propofol infusion therapy
is not recommended as the first line of treatment for TXA-associated
seizures, and its use is reserved for severe cases in children.</div><div>Inhalational anaesthetics are beneficial for the control of seizure
activity via inhibition of NMDA excitotoxicity and potentiation of
inhibitory functions of GABAA and glycine receptors. However, it is
essential to highlight that there are several limitations to the use of
inhalational anaesthetic agents. First, the only clinical evidence of
their use is from the minimal number of case reports. Second,
TXA-related seizures often manifest in the postoperative period in the
recovery room or in ICU, where delivery and scavenging of inhalational
agents via ventilator may not be feasible. Third effective end-tidal
concentration and optimal therapeutic duration are not known. Finally,
in higher concentrations, they cause cardiac depression and cerebral
vasodilation. Therefore, their use is limited as salvage therapy for the
management of TXA-associated RSE and super RSE.</div><div>In summary, the authors’ conclusion is incorrect, and clinicians should
follow currently available evidence-based professional guidelines to
manage TXA-associated status epilepticus.<sup>8,9</sup></div><div>References:</div><div>1. Aboul-Fotouh S, Habib MZ, Magdy SM, Hassan BEE. Tranexamic
acid-associated fatal status epilepticus in a paediatric non-cardiac
surgery: A case report and literature review. <i>Bri J Clin
Pharmacol</i> 2022;1-6. doi:10.1111/bcp.15296</div><div>2. Lecker I, Wang D, Whissell P, et al. Tranexamic acid-associated
seizures: causes and treatment. <i>Ann of Neurol</i> 2015;79(1):18-26.
doi:10.1002/ana.24558</div><div>3. Patel S, Robertson B, McConachie I. (2019). Catastrophic drug errors
involving tranexamic acid administered during spinal anaesthesia.<i>Anaesthesia</i> ,74(7),904-14 https://doi.org/10.1111/anae.14662</div><div>4. Platholi J, Hemmings H. (2022). Effects of general anesthetica on
synaptic transmission and spasticity. <i>Currt Neuropharmacol</i>2022;20(1):27-54. doi: 10.2174/1570159X19666210803105232.</div><div>5. Walder B, Tramèr MR, Seeck M. (2002). Seizure-like phenomena and
propofol: a systematic review. <i>Neurology 2002;</i> 58(9):1327-32.
10.1212/wnl.58.9.1327</div><div>6. Pantelakis L, Alvarez V, Gex G, Godio M. Severe neuroexcitatory
reaction: A rare and underrecognized life-threatening complication of
propofol-induced anesthesia. <i>The Neurohospitalist</i>2021;11(1):49-53. doi: 10.1177/1941874420929536.</div><div>7. Godec S, Gradisek MJ, Mirkovic T etal. Ventriculolumbar perfusion and
inhalational anesthesia with sevoflurane in an accidental intrathecal
injection of tranexamic acid: unreported treatment options. <i>Reg
Anesthe Pain Med</i> 2022;47(1):65-68 10.1136/rapm-2021-102498</div><div>8. Nelson SE, Varelas PN. Status epilepticus, refractory status
epilepticus, and super-refractory status epilepticus. <i>Continuum
(Minneap Minn).</i> 2018;24(6):1683-1707.</div><div>9. Vossler DG, Bainbridge JL, Boggs JG etal.. Treatment of refractory
convulsive status epilepticus: a comprehensive review by the American
Epilepsy Society Treatments Committee. <i>Epilepsy Curr.</i>2020;20(5):245-64.</div>