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 Table of Contents  
COMMENTARY
Year : 2018  |  Volume : 8  |  Issue : 1  |  Page : 1-6

Tranexamic acid: Beware of anaesthetic misadventures


Department of Anesthesiology, Geetanjali Medical College and Hospital, Udaipur, Rajasthan, India

Date of Web Publication13-Apr-2018

Correspondence Address:
Dr. Anil K Bhiwal
Department of Anesthesiology, Geetanjali Medical College and Hospital, Udaipur - 313 001, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joacc.JOACC_12_18

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  Abstract 


Tranexamic acid (TXA) is an antifibrinolytic agent that is commonly used in cardiac, gynecologic, and obstetric surgeries. Inadvertent intrathecal injection of the TXA may lead to serious side effects, including back pain, myoclonus, seizure, and ventricular fibrillation that can be attributed to similar appearance of ampoules, location of ampoules, and incorrect labeling of prefilled syringes and can be avoided by vigilance, correct labeling of syringes and ampoules, double checking medications prior to administration, and preventing manufacturing of vials of different drugs with similar appearance. Treatment of intrathecal injection of the TXA includes administration of the anticonvulsants, general anaesthetics, MgSO4, along with intensive haemodynamic monitoring, scalp electroencephalography monitoring guided burst suppression with thiopentone infusion and cerebrospinal fluid lavage.

Keywords: Cerebrospinal fluid lavage, electroencephalography, intrathecal injection, seizure, spinal anaesthesia, tranexamic acid


How to cite this article:
Gupta S, Bhiwal AK, Sharma K. Tranexamic acid: Beware of anaesthetic misadventures. J Obstet Anaesth Crit Care 2018;8:1-6

How to cite this URL:
Gupta S, Bhiwal AK, Sharma K. Tranexamic acid: Beware of anaesthetic misadventures. J Obstet Anaesth Crit Care [serial online] 2018 [cited 2018 Aug 20];8:1-6. Available from: http://www.joacc.com/text.asp?2018/8/1/1/230056




  Introduction Top


Medication errors during anaesthesia vary from <1% of anaesthetics to >5% of medication administrations.[1],[2],[3] The absolute incidence of drug administration errors in the neuraxial compartment during obstetric procedures cannot be known from published case reports as reporting bias, medicolegal implications, and lack of an established critical incident reporting system in our country tend to limit publications. Thus, many errors go unreported and what are reported likely represent just the tip of the iceberg. Moreover, these are infrequent events difficult to study and require long periods of data collection, with potential risks of introduction of confounding variables.

Failure to acknowledge human factors and system weaknesses along with the lack of accountability in anaesthesia has led to perioperative drug mishandling. We have been pioneers in sensitizing the world to our patient safety efforts with phenomenal efforts invested in making our equipment safer for anaesthesia. Yet, despite mounting evidence, we have not developed or implemented tamper-proof interventions to improve medication safety during anaesthesia to prevent medication errors. Brittle strategies such as “provider vigilance” and “reading the label” are the only safeguards practiced worldwide, especially in low-resource countries. Thus, unintentional intrathecal/epidural administration of intravenous (IV) medications continues with occasionally devastating consequences leading to death.[4]

The World Health Organization (WHO) recently included tranexamic acid (TXA) in its “Model List of Essential Medicines” with a strong recommendation for early use of IV TXA (within 3 h of birth), in addition to standard care for women with clinically diagnosed postpartum haemorrhage, following vaginal birth or cesarean section.[5]

It should be given at a fixed dose of 1 g (100 mg/ml) intravenously at 1 ml/min (i.e., given over 10 min), with a second dose of 1 g intravenously if bleeding continues after 30 min, or if bleeding restarts within 24 h of completing the first dose. Thus, TXA is advocated as a life-saving intervention that should be made readily available for the management of postpartum haemorrhage wherever emergency obstetric care is provided.[6]

Drug administration errors with TXA attributed to wrong drug drawn up from incorrect ampoule in error and administered in the neuraxial space are alarming case reports increasingly appearing in the literature. The actual number of intrathecal medication errors are vastly understated and the main goal of this review is to increase awareness among anaesthesia care providers regarding prevention strategies and treatment recommendations resulting in a positive outcome.

Our literature search yielded 17 case reports [7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23] which have been summarised with drug dose, surgical procedure, signs and symptoms, management, sequelae of errors, and final outcome in [Table 1]. Inadvertent intrathecal injection of the TXA instead of hyperbaric bupivacaine was given in all these case reports because of the similarity of appearance of both the ampoules. The most commonly reported neurological complications were failure of intended sensory and motor block, severe back pain radiating to the gluteal region and lower extremities, and involuntary motor activity, such as a “jerking” of the lower extremities (referred to as myoclonic movements). These abnormal movements rapidly progressed to generalised tonic–clonic seizures. Myoclonic movements may serve as a warning sign of impending seizures.[8],[14] Hypertension, tachycardia, refractory ventricular arrhythmias, cardiovascular collapse, and death occurred in nearly eight of these reports.
Table 1: Summary of published case reports of inadvertent intrathecal injection of tranexamic acid

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Common side effects reported with parenteral administration of TXA are headache, backache, nasal sinus congestion, abdominal pain, diarrhea, fatigue, anaemia, and rarely pulmonary embolism, deep vein thrombosis, anaphylaxis, visual disturbances, and seizures.[24]

It has been reported that IV injection with 1 g TXA results in a concentration of 5–20 mg/l in the plasma and 2–5 mg/l in the cerebrospinal fluid (CSF). Assuming that the drug was thoroughly diluted within the thecal space containing 500 ml of CSF, 500 mg TXA would produce a concentration of 1,000 mg/l in the CSF, which is 500 times greater than the therapeutic level (2–5 mg/l).[25]


  Proposed Mechanism Top


Severe pain in back and gluteal region

Gamma-aminobutyric acid (GABA) and glycine are co-released by spinal dorsal horn neurons and are important in regulating sensory processing. In addition, GABA and glycine receptors are abundant in the spinal cord, and antagonism of these receptors produces pain phenomena, such as allodynia and hyperalgesia. Indeed, several clinical studies have reported that patients to whom TXA was accidentally injected intrathecally immediately complained of severe back pain.[8],[11],[14],[26] Thus, it seems TXA directly inhibits GABA and glycine receptors located on postsynaptic sites of the recorded substantia gelatinosa (SG) neurons and also inhibits GABA-A and glycine receptors located on postsynaptic sites on excitatory interneurons. This leads to increased glutamate release from the excitatory interneurons to the recorded SG neurons located postsynaptically, resulting in increased spontaneous activity [Figure 1].[27]
Figure 1: Model circuit for underlying mechanism of TXA induced pain in the spinal dorsal horn circuit

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Seizures

The diagnosis of TXA-associated seizures may be facilitated by EEG monitoring and that could also help distinguish between TXA-associated seizures, shivering, myoclonic movements, and thereby prevent a misdiagnosis. It may also detect subclinical seizures that are not apparent by observing sedated patients.[19],[28]

Triggering of seizures may be explained by suppression of the inhibitory GABA-A receptors in the cerebral cortex or by direct cerebral ischaemia as a result of reduced cerebral blood flow. Blockade of GABA-A receptor by the TXA leads to lower threshold for neuronal depolarization and enhanced neurotoxicity.

The proconvulsant properties of TXA likely result from direct effects on the central nervous system, as application of TXA to the cortex or injection into the cisterna magna in experimental animals causes systemic as well as intracranial hypertension and seizures. Epileptic property of TXA is directly proportional to the concentration of the drug and area of the exposed cortex.[29],[30]

Furtmuller et al. first showed that TXA is a competitive antagonist of GABA-A receptors and that it inhibits recombinant GABA-A receptors (a1b2c2) with a half-maximal inhibitory concentration (IC50) of 7 mM. GABA-A receptors generate two distinct forms of inhibition, synaptic and tonic, which could exhibit different sensitivities to TXA. Synaptic currents are fast transient events that are activated by near saturating concentrations of agonist. In contrast, tonic currents are generated by low, ambient concentrations of transmitter.[31]

TXA competitively inhibits glycine because TXA is a structural analog of glycine receptors and this action contributes to seizures, which is supported by other glycine receptor antagonists, such as strychnine, and cause myoclonic movements and twitching, particularly in the lower limbs, as well as muscle spasms and convulsions similar to the pattern of the proconvulsant effects of TXA. Similar to GABA-A receptors, glycine receptors generate both synaptic currents and tonic inhibitory currents.[32] It is postulated that high doses of the drug would lead to massive sympathetic surge, which results in systemic hypertension and ventricular fibrillation.[19]

Several general anaesthetics, including the inhalational agents as isoflurane, sevoflurane, and desflurane and the IV anaesthetic such as propofol, act as positive allosteric modulators of glycine receptors that fully reversed TXA inhibition of tonic glycine current, which may prove to be effective for either treating or preventing TXA-associated seizures.[33],[34]

Prevention

Drug errors may be minimised by the following procedures: (1) infrequently used emergency medications stored in a distinctive location; (2) a standardised layout of drugs which is safest in the operating room helps create a mental model that makes mistakes less likely; (3) a team-based approach with reading aloud the drug label prior to drawing up the drug; (4) confusing medications should have different (size, color, shape) drug labels and vials; (5) continuous review of medication errors in hospitals to identify causative associated factors and systematic interventions for prevention.[4],[35]

Local institutions should be vigilant and aggressive in collecting data not only about negative outcomes but also about errors and near misses. A trend toward data sharing and transparency along with accessible electronic mechanisms to capture errors, mandatory critical incident reporting with a reinforcing culture can all lead to a decrease in medication errors in the future.

Management

Currently, there are no recommended treatments for TXA-induced seizures, however, understanding the cause of TXA-associated seizures, recognizing the early warning signs of impending seizures, and using anaesthetic agents may reduce the incidence and severity of seizures and lead to better patient outcomes.

The above case reports advocate administration of anticonvulsants including MgSO4, IV, and inhalational general anaesthetic agents, intensive haemodynamic monitoring, and CSF lavage.

Continuous infusion of thiopentone to induce burst suppression pattern has been used in a patient who had refractory status epilepticus as shown on EEG.[19] Hatch et al. (2015) used magnesium sulfate as bolus dose, followed by infusion along with phenytoin which was helpful in terminating the seizure activity.[22]

If the use of propofol or other anaesthetics is deemed to be unsafe or if these drugs are unavailable, alternative therapies can be considered. A second-line treatment for TXA-associated seizures includes compounds that increase GABA-A receptor activity, which may compensate for a reduction in glycinergic inhibition. Benzodiazepines (lorazepam, midazolam, diazepam, and clonazepam), which do not modify glycine receptors but rather upregulate GABA-A receptor function, have been used to treat seizures following inadvertent intrathecal injection of TXA.[36]

Cerebrospinal fluid lavage

After intrathecal injection of a wrong drug, immediate CSF drainage and early irrigation has been reported with good outcomes as CSF lavage removes and dilutes the injected drug and limits the neuronal toxic damage. To avoid a higher spread of the wrong drug, maintain a head-up position, and first aspirate CSF (with a 22 G needle), from a lower space, and then infuse crystalloids several times into the intrathecal compartment from a higher space.[14],[37]


  Conclusion Top


Recognizing the early warning signs of impending seizures, and using anaesthetics, administration of the anticonvulsants, intensive haemodynamic monitoring, scalp electroencephalography monitoring, magnesium sulfate, and CSF lavage may reduce the incidence and severity of seizures and lead to better patient outcomes.

Development and promulgation of a formal protocol by every institution to prevent wrong route drug administration could further contribute to prevention of iatrogenic drug administration errors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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