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Commentary
Tranexamic Acid: Beware of Anaesthetic Misadventures
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.
Sunanda Gupta,
Anil K. Bhiwal,
Karuna Sharma
Department of Anesthesiology,
Geetanjali Medical College and
Hospital, Udaipur, Rajasthan,
India
Keywords: Cerebrospinal fluid lavage, electroencephalography, intrathecal injection, seizure, spinal
anaesthesia, tranexamic acid
Introduction
Medication errors during anaesthesia
vary from <1% of anaesthetics to >5% of
medication administrations.[1‑3] 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
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“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
Address for correspondence:
Dr. Anil Kumar Bhiwal,
Department of Anesthesiology,
Geetanjali Medical College and
Hospital, Udaipur ‑ 313 001,
Rajasthan, India.
E‑mail: anilbhiwal@yahoo.co.in
Access this article online
Website: www.joacc.com
DOI: 10.4103/joacc.JOACC_12_18
Quick Response Code:
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.
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Gupta, et al.: Accidental Intrathecal tranexamic acid
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[7-23] 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.
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
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]
2
Figure 1: Model circuit for underlying mechanism of TXA induced pain in
the spinal dorsal horn circuit
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
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Gupta, et al.: Accidental Intrathecal tranexamic acid
Author
Table 1: Summary of published case reports of inadvertent intrathecal injection of tranexamic acid
Wong et al, 1988[7]
De Leede‑van der
Maarl et al, 1999[8]
Yeh et al., 2003[9]
Sabzi et al.,
2009[10]
Dose of TXA/
surgery
75 mg TXA
appendicectomy
150 mg TXA
500 mg in 10 ml
saline
Indwelling intrathecal
catheter for chronic
pain relief
500 mg elective
cesarean section
Signs & symptoms
Management
Sequelae
Persistent motor sensory
block both lower
extremities, Urinary
incontinence
Statusepilepticus
Diazepam
Myoclonus, generalized
seizure , Hyperthermia,
recovered
Diazepam, phenytoin and
thiopental
Diazepam, DC shock
Survived with bilateral
peroneal palsy
Generalized convulsions,
cardiovascular collapse,
and refractory ventricular
fibrillation
Severe pain in the back and
gluteal region, myoclonus
lower extremities,
Hypertension, tachycardia
Myoclonus, generalized
seizure refractory
ventricular fibrillation
General anaesthesia,
diazepam
Death after 1.5 h
Myoclonus, generalized
seizure refractory
ventricular fibrillation.
GA, propofol infusion,
phenytoin, sodium
valproate, dexamethasone,
General anaesthesia,
lidocainesedative drugs and
mechanically ventilated.
Death
Myoclonus, tonic clonic
convulsions, recovered fully
on sixth postoperative day
Tachyarrhythmia,
nystagmus, , seizure,
ventricular tachycardia,
fibrillation.death
Mohseni K et al.,
2009[11]
Orthopedic surgery
Perianal burning,
hypertension, tachycardia,
Veisi F et al.,
2010[12]
Emergency caesarean
section
Kaabachi et al.,
2011[13]
90 mg TXA
Tossing and turning,
severe sharp pain in lower
extremities, dysphoric,
dizziness. No sensory or
motor block.
Severe pain in the back and
gluteal region, myoclonus
lower extremities,
Hypertension, tachycardia
Butala BP et al.,
2012[14]
300 mg TXA
cystolithotripsy
Severe burning pain in
both lower limbs, back and
gluteal region, irritable.
Myoclonus lower limbs
Mahmoud K et al.,
2012[15]
300 mg TXA
lower‑limb skin
grafting
Severe pain in the back and
gluteal region, no sensory
motor block, hypertension,
tachycardia
Srivastava et al.
2012[16]
350 mg TXA
cholecystectomy
GA, Diazepam,
symptomatic management
Raghu et al.,
2013[17]
TXA 250 mg
Caesarean section
Severe pain back radiating
to lower limbs, restless,
Hypertension, tachycardia,
myoclonic movement of feet
Back pain, gluteal region,
lower limb pain, myoclonus,
Antwi‑kusi et al.,
2013[18]
200 mg TXA Elective
Caesarean section
General anaesthesia
Goyal G et al.,
2014[19]
250 mgTXA
herniorrhaphy
No sensory block,
Myoclonus lower extremity,
hypertension
Pain in the back, lower
limbs, generalized
tonic‑clonic seizures.,
Hypertension, tachycardia
GA, Clonazepam,
phenobarbital and sodium
thiopental infusion
Midazolam, propofol,
sodium thiopentone,
phenytoin, dexamethasone,
sodium valproate,
levetiracetam and mannitol.
CSF lavage with 20 ml NS
GA, Propofol, propranolol,
amiodarone, lidocaine, and
mannitol
General anaesthesia
GA, lorazepam, phenytoin,
clobazampropofol infusion,
EEG, induced coma with
thiopentone infusion,
Recurrent attacks of
polymyoclonus and
seizures, ventricular
tachycardia recovered
within 4 days without any
neurologic sequelae
Discharged on 7th day
without any neurological
sequelae
Generalized myoclonic
seizures, ventricular
fibrillation, fully recovered
without any neurologic
sequelae
Generalized convulsions,
complete CVS collapse,
multifocal PVC on ECG,
Death after 6hrs
ventricular arrhythmias,
Cardiovascular collapse,
death
Seizures, ventricular
tachycardia fibrillation,
death
Recurrent generalized
tonic clonic seizures,
refractory status epilepticus,
discharged after 7 days
without any neurological
deficit
Contd...
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Gupta, et al.: Accidental Intrathecal tranexamic acid
Author
Roy A et al.,
2015[20]
Dose of TXA/surgery
200 mg caesarean
section
Narra GR 2015[21]
250 mg TXA
Prostatectomy
Hatch DM et al.,
2015[22]
Cesarean delivery
Elkhateeb R et al.,
2017[23]
Elective caesarean
section
Table 1: Contd...
Signs & symptoms
Myoclonic seizures of
lower extremity followed
by generalized convulsion,
cardiac arrest
Severe pain back, gluteal
region, pereneal burning
radiating to lower limbs,
agitation, forceful urination,
severe myoclonus lower
extremity and mild in
upper limbs, hyperthermia,
hypertension, tachycardia
Severe pain back, gluteal
region, lower extremity
spasms, hypertension,
tachycardia
Management
Midazolam, Phenytoin,
Thiopentone General
anaesthesia
Sequelae
Recovered in 5 days
GA, dexamethasone,
mannitol, Sodium
valproate, CSF lavage with
normal saline, thiopental
infusion
Polymyoclonus, Recovered
with no neurological deficit
on sixth day
GA, amiodarone,
mannitol, fentanyl,
Magnesiumsulphate
Refractory status
epilepticus, ventricular
arrhythmias
Burning sensation at the
site of injection, back and
gluteal pain, restlessness
GA, Propofol
infusion, Thiopental
infusion, Clonazepam,
phenobarbital, DC shock
Recovering but died due to
interrupted Oxygen supply
Recurrentpolymyoclonus
and seizures,
tachyarrhythmis, ventricular
fibrillation death
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.
4
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
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Gupta, et al.: Accidental Intrathecal tranexamic acid
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]
12.
13.
Conclusion
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.
14.
15.
16.
17.
18.
Financial support and sponsorship
Nil.
19.
Conflicts of interest
There are no conflicts of interest.
20.
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