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[page 20] [Emergency Care Journal 2023; 19:11270]
Emergency Care Journal 2023; volume 19:11270
Abstract
In the 2020 annual report of the American Association of
Poison Control Centers, 2562 toxic exposures to carbamazepine
have been reported, 908 resulted in hospitalization, and among
these about 5-6% were life-threatening or resulted in significant
disability. A 15-year-old female patient was brought under suspi-
cion of alcohol poisoning. The result of alcoholemia was
11.0 mg/dL and the toxicological screening for THC, opiates,
methadone, tramadol, amphetamine, MDMA, cocaine, benzodi-
azepines, buprenorphine was negative. At admission she was
comatose (GCS=6), with metabolic acidosis, hypotension, rare
short-term partial seizures, isochoric and later dilated pupils, body
temperature was 36.4°C, with oxygen saturation from 89 up to
93%. Toxicological analysis were immediately extended. After
three hours of admission, a result was obtained where the plasma
concentration for carbamazepine was 167mmol/L. The patient was
quickly prepared for hemodialysis which was performed for four
hours. After 8 hours of admission the patient woke up with stable
vital parameters.
Introduction
In 2020, the American Association of Poison Control Centers
reported 2562 toxic exposures to carbamazepine. Of these, 1257
were isolated ingestions and 908 were treated in a health care facil-
ity. There was one death, and 52 patients experienced major toxic-
ity, defined as life-threatening or resulting in significant disability.¹
Data from the US Poison Control Centers documented 4149
toxic carbamazepine exposures in 2012, 14% of which had at least
a moderate effect. Carbamazepine has been used for many years
for the treatment of both partial and generalized seizures, as well
as trigeminal neuralgia. It has also been used as a mood stabilizer
and for treatment of neuropathic pain syndromes. Toxicity due to
carbamazepine overdose was first described in 1967 and continues
to be responsible for a large proportion of life-threatening cases
among anticonvulsant poisonings.²
Initial signs of overdose with Carbamazepine include lethargy,
nystagmus, ataxia and dysarthria. Anticholinergic effects as evi-
denced by decreased bowel motility, urinary retention and sinus
tachycardia are common. Increasing intoxication leads to fluctuating
level of consciousness, seizures, coma and respiratory depression.
Patients with an underlying seizure disorder are more susceptible to
seizures. Increased muscle tone, hyperreflexia and myoclonus are
reported. The latter has been confused with seizure activity.³
Cardiovascular effects include hypotension (secondary to reduced
myocardial contractility), sinus tachycardia, bradyarrhythmia,
widened QRS complex and atrioventricular conduction delay.
Cardiogenic pulmonary edema may occur. Aspiration pneumonitis
may occur from inhalation of vomitus.4 Mydriasis with sluggish reac-
tion to light is reported as well.5 Death from overdose is infrequent
but can result from severe cardiovascular toxicity, status epilepticus
or aspiration pneumonitis.4 Specifically, in a review of 427 patients,
seizures were statistically associated with a fatal outcome.6
Oxcarbazepine was primarily used in the treatment of epilep-
sy, but now it is prescribed for other indications, too, e.g. neuro-
pathic pain. It can also be used as mood stabilizer in management
of bipolar affective disorders. Oxcarbazepine is a structural
Correspondence: Natasha Simonovska, University Clinic for
Toxicology, Clinical Centre, “Mother Teresa”, Faculty of Medicine,
Ss Cyril and Methodius University, Vodnjanska 17, 1000 Skopje,
Republic of North Macedonia.
Tel.: +389.71277295.
E-mail: N.Simonovska@yahoo.com
Key words: toxicity; carbamazepine; renal dyalisis.
Contributions: NS, contributed to the conception of the work; NS,
BI, KN cared for the patient. All authors participated in the design of
the work, drafted the work, or critically reviewed it. All authors
approved the final version for publication.
Conflict of interest: the authors declare no conflict of interest.
Availability of data and materials: all data underlying the findings
are fully available.
Ethics approval and consent to participate: no ethical committee
approval was required for this case report by the Department,
because this article does not contain any studies with human partic-
ipants or animals.
Consent for publication: informed consent was obtained from the
patient and her parent included in this study.
Acknowledgements: the authors are grateful to the University Clinic
for Nephrology for facilitating this work, the physicians from the
University Clinic for Toxicology who contributed to the examination
of the patient, and Lenche Danevska for English proofreading of the
manuscript.
Received for publication: 20 Februaary 2023.
Accepted for publication: 16 May 2023
This work is licensed under a Creative Commons Attribution 4.0
License (by-nc 4.0).
©Copyright: the Author(s), 2023
Licensee PAGEPress, Italy
Emergency Care Journal 2023; 19:11270
doi:10.4081/ecj.2023.11270
Publisher's note: all claims expressed in this article are solely those of
the authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article or claim that may be
made by its manufacturer is not guaranteed or endorsed by the publisher.
From unknown poisoning to carbamazepine poisoning
Natasha Simonovska,1,2 Andon Chibishev,1,2 Niko Bekarovski,1,2 Aleksandra Babulovska,1,2 Biljana Ivanova,1
Kiril Naumovski,1,2 Kristin Kostadinovski1,2
1University Clinic for Toxicology; ²Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, Republic of North
Macedonia
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derivative of carbamazepine, with the advantage of being less
myelotoxic and not being a CYP3A inducer, resulting in less drug
interactions. Side effects are dose dependent. Most common are
hyponatremia, dizziness, somnolence, agitation, headache, atax-
ia, nausea, vomiting and difficulty in concentration. Rare adverse
effects include anaphylaxis, angioedema, toxic epidermal necrol-
ysis, Stevens-Johnson syndrome, photosensitivity and suicidality.
Unlike other antiepileptic drugs, it does not seem to be procon-
vulsant in overdose.7
Case Report
A 15-year-old female patient, weight 51kg, was brought by
ambulance to the University Clinic for Toxicology in Skopje. The
family said they did not have precise information about what hap-
pened. Allegedly, the patient was out with her friends the night
before and she might have drunk more than was good for her.
When she returned home, her family talked with her, but the next
day, they could not wake her up. She was unconscious with occa-
sional seizures and vomited. The last communication was approx-
imately 9 hours before admission at our Clinic. She had a history
of depressive episodes regularly treated with Escitaloparm of 5
mg/day. On admission, she was comatose (GCS=6), with isochoric
pupils and rare, short-term partial seizures. Blood pressure was
90/60 mmHg, body temperature was 36.4oC, with oxygen satura-
tion on room air from 89 up to 93%, with clear lungs, soft abdomen
and ECG with sinus rhythm HR=100/min, QRS=100 msec,
QTc=410 msec, without other changes. In the meantime, the result
of alcoholemia showed 11.0 mg/dL (value <100mg/dL-low level)
and the toxicological screening in urine sample for tetrahydro-
cannabinol (THC), opiates, methadone, tramadol, amphetamine,
3,4-methyl-enedioxy-methamphetamine (MDMA), cocaine, ben-
zodiazepines, buprenorphine was negative. Biochemical analyses
were normal except for increased white blood cells up to
24.4×109/L (normal value 4.00-9.00×109/L). The family informed
us that the patient had been sick the previous week. Polymerase
chain reaction (PCR) test for covid-19 was negative. On admission
blood gas analyses were performed with oxygen support by face
mask (PH:7.19; pCO2:5.39 kPa; pO2: 9.3kPa; base excess (BE): -
12.5; cHCO3: 15.3-decompesated metabolic acidosis). Firstly, the
patient was treated with crystalloids: sodium chloride (0.9% NaCl)
with a dose regime 2.5 mL/kg/h intravenous (iv) infusion, sodium
hydrogen bicarbonate (1 mmol/kg), ceftriaxone 2 gr/day. Two
hours after admission, the pupils were dilated (4 millimeters). We
assumed differential diagnostic that the reason of comatose state of
the patient could be caused both by non-toxicological trigger, both
by other toxic agent. A neurological examination was performed
by neurologist, and, in addition to the confirmed comatose state, a
positive Babinski was also seen. CT brain was with normal find-
ing. Although the time of the possible intake of the drug was
unknown, we adhered to the ABCDE approach to the poisoned
patient. Activated charcoal was given at a dose of 50 g via naso-
gastric tube.
We have been in contact with her parents continuously and
have informed them that it was almost certain that alcohol as they
stated at the admission of the patient was not the cause of her
unconsciousness. We explained them our differentially diagnostic
approach and which conditions could lead to comatose state.
Among other things, it was emphasized that it might be an acute
overdose with some other toxic agent. In the meantime, we
received information from her father that he found empty boxes of
Carbamazepine at home. It was possible for us to determinate car-
bamazepine concentration with the available fluorescent
immunoassay (FIA) method. After three hours of admission, plas-
ma carbamazepine concentrationwas 167 mmol/L (reference
value: 17.00-50.00 mmol/L). A nephrologist was called and the
patient was quickly prepared for hemodialysis. A right femoral
catheter was placed and hemodialysis was performed in duration
of four hours. The same evening, 8 hours after admission, the
patient woke up and she was with stable vital parameters, no
seizures, improvement of gas analyses. The next day, 22 hours
after admission, verbal contact was established with the patient,
and she confirmed that she took 20 tablets Carbamazepine 200 mg
with suicidal idea. These tablets were used from her grandmother.
A chest x-ray and abdominal ultrasonography were also performed
and reported normal findings. Ninety-six hours after admission,
plasma carbamazepine concentration was again analyzed and the
levels were 47.11 mmol/L. As soon as patient’s condition was sta-
bilized, she was discharged from hospital on the sixth day, and
referred to a psychiatrist.
Discussion
Аn interesting data for healthcare workers who operate in
emergency (either in pre-hospital either in hospital phase) is pub-
lished in one study by Lee et al. They reported the results of
patients with altered mental status in whom the cause could not be
determined via blood and imaging tests, and the altered mental sta-
tus in 31.5% of these patients was found to be caused by poisoning.
This finding is similar to that of previous studies showing that 19–
31% of patients visited the emergency room for altered mental sta-
tus due to poisoning.8
Any symptomatic patient can indicate a potential drug over-
dose. Altered mental status, gastrointestinal complaints, cardiovas-
cular compromise, seizures, and temperature-related disorders can
all be toxin-related.9
In our case, the diagnosis was unclear and the data obtained did
not correlate with the results of the initial toxicological analyses.
Airway, breathing, circulation (ABCs) is central to the man-
agement of unknown poisoned patient.9,10 In patients who have
unknown overdoses, a toxidrome can assist in making a diagnosis
and is also useful for anticipating other symptoms that may occur.10
A comatose state in a patient could be caused by either non-
toxicological trigger (e.g. intracranial hemorrhage, stroke, hypo-
glycemia, sepsis, etc.) or by toxic causes. Numerous drugs and tox-
ins (salicylates, iron, metformin, methanol/ethylene glycol may
determine coma and metabolic acidosis, etc.). Metabolic acidosis
can result from the ingestion of a substance that is either an acid or
has an acidifying metabolite.¹¹ Borron in his study mentioned the
association of metabolic acidosis with toxins such as metformin,
ethylene glycol, and methanol.¹²
Ingestions of other anticholinergic agents (e.g. tryciclic antide-
pressants, anti-histamines, anti-psychotics…) than carbamazepine
may yield similar clinical signs and symptom.¹³ Spagnolo et al.
reported in their article the need for physicians to be aware of the
potential emergence of tropicamide as a drug of misuse, to prevent
further harm.14 Tropicamide is an antimuscarinic ophthalmic solu-
tion used to produce short-acting mydriasis and cycloplegia. It is
feared that tropicamide abuse may become more frequent.15
Tropicamide has been recently anecdotally reported to be recre-
ationally misused from online sources.16 From 2013 in Italy, a
diverted use of tropicamide has been suspected by some pharma-
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cists, who observed an abnormal increase in eye drop sales. In its
annual report for 2014, the European Monitoring Centre for Drugs
and Drug Addiction (EMCDDA) identified intravenous tropi-
camide administration as a new practice in opioid abusers.17
Sympathomimetic toxicity (e.g. cocaine, MDMA, amphetamines,
mephedrone) may look clinically indistinguishable from carba-
mazepine toxicity though the neuromuscular effects may be more
prominent with carbamazepin.18 Also serotonin syndrome (e.g.
SSRI) may have similar vital sign abnormalities (e.g. tachycardia
and clonic disorders) and CNS depression though the hyperreflexia
is more pronounced in serotonin syndrome.19 Other antiepileptic
agents (e.g. phenytoin or valproic acid) can lead to CNS depres-
sion and nystagmus though these agents do not tend to have the
cardiovascular toxicity associated with carbamazepine overdose.²º
Coma, anticholinergic syndrome, and unexpected acts are seen
in patients with acute and chronic exposure. Ozhasenekler et al. in
their study reported that the physical examinations of all patients
showed respiratory depression in 4% while convulsion, ataxia and
diplopia were found in 6%, dysarthria in 10%, vertigo in 12%,
mydriasis in 18% and sinus tachycardia in 63% of patients.²¹
In our case report, there was impairment of consciousness, par-
tial convulsions, delayed mydriasis.
Basic treatment of carbamazepine poisoning is supportive, and
there is no antidote. Primary decontamination with activated char-
coal is widely used. Active charcoal decreases absorption of carba-
mazepine across intestine. Thus, its plasma half-life decreases, too.
Duration of coma may extend a few days because carbamazepine
absorption delays across gastrointestinal tract. Hence, an aggres-
sive approach is required for removal of carbamazepine and its
metabolites. Gastric lavage with active charcoal was shown to be
useful.²²
Early gastrointestinal decontamination is recommended.
Activated charcoal should be administered.²² Prevention of ongo-
ing absorption and control of any seizures are also priorities. There
should be a low threshold for intubation as pulmonary aspiration is
a significant concern and intubation facilitates decontamination.
Seizures are an indicator of a poor outcome and must be aggres-
sively managed; initially with a benzodiazepine, followed by a bar-
biturate if benzodiazepines are ineffective.²³ IV fluids should be
administered to hypotensive patients, but care must be taken not to
overload the patient as hypotension is typically due to poor
myocardial contractility. Due to sodium channel blocking proper-
ties, cardiac toxicity is well recognized although quite rare.
Sodium bicarbonate should be given if broad-complex cardiac dys-
rhythmia occurs.24 Multiple dose activated charcoal (MDAC) is
recommended following any large or symptomatic ingestion.25
Intubated patients should receive MDAC via nasogastric tube
(ensuring bowel sounds are present). Due to an anticholinergic
action on the gut motility must be monitored as ileus may occur. In
severe cases extracorporeal elimination is recommended; intermit-
tent hemodialysis is preferred but intermittent hemoperfusion or
continuous renal replacement therapies are acceptable alternatives
if hemodialysis is not available. Urinary retention may require
catheterization.²
Early hemoperfusion (HP) administered directly by emergency
doctors to patients with carbamazepine poisoning can significantly
reduce plasma carbamazepine concentration and accelerate the
elimination from the body. In addition, HP treatment can signifi-
cantly relieve impaired consciousness, respiratory depression and
seizure after carbamazepine poisoning.26
Despite the low quality of the available clinical evidence and
the high protein binding capacity of carbamazepine, the workgroup
suggested extracorporeal removal in cases of severe carba-
mazepine poisoning.27 Hemodialysis is simple, cheap and is a
widely used procedure. It is easier to apply compared to HP.
Hemodialysis is more advantageous than HP because of lower
cost, simplicity, easier accessibility and paucity of side effects
related to procedure (thrombocytopenia, coagulopathy, hypother-
mia, hypocalcemia). Consequently, it has been shown that standard
hemodialysis may also be a good therapeutic option in cases HP is
not available in patients with carbamazepine poisoning presenting
with coma and convulsion.²¹
In our patient, although the time of the possible intake of the
drug was unknown, we adhered to the ABCDE approach of the
poisoned patient. Activated charcoal was given at a dose of 50 g.
On the first day of admission, plasma carbamazepine concentration
was 167 mmol/L. After hemodialysis, the same evening the patient
woke up without convulsions.
Conclusions
Approach to an unconscious patient with unknown etiology
and a patient with unknown poisoning can be diagnostically and
therapeutically difficult, but at the same time a great challenge as
well. In the presented case collecting patient’s history was essential
to differentiate and identify the correct diagnosis as much as veri-
fying the correlation among suspected causes and clinical manifes-
tations. In our patient hemodialysis has been performed without
complications and this procedure may be helpful and considered in
severe carbamazepine poisoning.
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