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2. Jurnal Reading Keracunan TCA

A 26-Year-Old Man Who Passed Out at His Work Desk

Background

Paramedics bring a 26-year-old man to the emergency department (ED) with an acute
onset of altered mental status. The paramedics had picked up the patient at his place
of employment. His coworkers reported that he was acting normally when he arrived
at work at 9 am; however, at about noon, a colleague noticed the patient slumping in
his chair. He was minimally responsive and had an open, unlabeled pillbox on his
desk.

The coworkers were aware of the patient's history of chronic back pain, but nothing
more. They also reported some recent disciplinary problems at work. He arrives
obtunded and is unable to answer any questions or provide any additional history. He
is not wearing any medical alert bracelets. The paramedics have brought the pillbox,
which contains several types of pills in various amounts.

Physical Examination and Workup

Upon physical examination, the patient has an oral temperature of 96.5°F (35.8°C).
His heart has a regular rhythm and a rate of 96 beats/min. His blood pressure is
134/76 mm Hg, and his respiratory rate is 16 breaths/min. He has a pulse oximetry
reading of 100% on 15 liters via nonrebreather mask.

In general, the patient appears obtunded. He is not making any sounds, but he does
open his eyes briefly and withdraws from painful stimulation (sternal rub only). His
motor, verbal, and eye findings give him a Glasgow Coma Scale score of 7. He is
breathing spontaneously and appears to be controlling his airway secretions. The
patient has no signs of trauma on head-to-toe examination. His pupils are large at
about 5 mm bilaterally, but they react equally to light. He has no meningismus,
thyroid masses, or neck scars. Clear bilateral breath sounds are noted. He has a soft
abdomen, without any peritoneal signs. His skin and mucous membranes appear dry.
No rashes are detected. His distal extremities are warm, with normal capillary refill.
No needle track marks are noted on his extremities.
The patient receives 0.4 mg of intravenous naloxone, without any change in his
condition. A fingerstick glucose test has a result of 105 mg/dL (5.83 mmol/L). He
undergoes rapid sequence intubation for airway protection, as well as for an
anticipated worsening course. A chest radiograph shows appropriate endotracheal and
orogastric tube placement; no acute cardiopulmonary disease is detected. He receives
a dose of activated charcoal via orogastric tube and a liter of normal saline
intravenously. Laboratory studies are ordered. A stat CT scan of the head is ordered
but does not reveal any abnormalities or disease. An electrocardiogram (ECG) is
ordered as well (Figure 1).

窗体顶端

Based on this patient's history and ECG, which of the following treatments should be
initiated?

A. Begin immediate whole-bowel irrigation

B. Initiate therapy with sodium bicarbonate

C. Consult a nephrologist for hemodialysis initiation

 D. Give magnesium in repeated doses until the ECG normalizes

E. Give additional doses of naloxone, to a maximum of 10 mg

Discussion

This patient likely had a mixed overdose, but the ECG did exhibit signs of a
toxic tricyclic antidepressant (TCA) overdose. Although their use in the treatment
of depression has decreased over the years, TCAs are often used to treat chronic pain,
especially neuropathic pain. The patient's history had multiple concerning elements
that raised suspicion of an overdose. He had chronic pain and access to medicines.
Additionally, there was the presence of behavioral problems, and he suffered a sudden
change in mental status.

Clinically, the patient had an anticholinergic toxidrome. He was noted to be in a

coma, with dilated pupils, dry skin, and borderline tachycardia. His ECG showed a
widened QRS complex (> 100 msec), a prolonged QT interval, and a terminal R-wave
greater than 3 mm in lead aVR (Figure 1). All of these findings are concerning for a
TCA overdose.[1,2,3] Because a TCA overdose can be lethal, immediate treatment
based on the ECG findings and clinical picture is warranted.

TCAs remain widely used medications, and they are responsible for more deaths per
prescription than all other classes of antidepressants combined. [2] They are used for
multiple indications beyond depression, including chronic pain, attention deficit
hyperactivity disorder (ADHD), anxiety disorders, migraine
headache prevention, diabetic or other peripheral neuropathy, and pediatric enuresis.[2]

TCAs are thought to exert their principle therapeutic effects by inhibiting presynaptic

uptake of norepinephrine and serotonin.[2] Their toxicologic effects are complex, but
they can be divided into 4 main categories: inhibition of norepinephrine reuptake,
direct α-adrenergic blockade, antimuscarinic-type anticholinergic actions, and a
quinidine-like effect on myocardial cells.[4] Some antihistaminic effects and potassium
channel antagonism are also noted.[3] These various mechanisms manifest in various
body systems. Deaths from TCA overdose usually result from
dysrhythmia, cardiogenic shock, or status epilepticus with hyperthermia, and they
typically occur within the first few hours of admission.[1]
TCAs exert their quinidine like effect by inhibiting the fast sodium channel that
initiates the cardiac action potential.[1] This effect can lead to depressed contractility
and prolonged QRS, PR, and QT intervals that predispose the patient to dysrhythmias.
[4]
 When severe, TCA toxicity can also cause cardiogenic shock and pulmonary
edema from myocardial depression. These interval prolongations can also deteriorate
into various lethal dysrhythmias, including ventricular fibrillation, ventricular
tachycardia, and torsade de pointes.[1]

Seizures can occur in cases of TCA overdose and likely result from the inhibition of
gamma-aminobutyric acid (GABA) and of norepinephrine reuptake. As the seizures
continue, muscle activity and myoclonic jerking can lead to severe hyperthermia
and/or ensuing rhabdomyolysis, multisystem organ failure, brain injury, and death.
[1]
 Another side effect of intractable seizures is acidosis. As the acidosis worsens,
TCAs likely have an increased bioavailability resulting from decreased protein
binding.[4] This increased TCA availability further inhibits cardiac sodium channels,
thereby worsening any cardiac toxicity.[4]

Therapeutic dosing for TCAs is typically 1-5 mg/kg per dose. Toxic effects can be
anticipated for any ingestion greater than this, and life-threatening symptoms usually
occur at doses greater than 10 mg/kg.[3] TCA overdose should be suspected based on
the patient's clinical presentation. Of course, the history can be very helpful,
particularly if the overdose is witnessed or medication bottles are available. Patients
will have a wide range of symptoms depending on the severity of their overdose. The
most common symptom is altered mental status.[3] Most cases will manifest an
anticholinergic, antimuscarinic toxidrome. Key features of this toxidrome are altered
mental status (ranging from mild symptoms to coma), pupillary dilatation,
tachycardia, absent bowel sounds, dry skin and mucous membranes, and urinary
retention. More severe symptoms include cardiac disturbances (as discussed above),
hypotension, seizures, and hyperthermia. Serious toxicity almost always manifests
within 6 hours of ingestion.[3]

Given the wide variability in clinical presentation, a broad list of differential

diagnoses should be considered. Ancillary testing may help confirm the diagnosis of
TCA overdose as well as exclude other diagnoses in the differential. The first steps
should include a focused history-taking and physical examination specifically looking
to identify traumatic injuries or other causes of altered mental status necessitating a
CT scan of the head. A fingerstick glucose test and measurement of the vital signs
should be rapidly obtained. ECGs are readily available tests that provide substantial
information in cases of overdose with TCA or other sodium channel blockers. TCA
overdose should be considered in any patient with altered mental status, seizures, and
an abnormal ECG.[5] The specific changes that are most important, as described
above, are a prolonged QT interval, a prolonged QRS duration, and a large terminal
R-wave in lead aVR.[3] A patient with more significant toxicity may present in
ventricular fibrillation or tachycardia, as well as supraventricular or sinus tachycardia.
Laboratory testing for TCA overdose is also available. Most hospitals have qualitative
TCA screens available. Unfortunately, this test does not delineate between therapeutic
and toxic TCA levels. The qualitative screen is often rapidly available, however, and
can help confirm suspicions based on clinical examination and ECG findings. As in
most toxicologic screening tests, erroneous results stem from numerous causes.
Diphenhydramine, carbamazepine, cyclobenzaprine, and phenothiazines can cause
false-positive test results.[3] False negatives are unusual. Quantitative TCA tests
usually have a prolonged processing time and are rarely useful during the patient's ED
stabilization or initial hospital course.

A urine toxicology panel may help identify other substances that may be contributing
to the patient's condition; however, caution must be taken not to attribute a patient's
findings to commonly used illicit drugs without excluding potentially emergent
medical conditions or dangerous coincident ingestions. Additionally, an
acetaminophen level should be considered in all suspected overdoses. This does not
help treat the patient's TCA overdose, but acetaminophen has no identifiable
toxidrome; because of its widespread use and availability, it is often coingested.
Failure to initiate appropriate treatment for an acetaminophen overdose can be a fatal
oversight. Serum electrolytes, urinalysis, creatine phosphokinase (CPK), and
creatinine levels may be useful and should be also checked. [1] Other laboratory tests
may be useful to screen for other conditions but add little diagnostic yield to
evaluating a TCA overdose.

Once a TCA overdose is suspected (or confirmed), treatment should begin

immediately. Supportive care, such as ensuring a protected airway, administration of
IV fluids, and prevention of vomiting, should begin promptly for all patients. If no
contraindications are noted and ingestion is thought to have occurred within the
previous 4 hours, a dose of activated charcoal at 1 g/kg should be administered.
Gastric lavage may be considered for a massive overdose; however, it is rarely
justified if it cannot be started within 1 hour of ingestion.[1]

Sodium bicarbonate therapy is the principal treatment for overdose with TCA or any
other sodium-blocking agent, and it should be initiated in patients with the following
indications: hypotension refractory to fluids, QRS complex duration greater than 100
msec, or a terminal R wave in lead aVR greater than 3 mm. [3] It is given in an initial
bolus of 1-2 mEq/kg and should be repeated until clinical improvement is noted, with
a target serum pH of 7.50-7.55. Sodium bicarbonate has been shown to improve both
cardiac conduction and contractility, as well as suppress myocardial ectopy. [3] The
effectiveness of sodium bicarbonate stems from either an increase in extracellular
sodium concentration, a direct pH effect on the fast-acting sodium channels, an
increase in protein binding of TCAs, or a combination of the three.[1]

Hyperventilation may also be helpful as a treatment modality. By reducing carbon

dioxide and raising the patient's pH, some pH-dependent benefit may occur; however,
the effects will likely only be transient, and the risk of seizures by inducing alkalosis
may be increased.[1]

Hemodialysis is not effective for TCA treatment because extensive tissue and protein
binding cause a large volume of distribution.[1] Most antiarrhythmic medications, as
well as physostigmine, which was previously advocated for TCA treatment, should be
avoided; this is especially true if they are known to prolong the QT interval (such as
with the use of amiodarone or procainamide).[1,4] Vasopressors can be considered for
patients with refractory hypotension following fluid resuscitation. [4] Benzodiazepines
should be used for the treatment of seizures.[4] Lipid emulsion therapy and
extracorporeal membrane oxygenation are both emerging treatment options that may
be appropriate in certain overdose settings.[6,7]

Patients who are asymptomatic 6 hours after ingestion and did not need any specific
medical treatment do not require acute medical hospitalization [3]; however, if the
overdose is intentional, the patient likely requires psychiatric evaluation or
hospitalization. If the patient remains symptomatic, hospitalization in an intensive
care unit (ICU) or monitored bed is appropriate.

After examining the patient in this case and reviewing his ECG, treatment for a
presumed TCA overdose was initiated. After securing his airway and beginning
charcoal and fluid therapy, he received a dose of 2 ampules of sodium bicarbonate. A
repeat ECG showed improvement of his QRS and QT intervals, with a decrease in the
amplitude of his terminal R wave in aVR. His pH on a subsequent arterial blood gas
test was 7.52. The patient was then transferred to the ICU, where he received ongoing
treatment and eventual transfer for psychiatric evaluation.

Question 1 of 2

A patient is suffering from a suspected anticholinergic toxidrome. Which of the

following physical findings or symptoms should cause you to reconsider
anticholinergic toxidrome as a diagnosis?

Tachycardia

Urinary retention
Diaphoresis

Pupillary dilatation

Delirium

Question 2 of 2

Which of the following treatment modalities is least likely to help a patient with TCA
overdose?

Hemodialysis

Activated charcoal

Sodium bicarbonate

Hyperventilation

Fluid resuscitation

窗体底端

One of the key features of an anticholinergic (specifically antimuscarinic) toxidrome

is dry skin. This important clinical feature can help make the diagnosis of an
anticholinergic overdose. Furthermore, it can help distinguish anticholinergic from
sympathomimetic toxicity. In other respects, the entities can be quite similar. Both
can present with altered mentation, tachycardia, hyperthermia, and mydriasis;
however, recognizing dry versus diaphoretic skin may help the clinician choose the
management approach.
Hemodialysis is not effective for TCA treatment. Because of the extensive tissue and
protein binding with a large volume of distribution, dialysis is not an effective
treatment. All of the other treatments may prove useful. Activated charcoal, sodium
bicarbonate, and fluid resuscitation are all mainstays of therapy. Hyperventilation may
also provide a transient benefit for a TCA overdose while other modalities are used

References:
1. Olson K, ed. Poisoning & Drug Overdose. 4th ed. San Francisco,
CA:McGraw-Hill;2004.
2. Cushing TA, Benzer TI, Noori M. Selective Serotonin Reuptake Inhibitor
Toxicity. Medscape Reference. Last updated: April 24, 2018. Source
3. Tintinalli JE, Kelen GD, Stapczynski JS, Ma J, Cline D. Emergency Medicine:
A Comprehensive Study Guide. 6th ed. New York, NY:McGraw-Hill;2004.
4. Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a
review. Emerg Med J. 2001;18:236-41.
5. Veris-van Dieren J, Valk L, van Geijlswijk I, Tjan D, van Zanten A. Coma
with ECG abnormalities: consider tricyclic antidepressant intoxication. Neth J
Med. 2007;65:142-5.
6. Cao D, Heard K, Foran M, Koyfman A. Intravenous lipid emulsion in the
emergency department: a systematic review of recent literature. J Emerg Med.
2015;48(3):387-97. Source
7. Yates C, Galvao T, Sowinski KM, et al. Extracorporeal treatment for tricyclic
antidepressant poisoning: recommendations from the EXTRIP Workgroup.
Semin Dial. 2014;27(4):381-9. Source