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Alternatives in the Management of Cardiac Toxicity from Tricyclic Antidepressant Overdose in Light of the Present Intravenous Sodium Bicarbonate Shortage
by Jaxson Burkins, PharmD; PGY2 Emergency Medicine Pharmacy Resident, Rush University Medical Center; Anthony M Burda, BSPharm, DABAT; Clinical Toxicologist, Illinois Poison Center; Carol DesLauriers, PharmD, DABAT; Senior Director, Illinois Poison Center
Tricyclic antidepressants
(TCAs) are a class of medications commonly involved in overdoses; large ingestions
are potentially fatal. Tricyclic antidepressant toxicity can present as anticholinergic
symptoms, coma, seizures, hypotension, and dysrhythmias.1 Intravenous
sodium bicarbonate bolus is a mainstay of treatment for the sodium channel-blocking
effects on the heart caused by TCA overdose. Continuous sodium bicarbonate
infusion is not routinely recommended, as it is of unproven efficacy. Due to
manufacturing delays, intravenous sodium bicarbonate was recently included on
the current drug shortages list published by American Society of Health-System Pharmacists.
This drug shortage presents
a challenge for the medical community as alternate therapeutic options are
needed when intravenous sodium bicarbonate is unavailable. At toxic doses, TCAs
cause a blockade of the fast voltage-gated sodium channel in the myocardium,
which results in a widening of the QRS complex on an electrocardiogram (EKG).
Other EKG abnormalities include rightward shift of the QRS axis, rightward
shift of the terminal 40 msec of the QRS complex, and an R-wave of 3 mm or
greater in aVR. Ultimately, these EKG changes and cardiac disturbances can
result in dysrhythmias. Intravenous sodium bicarbonate provides two mechanisms
to correct this widened QRS complex. First, sodium bicarbonate provides
additional sodium ions to overcome the channel blockade, which in turn shortens
the QRS interval, provides cardiac stability, and may increase blood pressure.
Sodium bicarbonate also potentially offers serum alkalization via chemical
buffering and altering the binding of the toxin to the receptor site. Additionally,
the increased pH enhances the protein binding of TCAs, decreasing the amount of
free drug available to bind to receptors. In severe overdoses, the general
dosing is 1-2 mEq/kg to target an arterial pH of 7.45-7.55 and a QRS duration
of < 120 msec. While sodium bicarbonate is a first-line therapy in TCA overdoses,
given the current drug shortage, it is important to be aware of possible alternatives,
which are summarized below.
Hypertonic Saline
Hypertonic saline can
provide enough sodium ions to overcome the sodium channel blockade resulting from
the toxin. While only case reports exist for humans, multiple animal studies have
demonstrated the reversal of cardiotoxicity from TCAs with 3% sodium chloride. In
one case report, a patient with widening QRS from a nortriptyline overdose was
successfully treated with 200 mL of 7.5% sodium chloride through rapid
intravenous infusion.1 When utilized, it is necessary to monitor the
patient’s acid-base status as hypertonic saline can result in a hyperchloremic
acidosis further complicating the clinical picture.
Hyperventilation (if intubated)
If a patient is already
intubated, therapeutic hyperventilation can be used to reduce serum carbon
dioxide. It is important to monitor the serum pH, as an aggressive
hyperventilation may cause an over-reduction in carbon dioxide that can result
in a severe alkalemia. Hyperventilation may provide the most benefit in
patients who cannot tolerate large amounts of sodium, such as those who have acute
respiratory distress syndrome or congestive heart failure. One case report
demonstrated successful reversal of a life-threatening arrhythmia from an
amitriptyline overdose utilizing hyperventilation after prior therapies were
unsuccessful.2,3 Patients should not be intubated solely for a wide
QRS complex.
Intravenous Lipid Emulsion
Intravenous lipid emulsion
is an emerging therapy for many toxins, with recent literature suggesting benefit
in TCA overdose. The exact mechanism of action is unknown, but the therapeutic effects
are most commonly seen with lipophilic medications. A number of animal studies
have shown potential benefit for clomipramine overdose, and some case reports of
amitriptyline toxicity have noted positive outcomes following administration of
intravenous lipid emulsion.4,5 Although many current guidelines are
neutral, this therapy can be considered in severe cases of TCA overdose with
refractory hypotension, ventricular dysrhythmias, or cardiac arrest. For
additional information on dosing of intravenous lipid emulsion, contact the
Illinois Poison Center or visit lipidrescue.org.
Sodium Acetate
Similar to hypertonic
saline, sodium acetate may be used to provide additional sodium ions to
overcome the sodium channel blockade. Additionally, sodium acetate may buffer
the serum, resulting in an alkalemia similar to sodium bicarbonate. The
recommended dose of sodium acetate is 1 mEq/kg of sodium, to be administered
over 15 to 20 minutes. This slow rate of administration typically precludes its
successful use in unstable overdose patients.6
Lidocaine
Lidocaine is a Vaughan
Williams Class Ib antiarrhythmic that may increase the rate of phase 0
depolarization, which is dependent on sodium channels. There are limited
studies on the use of lidocaine in TCA cardiotoxicity, but it may serve as a
therapeutic alternative. Many emergency departments readily stock lidocaine for
injection, and the therapy may be most beneficial in patients who are
hypernatremic or severely alkalemic, when other therapies are contraindicated.
Other antiarrhythmics such as Class Ia and Class Ic are cardiac depressants
that slow phase 0 depolarization; this effect may worsen the widened QRS,
making these medications contraindicated in TCA overdose.7
During drug shortages, pharmacists
are often asked for therapeutic alternatives to medications in short supply. While
intravenous sodium bicarbonate plays an important role in the treatment of
overdoses, there are therapeutic alternatives that may be considered when the
drug is unavailable. For more information, please contact the Illinois Poison
Center at (800) 222-1222.
References
1. McKinney PE, Rasmussen R.
Reversal of Severe Tricyclic Antidepressant-Induced Cardiotoxicity With
Intravenous Hypertonic Saline Solution. Ann
Emerg Med. 2003; 42:20-4.
2. McCabe JL, Cobaugh DJ,
Menegazzi JJ, Fata J. Experimental Tricyclic Antidepressant Toxicity: A
Randomized, Controlled Comparison of Hypertonic Saline Solution, Sodium
Bicarbonate, and Hyperventilation. Ann
Emerg Med. 1998; 32(3): 329-33.
3. Kingston ME. Hyperventilation
in tricyclic antidepressant poisoning. Crit
Care Med. 1979; 7(12): 550-1.
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5. Levine M, Brooks DE,
Franken A, Graham R. Delayed-onset seizure and cardiac arrest after
amitriptyline overdose, treated with intravenous lipid emulsion therapy. Pediatrics. 2012; 130(2): e432-8.
6. Neavyn MJ, Boyer EW, Bird
SB, Babu KM. Sodium Acetate as a Replacement for Sodium Bicarbonate in Medical
Toxicology: a Review. J Med Toxicol.
2013; 9: 250-4.
7. Foianini A, Wiegand TJ,
Benowitz N. What is the role of lidocaine or phenytoin in tricyclic
antidepressant-induced cardiotoxicity? Clinical
Toxicology. 2010; 48: 325-330.