Vicious Cycles: Management of the Tricyclic Antidepressant Overdose - CanadiEM (2024)

You’re on a night shift in the ED and receive a patch about a 75-year-old female with altered LOC. EMS reports an empty bottle of doxepin was found in her home. The patient is tachycardic and hypotensive, and on arrival has a GCS of around 12. You quickly look up the class of medication that doxepin belongs to, and realize it’s a TCA.

What do you need to worry about in this patient, and which treatments should you start?

Mechanisms of Action

To understand the complications and management of TCA overdose, it’s helpful to consider the mechanisms of action of TCAs^​1,2​:

• sodium channel blockade => QRS widening, dysrhythmias, decreased inotropy leading to decreased cardiac output and hypotension
• alpha receptor blockade => decreased systemic vascular resistance and hypotension
• GABA blockade => seizures
• norepinephrine and serotonin reuptake inhibition => initial hypertension and subsequent hypotension; increased risk of serotonin syndrome when combined with other serotonergic drugs (e.g., SSRIs, MAOIs)
• potassium channel blockade => QTc prolongation
• anticholinergic toxidrome
• antihistaminergic sedation

ECG Signs of TCA Overdose ^​3–5​

• Sinus tachycardia (likely the first to appear, due to the anticholinergic effects)
• Wide QRS > 100 ms
• Prominent R wave in aVR (R > 3 mm, R/S > 0.7). May also see Right Axis Deviation, RBBB pattern, and a prominent R wave in V1.
• QTc prolongation > 430 ms
• Rarely, a Brugada-like pattern can be seen in V1-V3

The ECG is the best predictor of the clinical course in TCA Overdose, as opposed to drug levels. In one study, QRS width > 100 ms carried a 33% risk of seizures, and QRS > 160 ms carried a 50% risk of dysrhythmias. No seizures or dysrhythmias occured below these respective thresholds.^​6​

Management Priorities

1) Manage ABCs – Treat hypotension with IV fluids and vasopressors if needed. Norepinephrine or epinephrine are first-line choices. There is limited experimental evidence in animals suggesting that epinephrine may be more effective at reducing the cardiotoxic effects of TCAs. Norepinephrine is a physiologically sensible choice, given the alpha blocking effects of TCAs, as well as their inhibition of norepinephrine reuptake.^​1,3​

Intubation should be considered early, especially in a known massive overdose. Consider intubating earlier for GCS<8, refractory seizures, hypoventilation, or airway compromise^​3​.

2) Gastric decontamination – If less than 1 hour from ingestion (or unknown time), give activated charcoal. This requires the patient to be protecting their airway, or intubated, as there is a significant risk of aspiration with activated charcoal (a risk not completely eliminated by intubation). Particularly in a massive overdose, consider giving activated charcoal even up to 4 hours post ingestion. The anticholinergic effects of the drug slow gastric emptying, so there may still be some benefit from late gastric decontamination. Consider gastric lavage for a massive overdose within 1 hour of ingestion, again necessitating a protected airway.^​3​

3) Sodium bicarbonate – Start with 1-2 mEq/kg boluses of a 1 mEq/mL solution (50-100 mEq, or 1-2 amps), repeating every few minutes until the QRS narrows. Then start an infusion of 150 mEq bicarb in 1L D5W with 40 mEq KCL at ~250 mL/hr (titrated to QRS and pH targets). Goals of therapy are QRS < 100 ms and pH 7.5-7.55.^​3,7​

Mechanisms of Action:

• Sodium to counteract sodium channel blockade (decreases the time required for cells to depolarize, narrowing the QRS).
• The full mechanism by which bicarbonate improves toxicity is incompletely understood. Alkalinization of the blood increases protein-binding to TCAs, which decreases the amount of unbound TCA able to bind to sodium channels. It also increases the amount of unionized TCA in the blood, leading to decreased binding to sodium channel receptors. Finally, it may also more directly affect cardiac depolarization.

The exact contribution / clinical significance of each of these effects is unclear, but data from both animal and in vitro studies support the efficacy of both the sodium and bicarbonate components on narrowing the QRS.^​7​

There is no definitive evidence to guide dosing decisions with respect to the necessity of an infusion versus boluses alone, or even definitive targets.^​3,7​Based on a 2003 survey, most poison control directors still recommend a bolus followed by an infusion.^​8​ Multiple case reports of TCA overdose treated with upwards of 75 amps of sodium bicarbonate (!!) do suggest that large volumes of sodium bicarbonate can safely be administered if indicated (although a VBG should be checked after giving more than 2-4 amps).^​9,10​

4) Benzodiazepines – indicated for treatment of seizures or agitation. Do not use phenytoin.^​3​

5) Monitor electrolytes and pH with serial measurements – Look out for hypocalcemia and hypokalemia (secondary to bicarbonate-induced alkalosis), which can worsen hemodynamic instability and dysrhythmias, and may require replacement.^​7​

Second-Line Therapies:

These therapies all have minimal evidence that stems largely from case reports or experimental/animal studies.

Hypertonic saline – Similar mechanism as sodium bicarbonate in overwhelming the sodium channel blockade. Although there is a greater volume of evidence supporting sodium bicarbonate, some studies have found that hypertonic saline works equally well (and the two are unlikely to ever be compared in a large randomized control trial). Hypertonic saline is a good option in several circ*mstances:

• Significant alkalosis (pH > 7.55)
• Significant hypokalemia
• Sodium bicarbonate is unavailable
• Hypotension or dysrhythmias refractory to sodium bicarbonate^​1,11​

Intralipid Emulsion – Indicated (if available) for the treatment of refractory hypotension or dysrhythmias, after failure of sodium bicarbonate treatment. This should be administered in consultation with the poison center or a toxicologist. An initial bolus of 1.5 mL/kg of 20% lipid solution is a reasonable starting point, which can be repeated if no improvement after several minutes, and followed by an infusion if there is clinical improvement.^​1,3​

Lidocaine – A counterintuitive option, given that it is also a sodium channel blocker, but the proposed mechanism of action involves outcompeting TCAs in binding to sodium channels. Unlike TCAs, which act more slowly, lidocaine rapidly unbinds from sodium channels, resulting in more unbound channels available to generate a cardiac action potential. Indicated for the treatment of refractory dysrhythmias.^​12,13​

Magnesium Sulfate – For refractory dysrhythmias, especially in the context of prolonged QTc.^​3​ However, the effects of the prolonged QTc interval in TCA overdose are rarely clinically significant, as the sinus tachycardia typically seen has a protective effect by shortening the QTc.

ECMO – If available, ECMO should be initiated for refractory dysrhythmias, hemodynamic instability, or cardiac arrest. Although rarely used, several case reports have reported successful outcomes (including survival to hospital discharge and complete neurologic recovery) following the use of ECMO in these circ*mstances.^​14​

More FOAMed on this Topic

1. Emergency Medicine Cases: Massive TCA Overdose https://emergencymedicinecases.com/critcases-massive-tca-overdose/
2. EMCrit Podcast 98: Cyclic (Tricyclic) Antidepressant Overdose https://emcrit.org/emcrit/tricyclic-antidepressant-overdose/
3. EM:RAP Episode 138: TCA Overdose https://www.emrap.org/episode/march2013/tcaoverdose

This post was copy-edited by @jamievanderende.