Tricyclic Antidepressant Toxicity Treatment & Management

Endotracheal intubation is necessary in a patient who is obtunded and unable to protect the airway. Intravenous access should be established as soon as possible. Administer intravenous fluid if the patient is hypotensive. Prompt transport of the patient to the nearest emergency department is implicit.

Evidence-based management guidelines for tricyclic antidepressant (TCA) poisoning are available from the American Association of Poison Control Centers (AAPCC). This guideline is outlined for poison control center personnel to assist in prehospital triage and management of patients with possible TCA ingestion/overdose. A brief summary of the prehospital evidence-based consensus management guideline is as follows ^[12] :

• Patients with suspected self-harm or who are the victims of malicious administration of a TCA should be referred to an emergency department (ED) immediately (Grade D).

• Referral to an ED with close monitoring of clinical status and vital signs en route is recommended for (1) patients with acute TCA ingestions who are younger than 6 years, (2) patients with underlying conditions such as convulsions or cardiac arrhythmias, and (3) co-ingestion of other drugs with TCAs (Grade D).

• Referral to an ED is recommended for patients who are symptomatic after a TCA ingestion (Grade B).

• Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose would warrant consideration of referral to an ED (Grades B/C).

• Do not induce emesis (Grade D).

• The risk-to-benefit ratio of prehospital activated charcoal for TCA poisoning is unknown. Activated charcoal administration should only be carried out by health professionals and only if no contraindications are present. Do not delay transportation in order to administer activated charcoal (Grades B/D).

• Asymptomatic patients are unlikely to develop symptoms if the ingestion took place more than 6 hours before the initial call to a poison control center. These patients do not need referral to an ED facility (Grade C).

• Follow-up calls to determine the outcome for a TCA ingestion ideally should be made within 4 hours of the initial call to a poison control center and at appropriate intervals thereafter based on the clinical judgment of the poison control center staff (Grade D).

• An ECG/rhythm strip, if available, should be checked during the prehospital assessment of a patient with TCA overdose. A QRS duration longer than 100 msec is an indicator that the patient should be immediately stabilized, given sodium bicarbonate if there is a protocol for its use, and transported to an ED (Grade B).

• Symptomatic patients with TCA poisoning might require prehospital interventions in accordance with standard ACLS guidelines (Grade D).

• Administration of sodium bicarbonate might be beneficial for patients with severe or life-threatening TCA toxicity if a prehospital protocol exists for its use (Grades B/D).

• Benzodiazepines are recommended for TCA-associated convulsions (Grade D).

• Flumazenil is not recommended for patients with TCA poisoning (Grade D).

Refer to the AAPCC guideline for complete details. ^[12]

The greatest risk of seizures and arrhythmias occurs within the first 6-8 hours of cyclic antidepressant (CA) ingestion. The treatment of an asymptomatic patient with a history of CA ingestion is mainly supportive therapy. For all patients with possible CA toxicity, airway protection, ventilation and oxygenation, intravenous fluids, cardiac monitoring, and performing electrocardiography (ECG) are all essential measures. The patient should be admitted to the ICU if hemodynamic instability and ECG changes are observed.

Consider early gastric decontamination using charcoal if the patient presents within 2 hours of ingestion.

Once suicidal ideation is ruled out and the patient remains asymptomatic for 6-8 hours postingestion without any ECG changes, the patient may be discharged home. If suicidal ideation is present, evaluation for admission to a psychiatric facility is mandatory.

Treatment considerations include the following:

• Airway: Endotracheal intubation may be necessary for airway protection in patients who present with seizures or who are comatose.

• Hyperventilation: The use of hyperventilation is controversial. It has been recommended traditionally for the alkaline state it produces. Alkalinization is thought to increase protein binding of CA and promote CA excretion, thereby decreasing cardiotoxicity. However, a randomized controlled animal study found that hyperventilation has little effect on reversing CA toxicity. ^[13]

• Hypotension: Intravenous infusion of normal saline is indicated for CA-induced hypotension. For hypotension refractory to intravenous saline, vasopressors may be used.

• Gastrointestinal (GI) decontamination: Once the patient is stabilized, activated charcoal can be considered.

• Intravenous sodium bicarbonate

GI decontamination may be helpful within the first several hours postingestion because CAs can slow gastric emptying through their anticholinergic activity.

Gastric lavage may be helpful in recovering and identifying the CA ingested. However, one study that compared the use of gastric lavage and activated charcoal versus charcoal alone showed no benefit in clinical outcome. ^[14] Usually, lavage is recommended for patients who developed significant toxicity requiring endotracheal intubation and who presented relatively soon after ingestion (within several hours).

Activated charcoal reduces the absorption of CAs. It may also be beneficial in cases of multisubstance ingestion. It should be administered only in patients who are able to protect the airway.

Endotracheal intubation is indicated if the patient cannot adequately maintain a safe airway.

Serum alkalinization with intravenous sodium bicarbonate has been the mainstay of therapy in CA-induced cardiovascular toxicity. QRS prolongation is most often the indication for serum alkalinization in CA toxicity. Not all physicians agree on what duration of QRS should be the indication for starting intravenous sodium bicarbonate therapy. However, about 88% of the poison control directors in the United States use a QRS of 100 milliseconds or greater as the threshold for use of intravenous sodium bicarbonate. ^[15]

Evidence suggests the reversal of toxic effects of CA (eg, QRS prolongation, myocardial depression) following serum alkalization and sodium loading with sodium bicarbonate. Sodium bicarbonate may be initially administered as an intravenous bolus at a dose of 1 - 2 mEq/kg. Serial ECG performed before and after administration of bicarbonate may be used to determine if cardiac conduction abnormalities are responsive to the therapy. Boluses of sodium bicarbonate may be repeated to treat cardiac conduction abnormalities and impaired contractility, with a maximum target blood pH of 7.50 - 7.55.

Alternatively, a bicarbonate infusion may be initiated after the bolus by adding 3 ampules of sodium bicarbonate (50 mEq each for a total of 150 mEq) to 1 L of 5% dextrose in water (D5W) and infusing at 1.5 - 2 times the maintenance rate. The same maximum target blood pH of 7.50 - 7.55 should be used for bicarbonate infusions. In patients who can not tolerate the volume of fluid associated with an infusion (eg, those with congestive heart failure, renal impairment, or end-stage renal disease), use of repeated boluses may be preferable.

Ventricular bradyarrhythmias, due to depressed atrioventricular conduction and automaticity, can be treated by placement of a temporary pacemaker. Alternatively, consider the use of a chronotropic agent.

Lidocaine, when used to treat ventricular arrhythmia, should be administered with caution to avoid precipitating seizures.

Intravenous lipid emulsion (ILE) has demonstrated efficacy in the treatment of local anesthetic agent–induced cardiotoxicity, in laboratory studies. ^[16] The theorized mechanism of action of ILE is the creation of "lipid sink" in the intravascular compartment, sequestering lipophilic drugs and reducing bioavailability. ^[17] No clinical studies have been done on ILE in the treatment of CA toxicity; however, case reports from Europe and New Zealand describe successful resuscitation using ILE therapy in patients demonstrating severe CA cardiotoxicity. ^{[18, 19]}

In the case studies published, ILE was used with success in patients with severe hemodynamic instability and QRS widening. ILE may be administered in a 1.5 mL/kg or 100 mL bolus (in adults) over 1 minute. This bolus may be repeated for patients in cardiac arrest or with recurrent toxicity. Alternatively, the bolus may be followed with an ILE infusion at 0.25 mL/kg/min for 30 - 60 minutes. ^[20]  

The seizures in CA toxicity are usually self-limited. The treatment of choice for prolonged or recurrent seizures in CA toxicity is a benzodiazepine. Most CA-induced seizures are usually brief and resolve prior to the administration of anticonvulsants. General anesthesia should be reserved for patients with status epilepticus who are unresponsive to the standard treatment regimen (eg, benzodiazepines, barbiturates, propofol). This may prevent hyperthermia and rhabdomyolysis.

A case study reported successful use of ILE therapy to treat refactory status seizures following ingestion of 3.0g of amozapine. In this case, seizures persisted after diazepam was administered.  Levetiracetam and phenobarbital were also administered with no effect. ILE was injected for over 1 minute with the patient's status seizures ceasing after 2 minutes. Within an hour after ILE, the seizures recurred and ILE was again administered. The seizures stopped and did not recur. ^[21]

The use of hypertonic saline in CA toxicity remains controversial. Although 7.5% hypertonic saline has been shown to correct hypotension and QRS widening in severe CA overdose in a swine model, ^[13] limited evidence supports the use of hypertonic saline in CA toxicity in humans. No study has adequately compared the efficacy of hypertonic saline versus sodium bicarbonate, and sodium loading may be the most important factor in the reversal of the symptoms of cyclic antidepressant toxicity.

Because of the large volume of distribution and high protein-binding characteristics of CAs, hemodialysis has not been shown to be effective in the treatment of CA overdose.

The following drugs should be avoided in patients with CA toxicity:

• The use of physostigmine in CA poisoning has been associated with complete heart block, asystole, and hypotension

• Inducing emesis with ipecac syrup is not recommended for GI decontamination because of the possibility that the patient may experience sudden neurologic deterioration (eg, lethargy, seizures) and aspirate

• The use of type IA and IC antidysrhythmics or other sodium channel blockade agents may exacerbate toxic effects of CAs on the myocardium

• The use of flumazenil for reversal of benzodiazepine overdose with concomitant CAs exposure can precipitate seizures

Level of consciousness and ECG changes at presentation are the most sensitive clinical predictors of serious complications. Consider intensive care unit admission for any patient with ECG changes. Admission to a monitored bed is appropriate for patients exhibiting only anticholinergic symptoms and no cardiac manifestations.

CA toxicity typically lasts 24-48 hours following a significant overdose. However, studies have reported prolonged CA toxicity lasting as long as 4-5 days. ^[22]  Amitriptyline is the drug most commonly implicated in these cases.

Poison control center and toxicologist consultation may be helpful in diagnosing and treating tricyclic antidepressant toxicity. A cardiologist should be consulted for pacemaker placement and arrhythmia management, when indicated. ICU admission is needed for patients with cardiovascular and/or neurologic manifestations.