Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM
Review Date: 3/17/2013
Definition 
Intentional or accidental overdose of tricyclic antidepressants (TCAs) is a common occurrence. Tricyclic antidepressants are commonly prescribed despite this risk of cardiovascular and neurological effects in patients who choose to ingest supratherapeutic doses of TCAs.
Description
- Tricyclic agents have commonly been used for treatment of depression, panic attacks, anxiety disorder, phobic disorders, obsessive-compulsive disorder, eating disorders, neuropathy, and attention deficit hyperactivity disorder. TCA's also are prescribed for enuresis in children and as an adjunct for neuropathic pain
- Drugs belonging to this class include amitriptyline, nortriptyline, clomipramine, desipramine, imipramine, doxepin and dothiepin/dosulepin
- TCAs act by inhibition of neuronal reuptake of noradrenaline and serotonin after their release at presynaptic sympathetic nerves
- TCAs exert effects via antagonism of peripheral alpha-1-adrenergic receptors, a membrane-stabilizing effect on the myocardium, and anticholinergic action
- TCA overdose leads to cardiac toxicity, which can be life threatening, along with neurological toxicity which can include coma an seizures
- In many cases of TCA overdose, other symptoms/findings can include tachycardia, mydriasis, dry mouth, warm flushed dry skin, delayed gastric emptying, slowed intestinal peristalsis or ileus, urinary retention, confusion or agitation, headache, fatigue, anxiety, increased intraocular pressure, blurred vision, drowsiness, weakness, and dizziness
- When death occurs due to TCA overdose, it usually occurs within hours of ingestion
- TCAs are potentially both more effective for depression, and more toxic than selective serotonin reuptake inhibitors (SSRIs) and other more recent agents
- 300–450 deaths/year may be prevented if SSRIs are used as first-line depression treatment rather than TCAs
- Treatment of TCA poisoning is supportive, but also includes specific measures to treat seizures and cardiac toxicity. Complicating factors such as acidosis and hypoxia need to be avoided
Epidemiology
- Incidence/Prevalence
- In 2011, the U.S. association of poison control center reported antidepressants as the sixth most frequent toxic agent in overdose
- One study found that TCA overdoses had higher rates of hospitalization (78.7% vs 64.7%) and much higher fatality rates than SSRI overdose (0.73% vs 0.14%)
- Age
- TCA toxicity occurs in all ages, however, the peak incidence occurs in those aged 20–45 years
- Gender
- Women are more prone to depression than men
- TCA overdose is more common in women due to gender specific availability to this agent for use in overdose
- Risk factors
- The common risk factor for TCA overdose is a history of depression or other psychiatric conditions requiring antidepressant medication, along with patient access to TCA's
Etiology
- Unintentional or intentional, single acute overdoses may lead to significant clinical effects. Acute exposure may be due to following scenario:
- Unintentional second therapeutic dose by patient's prescribed TCAs
- Unintentional intake by a patient who was not prescribed a TCA
- Unintentional intake by children
- Intentional ingestion
[Outline]
History
- Common anticholinergic symptoms of TCAs at therapeutic doses include
- Agitation
- Confusion
- Delirium
- Dilated pupils
- Dry mouth
- Fever
- Urinary retention
- Warm flushed dry skin
- Other common symptoms include
- Anxiety
- Blurred vision
- Coma
- Convulsions (Seizures)
- Delirium
- Dizziness
- Drowsiness
- Fatigue
- Headache
- Restlessness
- Weakness
- Common gastrointestinal symptoms include
- Anorexia
- Constipation
- Epigastric distress
- Nausea
Physical findings on examination
Physical findings can consist of the following
- Altered mental status, coma, confusion, delirium
- Asystole
- Cardiogenic shock
- Delayed gastric emptying, slowed intestinal peristalsis, or ileus
- Dry skin and mucous membranes
- Extrapyramidal signs
- Fever
- Heart block
- Hypotension
- Increased intraocular pressure
- Muscular rigidity
- Mydriasis
- Myoclonic twitching
- Ophthalmoplegia
- Prolonged PR/QRS/QT
- Pulmonary edema
- Respiratory depression
- Seizures (generalized tonic-clonic)
- Sinus tachycardia
- ST/T wave changes
- Ventricular fibrillation/tachycardia
[Outline]
Blood tests findings
Laboratory testing of blood includes checking for parameters such as:
- Complete blood count, comprehensive panel, and acetaminophen/paracetamol levels should be obtained in most cases of suspected overdose (along with ß-HCG as indicated)
- In rare cases toxicology testing for TCAs may be indicated where the history, physical and ECG findings are equivocal (Urine or blood toxicology)
- Venous (rarely arterial) blood gas analysis may be of value to assess degree of acidosis and nature of this (respiratory or metabolic)
Other laboratory test findings
- Urine toxicology provides rapid results confirming or excluding exposure to TCA's
- Be aware of false positive results, as cyclobenzaprine and other agents can generate a positive result due to cross reactivity
- Be aware that urine toxicology simply indicates exposure to a given class of medication, but fails to quantify if that agent is present at a toxic level
Radiographic findings
- Chest X-ray in significantly affected patients is appropriate due to risk of aspiration, cardiogenic shock, and negative pressure pulmonary edema
Other diagnostic test findings
- A 12-lead electrocardiogram (ECG) helps to assess the clinical severity of overdose as TCAs delay myocardial conduction by inhibiting sodium channels. Primary dysrhythmias which may be found on ECG include:
- Asystole
- Sinus tachycardia
- Supraventricular arrhythmias
- Ventricular fibrillation
- Ventricular tachycardia
- Ventricular ectopy
- Primary conduction delays which commonly occur with TCA ingestion include:
- QRS prolongation, with >100 msec being concerning for TCA toxicity, with most cases of significant cardiac toxicity having a QRS duration of >120 msec
- PR/QT prolongation
- Terminal R wave extension in QRS in lead aVR
- First degree atrioventricular (AV) block
- Bundle branch blocks
[Outline]
General treatment items
An evidence-based consensus guideline for both pre-hospital and emergency department (ED) management of TCA ingestion has been authored by the American Association of Poison Control Center. They recommend:
Prehospital treatment measures
- The guideline recommends that the following patients be seen in an ED:
- Cases which are concerning for self-harm or victims of malicious administration of TCA
- Children
- TCA ingestion in combination with other drugs
- Patients with significant underlying cardiovascular or neurological disease who ingest TCAs even at low doses
- Symptomatic patients
- Patient who have ingested an amount greater than the usual maximum single therapeutic dose, or equal to or greater than the lowest reported toxic dose
- Initial treatment of TCA toxicity should include supportive care, and where possible, detoxification to reduce the patient's exposure to the toxic agent
- Advanced cardiac life support (ACLS) is advised for patients presenting with dysrhythmia, hypoventilation, and hypoperfusion
- Intubation may be necessary in patients with substantially decreased mental status
- Intravenous access should be established as soon as possible
- Ipecac-induced emesis is not indicated in such patients
Emergency department measures
- GI decontamination using activated charcoal is appropriate to decrease the absorption of TCA in patients presenting within 1-2 hours of ingestion. It is critical to consider whether establishing a definitive airway prior to administration of charcoal is indicated
- Gastric lavage may be considered if the patient presents within 1 hour of ingestion (charcoal typically adequate)
- If cardiac toxicity is present, this is a critical issue and needs to be recognized as a significant immediate mortality risk. A QRS interval of >100 msec should be recognized as concerning for cardiac toxicity, with an interval of >120 msec indicating serious cardiac toxicity. This can be complicated in patients with pre-existing interventricular conduction delays or bundle branch block
- Administration of sodium bicarbonate is indicated in cases of cardiac toxicity, with a QRS interval of >100 msec being a clinical indicator for this agent
- Dosing is typically 1 meq (mmol)/kg IV slow over a few minutes, repeated as needed
- After stabilization of prolonged QRS interval, an infusion with 100 meq of sodium bicarbonate in 1 liter of normal saline infused at a rate to deliver 0.25 meq/kg/hr is reasonable
- Goal arterial pH is 7.50-7.55 in cases with cardiac toxicity (this can be maintained both with mild hyperventilation in intubated patients, along with administration of sodium bicarbonate)
- Hypertonic (3%) saline solution should be considered for wide complex QRS and hypotension caused by TCA-induced cardiotoxicity. In some models, comparison of sodium bicarbonate with hypertonic saline favors hypertonic saline
- It appears as though the sodium load may be more critical than alkalinization
- Dosing of 3% saline is typically 3 mL/kg infusion over 10-20 minutes, this may be repeated several times (up to 3 doses) if needed
- Benzodiazepines such as midazolam, diazepam and lorazepam are commonly used to control seizures (phenytoin should be avoided as it may add to cardiac toxicity)
- Antiarrhythmic agents are used when other interventions focusing on the correction of hypotension, hypoxia, and acidosis fail to control the cardiotoxicity of TCA. Some antiarrhythmic agents may worsen the cardiovascular effects of TCA ingestions. Antiarrhythmic agents as a second-line therapy after sodium bicarbonate include lignocaine. However, magnesium sulfate may be a better choice in cases of VT/VF as it is quite typical for other agents to be ineffective and potentially worsen cardiac toxicity
- Intravenous (IV) infusion of lipid emulsion has been shown to decrease the plasma concentration of TCAs due to the lipophilic nature of TCAs, and helps to reduce the cardiotoxic effects. Multiple case reports in the literature report patients with severe cardiac toxicity having substantial and rapid recovery with administration of intravenous lipids (such as Intralipid). In one case report, QRS duration initially of 180 msec, with improvement to 96 msec with sodium bicarbonate, but with continued cardiac toxicity with a BP of 70/58 and HR 130/min had rapid improvement with stabilization of the BP with an increase to 140/80 mmHg and QRS further narrowing to 80 msec within 15-20 minutes after administration of Intralipid (adult protocol 100 mL over 1 minute, then 400 mL over 30 minutes)
Medications indicated with specific doses
GI decontaminant
Cardiovascular agents- Lidocaine [Injectable]
- Norepinephrine
- Sodium bicarbonate [IV]
Anticonvulsants- Diazepam [IM/IV]
- Lorazepam [IM/IV]
- Midazolam [IM/IV]
- Phenobarbital [IM/IV]
Other- Magnesium sulfate [IM/IV]
- Fat emulsion [IV]
Disposition
- Admission criteria
- Patients who are symptomatic after 6 hours of TCA ingestion require hospitalization
- Patients presenting with altered mental status, dysrhythmia, or conduction delays and seizure require hospital admission, often to an intensive care unit
- Patients with a heart rate >100 beats per minute 6 hours after ingestion
- Prolonged observation is needed in cases involving concomitant ingestion of any other drug which may complicate the outcome
- Discharge Criteria
- Patients who remain asymptomatic after 6 hours of observation are medically fit for discharge
- The ADORA criteria effectively rule out significant toxicity if none of the following are present during the 6 hour period following ingestion. If any are present, further observation or hospital admission is generally indicated
- QRS >100 msec
- Any cardiac arrhythmia
- Altered mental status
- Seizure
- Respiratory depression
- Hypotension
- Patients with suicidal intent must receive psychiatric clearance prior to discharge
[Outline]
100 ms is compulsory until this normalizes and remains normal