eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Toxicology

Toxicity, Tricyclic Antidepressant

Samara Soghoian, MD, MA, Clinical Assistant Professor of Emergency Medicine, New York University School of Medicine, Bellevue Hospital Center
Christopher I Doty, MD, FACEP, FAAEM, Assistant Professor of Emergency Medicine, Residency Program Director, Department of Emergency Medicine, Kings County Hospital Center, State University of New York Downstate Medical Center; Frank A Maffei, MD, FAAP, Associate Professor of Pediatrics, Temple University School of Medicine; Director of Medical Student Affairs, Geisinger Health System; Pediatric Critical Care Attending Physician, Janet Weis Children's Hospital at Geisinger Medical Center; Heidi Connolly, MD, Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center

Updated: Oct 22, 2009

Introduction

Background

Cyclic antidepressants (CAs) have been used in the treatment of major depression since the late 1950s. Originally termed tricyclic antidepressants (TCAs), they are now more accurately called cyclic antidepressants because some newer members of this class have a 4-ring structure. They are also currently used in the treatment of chronic pain syndromes and for migraine prophylaxis. In the pediatric population, they are commonly prescribed for the treatment of enuresis, obsessive-compulsive disorder, attention deficit hyperactivity disorder, school phobia, and separation anxiety. The most commonly prescribed cyclic antidepressants include amitriptyline, desipramine, imipramine, nortriptyline, doxepin, and clomipramine.

Cyclic antidepressants have a narrow therapeutic window, increasing their likelihood for toxicity. The clinical features of cyclic overdose were first reported in 1959, only 2 years after they began to be used clinically. In the past decade, the prescription of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has far surpassed that of cyclic antidepressants. However, the incidence of cyclic antidepressant toxicity is currently on the rise due to changes in prescribing practices, and increasing interest in the therapeutic potential of cyclic antidepressants for chronic pain syndromes. Cyclic antidepressants remain second only to analgesics as the most common drugs implicated in overdose fatalities. Some evidence suggests that cyclic antidepressants are associated with more overdose fatalities per number of prescriptions issued than other antidepressant classes.

Pathophysiology

Cyclic antidepressants are named for their 3-ring or 4-ring aromatic (heterocyclic) structure. They are rapidly absorbed in the GI tract and undergo first-pass metabolism in the liver. Conjugates are then renally eliminated. Cyclic antidepressants are very lipophilic and highly protein-bound, leading to large volumes of distribution. They have long elimination half-lives that often exceed 24 hours (>31-46 h for amitriptyline). In an overdose, altered pharmacokinetics may prolong elimination and increase toxic effects. Cyclic antidepressants have significant anticholinergic effects that can delay gastric emptying. Additionally, the acidosis that results from respiratory depression and hypotension reduces protein-binding, resulting in higher serum levels of active free drug.

Although the exact therapeutic mechanism of cyclic antidepressants is not known, it is most likely related to decreased central norepinephrine and serotonin reuptake, resulting in increased levels of these biogenic amines in the brain. The therapeutic dose for most cyclic antidepressants in children is 5-10 mg/kg/d, and toxicity may be observed at doses of 10-20 mg/kg/d. Significant adverse effects are generally seen only with doses greater than 20 mg/kg/d. The toxic effects of cyclic antidepressants are related to the following 4 pharmacologic effects:

• Anticholinergic effects
• Direct alpha-adrenergic blockade
• Inhibition of norepinephrine and serotonin reuptake
• Blockade of fast sodium channels in myocardial cells, resulting in quinidinelike membrane-stabilizing effects

The most serious adverse effects of cyclic antidepressant toxicity are due to CNS effects and cardiovascular instability. Depressed mental status is generally caused by the antihistamine and anticholinergic properties of cyclic antidepressants, whereas seizures are thought to be due to increased CNS levels of biogenic amines. Life-threatening cardiovascular complications are due to impaired conduction from fast sodium channel blockade. This decreases the slope of phase zero depolarization, widens the QRS complex, and prolongs the PR and QT intervals. Impaired cardiac conduction may lead to heart block and unstable ventricular arrhythmias or asystole. cyclic antidepressants have also been shown to directly depress myocardial contractility. However, the profound hypotension seen in serious cyclic antidepressant poisoning is primarily due to vasodilatation from direct alpha-adrenergic blockade.

Frequency

United States

The 2004 American Association of Poison Control Centers (AAPCC) annual report on toxic exposures in the United States included 103,155 reported cases of antidepressant toxicity; 12,269 were due to heterocyclic agents, with a total of 86 deaths.¹ Cyclic antidepressants poisoning was reported in 2,948 children. Of these cases, 1,355 occurred in children younger than 6 years, while another 1,593 occurred in children aged 6-19 years.

Among antidepressant agents, cyclic antidepressants were the third most common class implicated in toxic exposures. SSRIs were the most common antidepressants taken in toxic doses. This is most likely due to the frequency with which they are prescribed.

Mortality/Morbidity

Cyclic antidepressants toxicity accounts for approximately 12% of reported toxic exposures for antidepressants but accounts for approximately 29% of deaths due to antidepressant poisoning. Cyclic antidepressants were the most common cause of overdose-related fatalities until the past decade, when analgesics surpassed them as a class.

In addition to acute poisoning from intentional or unintentional overdose, several well-documented adverse drug reactions (ADRs) are associated with tricyclic antidepressant use, including sedation, insomnia, orthostatic hypotension, cardiac dysrhythmias, movement disorders,² and skin hyperpigmentation.³ Some of these ADRs may be responsible for the increased risk of falls, with associated morbidity, seen among elderly patients taking cyclic antidepressants. A recent prospective cohort study noted an association between cyclic antidepressant use and an increased risk of coronary heart disease.⁴

Some of the morbidity associated with cyclic antidepressant ADRs may be linked to genetic variations in the CYP2D6 enzyme, which is important for the hepatic metabolism of this class of medication.⁵

Sex

The incidence of cyclic antidepressants poisoning is higher in women than in men. This most likely reflects a higher rate of depression and suicide attempts among women.

Age

The distribution of toxic cyclic antidepressant exposures in children is bimodal, with peaks in early childhood and the later teenaged years. Accidental exposure is typically seen in toddlers, whereas adolescents tend to present with intentional overdoses.

Clinical

History

The history in patients with cyclic antidepressant (CA) poisoning may include either intentional or unintentional ingestion. Older children should be screened for suicidal ideation and prior self-harm.

• An attempt should be made to determine the specific agent ingested because the toxic profiles of different cyclic antidepressants may vary. For example, amoxapine is associated with a higher incidence of seizures, whereas maprotiline is more likely to be cardiotoxic. Both dothiepin and amitriptyline have been shown to have greater toxicity than the other cyclic antidepressants.
• Patients and their families should be questioned as to the dose and time of ingestion. Onset of symptoms typically occurs within 2 hours, and major complications typically occur within the first 6 hours after exposure.
• Determine if any co-ingestions have occurred.

Physical

Physical examination findings relate to the anticholinergic, cardiovascular, and CNS effects of cyclic antidepressants. Anticholinergic effects are typically the first to appear and should raise clinical suspicion of cyclic antidepressant overdose. Recently, a sodium channel blockade toxidrome has been proposed and described, using the mnemonic "S-A-L-T" (ie, shock, altered mental status, long-QRS interval duration, terminal R wave in aVR).⁶

• Anticholinergic effects may include the following:
  • Xerostomia
  • Blurred vision, mydriasis
  • Urinary retention
  • Hypoactive or absent bowel sounds
  • Pyrexia
  • Myoclonic twitching
• Cardiovascular effects may include the following:
  • Sinus tachycardia
  • Prolonged PR, QRS, and QT intervals
  • Heart block
  • Peripheral vasodilatation
  • Hypotension
  • Cardiogenic shock
  • Ventricular arrhythmias
  • Asystole
• CNS effects may include the following:
  • Drowsiness
  • Extrapyramidal signs
  • Rigidity
  • Ophthalmoplegia
  • Respiratory depression
  • Delirium
  • Seizure
  • Coma

Differential Diagnoses

Other Problems to Be Considered

Toxicity, Anticholinergic
Toxicity, Antihistamine
Toxicity, Antidysrhythmic
Toxicity, Clonidine
Toxicity, Cocaine
Toxicity, Monoamine Oxidase Inhibitor
Toxicity, Neuroleptic Agents
Toxicity, Phencyclidine
Cyclobenzaprine toxicity
Serotonin syndrome

Workup

Laboratory Studies

The following studies are indicated in cyclic antidepressant (CA) poisoning:

• Routine monitoring: CBC count, electrolyte levels (with determination of anion gap), urinalysis (UA), and urinary chorionic gonadotropin (UCG) levels should be routinely monitored in all patients with potential overdose.
• ABG: An arterial or venous blood sample should be sent to assess plasma pH. Cyclic antidepressant toxicity usually results in mixed acidosis due to respiratory depression coupled with hypotension caused by both myocardial depression and peripheral vasodilation, thus resulting in increased lactate production. Acidemia decreases protein binding and increases plasma levels of free drug. Therefore, correction of serum pH is a primary target of therapy in cyclic antidepressant overdose.
• Serum potassium level: Hypokalemia frequently occurs because of increased stimulation of catecholamine receptors due to blockage of norepinephrine reuptake. In one series, 9% of patients with tricyclic antidepressant (TCA) overdose had serum potassium levels of less than 3.
• Renal function tests: Cyclic antidepressant metabolites are excreted by the kidneys after hepatic metabolism by the cytochrome P450 system. Some of these metabolites are pharmacologically active, and impaired renal function may prolong or exacerbate toxicity.
• Toxicology screen: Because of the ubiquity of cyclic antidepressants and the lack of acute symptoms associated with cyclic antidepressant toxicity, serum acetaminophen levels should be routinely checked. A urine toxicology screen and screening for other potential co-ingestants (eg, ethanol, acetylsalicylic acid [ASA]) may be performed if indicated based on the clinical picture.
• Serum cyclic antidepressant level
  • Serum cyclic antidepressant levels are not readily available and not likely to be helpful in the immediate treatment of the patient with cyclic antidepressant poisoning. levels may be used to confirm suspected poisoning or give a rough estimate of overdose. However, levels do not correlate with toxic effects. This is due to the highly lipophilic nature of cyclic antidepressants and high degree of protein binding. A large volume of distribution means that tissue levels of cyclic antidepressant are often much higher than serum levels of free drug.
  • A recent meta-analysis of prognostic indicators to predict seizures, arrhythmias, and death in cyclic antidepressant overdose pooled data from 18 studies and found that the sensitivity and specificity of serum cyclic antidepressant concentration to predict ventricular arrhythmias were 0.78 (95% confidence interval [CI], 0.56-0.9) and 0.57 (95% CI, 0.46-0.67), respectively.⁷ The sensitivity and specificity of cyclic antidepressant concentration to predict death were 0.76 (95% CI, 0.49-0.91) and 0.6 (95% CI, 0.47-0.72), respectively.

Imaging Studies

• Chest radiography should be performed if a history or suspicion of aspiration is noted or to rule out other causes of fever, hypotension, or respiratory failure.
• Neuroimaging should also be considered for patients with altered mental status, especially if the history is unclear or if trauma is a potential comorbid contributor.

Other Tests

• ECG is useful as both a screening tool for cyclic antidepressant exposure and as a prognostic indicator in cyclic antidepressant poisoning.⁸
  
  

  

  Toxicity, antidepressant. ECG shows the terminal R wave in aVR and the widened QRS complex associated with tricyclic antidepressant (TCA) toxicity.

  
  
• The most common ECG finding in cyclic antidepressant poisoning is sinus tachycardia, usually due to peripheral anticholinergic effects. Other ECG changes that should be sought include prolongation of the PR, QRS, and QT intervals; atrioventricular (AV) blocks; ventricular ectopy; nonspecific ST-T changes; terminal 40-millisecond right-axis deviation of the QRS in the frontal plane; and the Brugada pattern, including right bundle branch block (RBBB) and a downsloping ST segment elevation in leads V₁ -V₃.
• Cyclic antidepressants block fast sodium channels in the myocardium and slow phase zero depolarization of the action potential. Ventricular depolarization is delayed, which leads to a prolonged QRS interval. QRS interval is evaluated best using the limb leads. Widening of the QRS complex is associated with the development of seizures and arrhythmias, and QRS duration in the limb leads can be used to assess the severity of cyclic antidepressant toxicity. Patients with a QRS of less than 100 milliseconds are unlikely to develop seizures and arrhythmias. When the QRS is more than 100 milliseconds, patients have a 34% chance of seizure and a 14% chance of serious arrhythmia. QRS complexes of more than 160 milliseconds have a 50% chance of developing ventricular arrhythmias.
• Cyclic antidepressants affect the right fascicle of the heart. The reason is unknown, but the effect can be observed as an exaggerated height of the R wave in lead aVR. A large R wave in lead aVR is a highly sensitive screening tool for cyclic antidepressant exposure. In addition, the amplitude of this R wave has been associated with increased risk of toxic effects. Data suggest that the finding of a large R wave in lead aVR may be even more predictive of seizure and arrhythmia than prolongation of the QRS complex. Liebelt et al found that an R wave of more than 3 mm in lead aVR was 81% sensitive and 73% specific for the development of seizures and arrhythmias.⁹

Procedures

• Gastric lavage: This may be indicated in cases in which a potentially significant ingestion is known to have occurred within 1 hour of presentation. In a study of 592 patients with TCA poisoning, Kulig et al showed that gastric lavage improved clinical outcome only when performed within 1 hour of ingestion.¹⁰ No evidence suggests that gastric lavage reduces morbidity and mortality if instituted outside of this time frame.
• Tracheal intubation
  • Clinical deterioration of symptomatic patients should be anticipated, and early intubation should be considered in these patients.
  • Patients should be intubated prior to gastric lavage.
  • Patients who are obtunded or comatose should be intubated for airway protection.
  • Elective intubation should be considered for symptomatic patients with poor cardiopulmonary reserve who may not be able to tolerate large fluid loads induced by fluid and sodium bicarbonate therapy. Early intubation with mild hyperventilation may be used to help alkalinize the serum in these patients.

Treatment

Medical Care

As always, the first priority in patients with cyclic antidepressant (CA) poisoning is to assess and treat ABCs as appropriate. Good supportive care is the mainstay of treatment in any overdose.

• Early intubation for patients with significant signs of toxicity, including seizures and CNS depression, is prudent. Patients who are obtunded and those with impending respiratory failure should clearly be intubated for airway protection and ventilatory support.
• Intravenous fluids should be started for patients who are hypotensive.
• Cardiac monitoring should be instituted as soon as possible because of the risk of arrhythmias in patients with cardiovascular toxicity.
• Seizures should be treated with benzodiazepines.
• If the patient is symptomatic, a Foley catheter should be placed to relieve urinary obstruction due to anticholinergic effects and to monitor the adequacy of fluid resuscitation.
• The patient should be examined for signs and symptoms of cyclic antidepressant toxicity, and ECG should be performed early to look for a terminal R wave in lead aVR and for prolongation of the QRS and QT intervals.
• Symptoms of cyclic antidepressant toxicity generally present within 2 hours of ingestion. Seizures and arrhythmias are most likely to occur in the first 6 hours after ingestion. All patients with suspected cyclic antidepressant ingestion should undergo cardiac monitoring for a minimum of 6-8 hours. Monitoring should continue in symptomatic patients until the ECG findings have been normal for 24 hours.
• Asymptomatic patients should be screened for suicidal intent and admitted to a psychiatric facility as appropriate after an observation period of at least 8 hours.
• Decontamination measures include the following:
  • Syrup of ipecac is contraindicated because of the high risk of aspiration if patients become symptomatic during emesis. Patients with exposures large enough to cause symptoms may have acute alterations in mental status due to either direct CNS effects (drowsiness, delirium, seizure) or hemodynamic instability.
  • Consider gastric lavage if the patient has a known or suspected significant ingestion that occurred within 1 hour of presentation. If a lavage is to be performed, the patient should be intubated first, and a dose of charcoal should be administered via the orogastric tube prior to lavage. The same amount, or more, of the ingested dose is propelled into the small intestine as is recovered during lavage, and this bolus is preferably mixed with an adsorbing substance.
  • Regardless of the decision to lavage, 1 g/kg of activated charcoal should be administered as soon as possible. Multidose charcoal may enhance elimination and should be considered.
  • Because of the large volume of distribution and high protein binding of cyclic antidepressants, hemodialysis and hemoperfusion are not effective in enhancing drug removal.
  • Tricyclic-specific fragment antigen–binding (FAB) fragments have been developed and may eventually play a role in the decontamination of patients with cyclic antidepressant poisoning. The FAB fragments have been shown to reverse cardiotoxicity in some animal studies, and a small preliminary study in humans demonstrated no significant side effects and some clinical improvement in patients with severe cyclic antidepressant poisoning.¹¹
• Hypotension should be initially treated with intravenous fluid boluses. Refractory hypotension should be treated with pressors. Agents with alpha-adrenergic effects should be chosen. Dopamine is not usually effective in these patients because it partially depends on the release of endogenous norepinephrine for its action. Cyclic antidepressants block reuptake of norepinephrine, and stores may be depleted in overdose. Animal studies have suggested that epinephrine may cause fewer arrhythmias than norepinephrine in this setting.
• Treatment of cardiac arrhythmias is as follows:
  • Cardiac arrhythmias should be treated according to the hemodynamic stability of the patient. Correction of hypoxia, hypotension and acidosis should be the first-line approach to conduction abnormalities
  • If antiarrhythmics are needed, class IA, class IC, class II, and class III drugs should be avoided. Like cyclic antidepressants, class IA and IC drugs block sodium channels and prolong depolarization and, therefore, may exacerbate their effects on the myocardium. Beta-blockers are likely to further depress myocardial contractility and cause worsening hypotension. Class III drugs prolong the QT interval and may increase the risk of a malignant ventricular arrhythmia.
  • However, class IB antiarrhythmics can increase the rate of phase zero depolarization, and phenytoin has been reported to correct conduction defects in at least one small series of patients. Several case reports of the use of magnesium and glucagons have suggested that these agents may correct ventricular arrhythmias in patients with severe cyclic antidepressant toxicity.
• Sodium bicarbonate therapy
  • Serum alkalinization with sodium bicarbonate is the mainstay of therapy in cyclic antidepressant overdose. Alkalinization of the serum to a pH level of 7.45-7.55 increases protein binding and has been shown to decrease the QRS interval, stabilize arrhythmias, and increase blood pressure in patients with tricyclic antidepressant (TCA) poisoning.
  • Sodium bicarbonate may also be beneficial in treating cyclic antidepressant overdose because of the high sodium load. Animal studies and some human case reports of treatment with hypertonic saline (without serum alkalinization) have shown similar effects on myocardial conduction parameters.¹² Therapy with hypertonic saline should be strongly considered in patients who are already alkalemic and in those who cannot tolerate the large volume load associated with intravenous bicarbonate administration.
  • Blood gases should be monitored for the development of acidosis. Sodium bicarbonate should be administered if the patient has a pH level of less than 7.1, QRS interval of more than 100 milliseconds, arrhythmias, or hypotension.
  • Bicarbonate should be administered as an initial bolus of 1-2 mEq/kg, followed by an infusion titrated to a QRS width of 100 milliseconds.
  • The serum pH should be closely monitored and should not be allowed to exceed 7.55. Serum potassium should also be closely monitored for the development of hypokalemia.
  • ECG should be monitored for the desired effect of QRS narrowing during and immediately after bolus therapy. The QTc interval should also be monitored because bicarbonate therapy may prolong the QTc. Case reports and an animal model suggest that the use of extracorporeal life support may be lifesaving in TCA overdoses that are refractory to advanced life-support measures and traditional therapies.
• All patients should be monitored for arrhythmias for at least 12 hours, and symptomatic patients should be admitted to an ICU setting.

Consultations

• The local poison control center or a clinical toxicologist should be consulted in all cases of suspected poisoning.
• A pediatric psychiatrist should be consulted if intentional ingestion is suspected.
• Child protective services should be notified if inadequate supervision or Münchhausen syndrome by proxy is suspected.

Medication

Cardiotoxicity

As discussed above, sodium bicarbonate therapy is the cornerstone of treatment for cyclic antidepressant (CA)-induced conduction disturbances, ventricular arrhythmias, and hypotension. Serum alkalinization to a pH of 7.45-7.55 appears to uncouple tricyclic antidepressant (TCA) from myocardial sodium channels, and the sodium load increases extracellular sodium concentration, improving the gradient across the channel.

Controlled studies have demonstrated that bicarbonate loading with an initial bolus of 1-2 mEq/kg of sodium bicarbonate is beneficial. Continuing a bicarbonate drip after the initial bolus, which is titrated to achieve a QRS width of 100 milliseconds, is accepted practice.

Ventricular arrhythmias that are refractory to sodium bicarbonate may require treatment with lidocaine, magnesium sulfate, or both. Class IA (eg, quinidine, procainamide, disopyramide) and class IC (eg, flecainide, propafenone) drugs are contraindicated because they may worsen sodium channel inhibition. Class III drugs (eg, amiodarone, bretylium, sotalol) are contraindicated because they can further prolong the QT interval, leading to ventricular arrhythmia. Class II beta-blockers (eg, propranolol, esmolol, metoprolol) and class IV calcium channel blockers (eg, verapamil, diltiazem, nifedipine, nicardipine) are contraindicated because they may potentiate or worsen hypotension.

Patients with hypotension refractory to fluid resuscitation and sodium bicarbonate require vasopressor support. Direct-acting alpha-agonists (eg, norepinephrine, phenylephrine) are most effective because severe hypotension is generally due to direct alpha1-blocking effects in these cases. Dopamine may not be as effective because its action is partially mediated by the release of endogenous catecholamines, and these may be depleted.

CNS toxicity

Seizures secondary to cyclic antidepressant toxicity are generally self-limiting but should be treated because the acidosis produced by vigorous muscle contraction and impaired ventilation during seizure activity may increase the concentration of free drug and increase toxicity.

Benzodiazepines are the agents of choice. Phenobarbital may also be used as a long-acting anticonvulsant.

Phenytoin is not recommended because it also blocks sodium channels and may exacerbate or cause dysrhythmias in a patient with cyclic antidepressant poisoning. Despite the fact that phenytoin has been reported to correct cardiac conduction defects in at least one small series of patients, it is still not recommended for seizure control.

Physostigmine is an acetylcholinesterase inhibitor that is contraindicated in patients with cyclic antidepressant overdoses. Although physostigmine was previously advocated for relief of anticholinergic effects, it may cause bradycardia and asystole in cyclic antidepressant cardiotoxicity.

Flumazenil, a benzodiazepine antagonist, is also contraindicated, even in the presence of benzodiazepine co-ingestion. Several case reports describe patients with concomitant cyclic antidepressant overdoses who had seizures after the administration of flumazenil.

Decontaminants

Activated charcoal is used to prevent drug absorption. Activated charcoal is not absorbed and is excreted entirely through the GI tract. It decreases the extent of cyclic antidepressant absorption from the GI tract, thereby reducing systemic toxicity.

Activated charcoal (Actidose-Aqua, Liqui-Char)

Network of pores present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. Binds TCAs present in GI tract, thereby limiting systemic absorption and hastening elimination.

Dosing

Adult

60-100 g PO/NG

Pediatric

1 g/kg PO/NG

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties)

Contraindications

Documented hypersensitivity; poisoning with or overdose of mineral acids and alkalies

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Not effective in poisonings with ethanol, methanol, and iron salts; induce emesis before administering activated charcoal; after emesis with ipecac syrup, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; gastric lavage return is black without sorbitol

Alkalinizing agents

Sodium bicarbonate remains the first-line therapy for cyclic antidepressant-induced cardiotoxicity. Sodium bicarbonate may have beneficial effects in the treatment of cyclic antidepressant-induced seizures, although data have been far less compelling. Prophylactic use is not indicated in a patient who displays no signs of cardiotoxicity. Sodium bicarbonate provides a source of sodium and alkali, both of which are useful in cyclic antidepressant overdose.

Sodium bicarbonate

DOC in limiting cardiovascular morbidity in TCA overdoses.

Dosing

Adult

Initial bolus: 1-2 mEq/kg IV push over 1-2 min; not to exceed 100 mEq/dose
Follow-up infusion: 100-150 mEq in 1 L D5/0.45% NaCl infused 100-200 mL/h IV; titrate infusion to achieve blood pH of 7.45-7.55

Pediatric

Prepare infusion as in adults; infuse at 1.5- to 2-times maintenance fluid requirements

Interactions

Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine

Contraindications

Documented hypersensitivity; alkalosis, hypernatremia, hypocalcemia, severe pulmonary edema, and abdominal pain of unknown origin

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor closely for development of severe metabolic alkalosis, hypernatremia, hypokalemia, or hypocalcemia; leftward shift of oxyhemoglobin dissociation curve; tissue necrosis with extravasation

Vasopressors

These agents are indicated for persistent hypotension that is unresponsive to fluid resuscitation and sodium bicarbonate.

Norepinephrine (Levophed)

DOC for calcium-induced hypotension refractory to fluid or sodium bicarbonate. Stimulates beta1-adrenergic and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases.

Dosing

Adult

Refractory hypotension: 0.5-30 mcg/min continuous IV infusion; titrate to effect

Pediatric

0.05-1 mcg/kg/min continuous IV infusion; titrate to effect

Interactions

Calcium antagonists, MAOIs, antihistamines, guanethidine, ergot alkaloids, and methyldopa may potentiate norepinephrine effects

Contraindications

Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia and area of infarction may be increased

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Correct blood-volume depletion, if possible, before administering norepinephrine therapy; extravasation may cause severe tissue necrosis and, thus, should be administered into large veins; caution in occlusive vascular disease

Phenylephrine (Neo-Synephrine)

Strong postsynaptic alpha-receptor stimulant with little beta-adrenergic activity that produces vasoconstriction of arterioles in the body. Increases peripheral venous return.

Dosing

Adult

1-4 mcg/kg/min (range 20-200 mcg/min) continuous IV infusion

Pediatric

0.1-0.5 mcg/kg/min continuous IV infusion; titrate to effect

Interactions

Bretylium may potentiate action of vasopressors on adrenergic receptors, possibly resulting in arrhythmias; MAOIs may significantly enhance adrenergic effects of phenylephrine, and pressor response may be increased 2-3 fold; guanethidine may increase pressor response of direct-acting vasopressors, possibly resulting in severe hypertension

Contraindications

Documented hypersensitivity; severe hypertension; ventricular tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Central venous infusion strongly recommended because of significant risk of ischemic or extravasation injury when infused peripherally; caution in hyperthyroidism, myocardial disease, bradycardia, partial heart block, or severe arteriosclerosis; in hypovolemia, is not substitute for replacement of blood, fluids, electrolytes, and plasma (these should be restored promptly when loss has occurred)

Inotropic agents

Positive inotropic agents increase the force of contraction of the myocardium and are used to treat acute and chronic congestive heart failure. Some may also increase or decrease the heart rate (ie, positive or negative chronotropic agents), provide vasodilatation, or improve myocardial relaxation.

These agents are indicated for hypotension that is unresponsive to fluid, sodium bicarbonate, and norepinephrine therapy and is believed to be caused by myocardial depression.

Dopamine

Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on the dose. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation are produced by higher doses.
After initiating therapy, increase dose by 1-4 mcg/kg/min q10-30min until optimal response is obtained. Satisfactory maintenance is obtained using doses of <20 mcg/kg/min in more than 50% of patients.
In TCA cardiotoxicity, higher starting doses should be initiated to avoid unopposed beta effects.
Not usually effective in these patients because it partially depends on the release of endogenous norepinephrine for its action.

Dosing

Adult

10-20 mcg/kg/min continuous IV infusion

Pediatric

Administer as in adults

Interactions

Phenytoin, alpha-adrenergic and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects of dopamine

Contraindications

Documented hypersensitivity; pheochromocytoma or ventricular fibrillation

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Central venous infusion is strongly recommended because of significant risk of ischemic or extravasation injury when infused peripherally; closely monitor urine flow, cardiac output, and blood pressure during infusion; correct hypovolemia before infusion; monitoring central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia

Dobutamine (Dobutrex)

Strong beta1-agonist producing excellent inotropy. Weak beta2-agonist that produces mild-to-moderate peripheral vasodilation.

Dosing

Adult

2-20 mcg/kg/min continuous IV infusion; titrate to effect

Pediatric

Administer as in adults

Interactions

Beta-adrenergic blockers antagonize effects of dobutamine; general anesthetics may increase toxicity

Contraindications

Documented hypersensitivity; idiopathic hypertrophic subaortic stenosis and atrial fibrillation or flutter

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Use with extreme caution and only with appropriate pharmacologic alpha-stimulation (norepinephrine or phenylephrine); central venous infusion strongly recommended; hypovolemic state should be corrected before therapy

Antiarrhythmic agents

Sodium bicarbonate is the initial and most effective drug for the treatment of cyclic antidepressant-induced conduction disturbances and arrhythmias. Lidocaine and magnesium sulfate should be reserved for arrhythmias that are unresponsive to alkalization and sodium loading.

Lidocaine (Xylocaine)

Class IB antiarrhythmic that increases electrical stimulation threshold of the ventricle, suppressing automaticity of conduction through the tissue.
Second-line treatment for CA-induced arrhythmias. Alkalinization and sodium loading must be attempted before the use of any antiarrhythmic for CA-induced cardiotoxicity.

Dosing

Adult

1-1.5 mg/kg IV push initially; followed by 1-4 mg/min continuous IV infusion; titrate to effect

Pediatric

1-1.5 mg/kg IV push initially; followed by 20-50 mcg/kg/min continuous IV infusion; titrate to effect

Interactions

Coadministration with cimetidine or beta-blockers increases toxicity of lidocaine; coadministration with procainamide and tocainide may result in additive cardiodepressant action; may increase effects of succinylcholine

Contraindications

Documented hypersensitivity; avoid in Adams-Stokes syndrome and Wolf-Parkinson-White syndrome; avoid in severe sinoatrial, AV, or intraventricular block if artificial pacemaker is not in place

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Use solution without preservatives; caution in heart failure, hepatic disease, hypoxia, hypovolemia or shock, respiratory depression, and bradycardia; may increase risk of adverse CNS and cardiac effects in elderly persons; high plasma concentrations can cause seizures, heart block, and AV conduction abnormalities

Magnesium sulfate

Prevents calcium influx. Also activates sodium-potassium ATPase, thus affecting sodium and potassium transport across cell membranes, which can facilitate the maintenance of the resting potential. May be of particular use in patients with torsade de pointes type of ventricular tachycardia.

Dosing

Adult

1-2 g IV diluted in 10 mL of D5W administered over 1-2 min

Pediatric

25-50 mg/kg/dose IV diluted in 10 mL of D5W administered over 1-2 min; not to exceed 2 g/dose

Interactions

Concurrent use with nifedipine may cause hypotension and neuromuscular blockade; may increase neuromuscular blockade observed with aminoglycosides and potentiate neuromuscular blockade produced by tubocurarine, vecuronium, and succinylcholine; may increase CNS effects and toxicity of CNS depressants and betamethasone and cardiotoxicity of ritodrine

Contraindications

Documented hypersensitivity; heart block; Addison disease; myocardial damage; severe hepatitis

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Magnesium may alter cardiac conduction, leading to heart block in patients taking digitalis; respiratory rate, deep tendon reflex, and renal function should be monitored when electrolyte is administered parenterally; caution when administering magnesium dose because may produce significant hypertension or asystole; in overdose, calcium gluconate, 10-20 mL IV of 10% solution, can be administered as antidote for clinically significant hypermagnesemia

Anticonvulsant agents

These agents are used to prevent seizures and terminate clinical and electrical seizure activity.

Lorazepam (Ativan)

Sedative and anticonvulsant that may be effective in controlling CA-induced agitation or seizures. By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of the CNS, including limbic and reticular formation.

Dosing

Adult

2-4 mg/dose IV slowly over 2-5 min, may repeat in 10-15 min prn; not to exceed cumulative dose of 8 mg

Pediatric

0.1 mg/kg IV slowly over 2-5 min, may repeat prn in 10-15 min at 0.05 mg/kg; not to exceed cumulative dose of 4 mg

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Use with caution in patients with hypotension or respiratory depression; health care providers must be prepared to manage airway and breathing

Diazepam (Valium, Diastat)

Depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Sedative and anticonvulsant that may be effective in controlling CA-induced agitation or seizures.

Dosing

Adult

5-15 mg IV q5min, repeat prn; not to exceed 30 mg/8 h

Pediatric

0.05-0.3 mg/kg/dose IV over 2-3 min q15-30min; not to exceed cumulative dose of 10 mg/2-4 h; may repeat q2-4h prn
Diastat rectal gel:
<2 years: Not established
2-5 years: 0.5 mg/kg PR
6-11 years: 0.3 mg/kg PR
>12 years: 0.2 mg/kg PR

Interactions

Increases toxicity of benzodiazepines in CNS with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity)

Phenobarbital (Luminal)

In status epilepticus, achieving therapeutic levels as quickly as possible is important. IV dose may require approximately 15 min to attain peak levels in the brain. If injected continuously until convulsions stop, brain concentrations may continue to rise and can exceed that required to control seizures. Important to use minimal amount required and to wait for anticonvulsant effect to develop before administering a second dose.

Dosing

Adult

300-800 mg IV followed by 120-240 mg/dose at 20-min intervals until seizures are controlled or cumulative dose of 1-2 g is administered

Pediatric

15-20 mg/kg over 10-15 min IV in single or divided dose
Some patients may require 5 mg/kg/dose IV q15-30min until seizure is controlled or cumulative dose of 40 mg/kg is administered

Interactions

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if regimen is added to or withdrawn); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of PO contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy; menstrual irregularities may occur)

Contraindications

Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritis

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema

Follow-up

Further Inpatient Care

• Patients with severe CNS toxicity or any cardiotoxicity should be admitted to an ICU setting. Patients should be monitored for at least 24 hours after the ECG findings normalize and alkalinization therapy is stopped.
• All patients with suspected or confirmed cyclic antidepressant (CA) overdose should be admitted for cardiac monitoring for at least 12-24 hours. Patients may be admitted to a non-ICU ward for telemetry monitoring if they have persistent signs of mild-to-moderate anticholinergic toxicity (ie, resting tachycardia, mydriasis, behavioral changes, hyperthermia) without serious CNS or cardiac manifestations.
• Patients with suspected overdose should be screened for suicidal behavior and admitted to a psychiatric facility, if indicated, once they are medically cleared.
• Children with unintentional overdose should be admitted if inadequate supervision in the home is suspected or if adequate follow-up cannot be assured.

Further Outpatient Care

• Patients may be discharged from the emergency department (ED) if the ingestion was unintentional, if no signs or symptoms of cyclic antidepressant toxicity are evident during a minimum observation of 6-8 hours, if the parents are reliable, and if appropriate follow-up is assured.

Transfer

• All serious pediatric cyclic antidepressant overdoses should be admitted to a pediatric ICU. Transfer may be indicated after the patient has been stabilized if the treating hospital has no such facility.

Deterrence/Prevention

• Prevention remains the first line of defense against all pediatric ingestions. Important prevention measures include child-resistant packaging of all medications, proper storage of medications in the home, education of parents and children as to the risks and proper use of medications, and easy access to poison control center information.

Prognosis

• Approximately 70% of intentional cyclic antidepressant overdoses may be fatal prior to arrival in the ED. However, among patients who present for medical treatment, serious complications are rare compared with the total number of toxic ingestions, and in-hospital mortality is as low as 2-3%. With early recognition and aggressive treatment, a good outcome can be expected.

Patient Education

• For excellent patient education resources, visit eMedicine's Poisoning - First Aid and Emergency Center, Substance Abuse Center, and Mental Health and Behavior Center. Also, see eMedicine's patient education articles Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.

Miscellaneous

Medicolegal Pitfalls

• Failure to anticipate a rapid deterioration in a patient with cyclic antidepressant (CA) poisoning
• Failure to intubate an unstable patient or to manage the airway properly during decontamination
• Failure to recognize anticholinergic symptoms or a newly onset ventricular arrhythmia as signs of cyclic antidepressant poisoning
• Failure to administer sodium bicarbonate in a timely fashion

Multimedia

Media file 1: Toxicity, antidepressant. ECG shows the terminal R wave in aVR and the widened QRS complex associated with tricyclic antidepressant (TCA) toxicity.

References

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Keywords

cyclic antidepressant, cyclic antidepressant toxicity, CA toxicity, CA overdose, CA poisoning, CA, tricyclic antidepressant toxicity, TCA, TCA overdose, TCA toxicity, TCA poisoning, antidepressant overdose, antidepressant toxicity, antidepressant poisoning

Contributor Information and Disclosures

Author

Samara Soghoian, MD, MA, Clinical Assistant Professor of Emergency Medicine, New York University School of Medicine, Bellevue Hospital Center
Samara Soghoian, MD, MA is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Christopher I Doty, MD, FACEP, FAAEM, Assistant Professor of Emergency Medicine, Residency Program Director, Department of Emergency Medicine, Kings County Hospital Center, State University of New York Downstate Medical Center
Christopher I Doty, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, Council of Emergency Medicine Residency Directors, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Frank A Maffei, MD, FAAP, Associate Professor of Pediatrics, Temple University School of Medicine; Director of Medical Student Affairs, Geisinger Health System; Pediatric Critical Care Attending Physician, Janet Weis Children's Hospital at Geisinger Medical Center
Frank A Maffei, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Heidi Connolly, MD, Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center
Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

Medical Editor

Michael E Mullins, MD, Assistant Professor, Department of Emergency Medicine, Washington University School of Medicine
Michael E Mullins, MD is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Emergency Physicians
Disclosure: Johnson & Johnson stock ownership None; Savient Pharmaceuticals stock ownership None

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut and Connecticut Children's Medical Center
Jeffrey R Tucker, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Pediatrics, and Massachusetts Medical Society
Disclosure: Merck Salary Employment

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Timothy E Corden, MD is a member of the following medical societies: American Academy of Pediatrics, Phi Beta Kappa, Society of Critical Care Medicine, and Wisconsin Medical Society
Disclosure: Nothing to disclose.

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