AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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-hyperactivity disorder, school phobia, and separation anxiety. The most commonly prescribed CAs include amitriptyline, desipramine, imipramine, nortriptyline, doxepin, and clomipramine.

CAs have a low threshold 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 CAs. However, CAs remain second only to analgesics as the most common drugs implicated in overdose fatalities. Some evidence suggests that CAs are associated with more overdose fatalities per number of prescriptions issued than other antidepressant classes.

Pathophysiology

CAs are named for their 3- 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. CAs are very lipophilic and highly protein-bound, resulting in large volumes of distribution. They have long elimination half-lives that often exceed 24 hours (>31-46 h for amitriptyline). In overdose, altered pharmacokinetics may prolong elimination and increase toxic effects. CAs 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 CAs 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 CAs 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 CAs 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 CA toxicity are due to CNS effects and cardiovascular instability. Depressed mental status is generally caused by the antihistamine and anticholinergic properties of CAs, while 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. CAs have also been shown to directly depress myocardial contractility. However, the profound hypotension seen in serious CA 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. CA 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, CAs 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

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

Sex

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

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The history 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 (CAs) may vary. For example, amoxapine is associated with a higher incidence of seizures, while maprotiline is more likely to be cardiotoxic. Both dothiepin and amitriptyline have been shown to have greater toxicity than the other CAs.
• 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 CAs. Anticholinergic effects are typically the first to appear and should raise clinical suspicion of CA overdose.

• 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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• 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.
• Arterial blood gas: An arterial or venous blood sample should be sent to assess plasma pH. Cyclic antidepressant (CA) 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 CA 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 TCA overdose had serum potassium levels of less than 3.
• Renal function tests: CA 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 CAs and the lack of acute symptoms associated with CA 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 CA level
• • Serum CA levels are not readily available and not likely to be helpful in the immediate treatment of the patient with CA 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 CAs and high degree of protein binding. A large volume of distribution means that tissue levels of CA are often much higher than serum levels of free drug.
  • A recent meta-analysis of prognostic indicators to predict seizures, arrhythmias, and death in CA overdose pooled data from 18 studies and found that the sensitivity and specificity of serum CA concentration to predict ventricular arrhythmias were 0.78 (95% CI, 0.56-0.9) and 0.57 (95% CI, 0.46-0.67), respectively. The sensitivity and specificity of CA 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.

Other Tests

• Electrocardiography is useful as both a screening tool for CA exposure and as a prognostic indicator in CA poisoning.
• The most common ECG finding in CA 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.
• CAs 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 CA 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.
• CAs 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 CA exposure. In addition, the amplitude of this R wave has been associated with increased risk of toxic effects. Recent 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.

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. 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

As always, the first priority 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 (CA) toxicity, and echocardiography 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 CA 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 CA 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
• • 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 CAs, 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 CA 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 CA poisoning.
• 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. CAs 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
• • 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 CAs, 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 CA toxicity.
• Sodium bicarbonate therapy
  • Serum alkalinization with sodium bicarbonate is the mainstay of therapy in CA 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 TCA poisoning.
  • Sodium bicarbonate may also be beneficial in treating CA 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.
  • 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.
• 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 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.

Central nervous system toxicity

Seizures secondary to CA 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 CA poisoning.

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

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

Drug Category: 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 CA absorption from the GI tract, thereby reducing systemic toxicity.

Drug Category: Alkalinizing agents

Sodium bicarbonate remains the first-line therapy for CA-induced cardiotoxicity. Sodium bicarbonate may have beneficial effects in the treatment of CA-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 CA overdose.

Drug Category: Vasopressors

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

Drug Category: Inotropic agents

Positive inotropic agents increase the force of contraction of the myocardium and are used to treat acute and chronic CHF. 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.

Drug Category: Antiarrhythmic agents

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

Drug Category: Anticonvulsant agents

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 accidental, if no signs or symptoms of CA 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 CA 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 CA 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 low. With early recognition and aggressive treatment, only about 2-3% of CA poisoned patients die.

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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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 CA poisoning
• Failure to administer sodium bicarbonate in a timely fashion

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bailey B, Buckley NA, Amre DK. A meta-analysis of prognostic indicators to predict seizures, arrhythmias or death after tricyclic antidepressant overdose. Journal of Toxicology: Clinical Toxicology. 2004;42(6):877-889.
• Boehnert MT, Lovejoy FH Jr. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med. Aug 22 1985;313(8):474-9. [Medline].
• Callaham M, Kassel D. Epidemiology of fatal tricyclic antidepressant ingestion: implications for management. Ann Emerg Med. Jan 1985;14(1):1-9. [Medline].
• Chyka PA, Seger D. Position statement: single-dose activated charcoal. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1997;35(7):721-41. [Medline].
• Ellenhorn MJ. Ellenhorn's Medical Toxicology. 2nd ed. Baltimore, Md:. Williams & Wilkins;1997:624-36.
• Farrar HC, James LP. Characteristics of pediatric admissions for cyclic antidepressant poisoning. Am J Emerg Med. Sep 1999;17(5):495-6. [Medline].
• Goodwin DA, Lally KP, Null DM Jr. Extracorporeal membrane oxygenation support for cardiac dysfunction from tricyclic antidepressant overdose. Crit Care Med. Apr 1993;21(4):625-7. [Medline].
• Heard K, Dart RC, Bogdan G, et al. A preliminary study of tricyclic antidepressant (TCA) ovine FAB for TCA toxicity. Clin Toxicol (Phila). 2006;44(3):275-81. [Medline].
• James LP, Kearns GL. Cyclic antidepressant toxicity in children and adolescents. J Clin Pharmacol. Apr 1995;35(4):343-50. [Medline].
• Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emergency Medicine Journal. 2001;18:236-241.
• Liebelt EL, DeAngelis CD. Evolving trends and treatment advances in pediatric poisoning. JAMA. Sep 22-29 1999;282(12):1113-5. [Medline].
• Liebelt EL, Ulrich A, Francis PD, Woolf A. Serial electrocardiogram changes in acute tricyclic antidepressant overdoses. Crit Care Med. Oct 1997;25(10):1721-6. [Medline].
• Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. Ann Emerg Med. Aug 1995;26(2):195-201. [Medline].
• Liebelt EL, Shanon M. Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal role for alkalinization and sodium loading. Pediatr Emerg Care. Aug 1998;14(4):293-8. [Medline].
• Newton EH, Shih RD, Hoffman RS. Cyclic antidepressant overdose: a review of current management strategies. Am J Emerg Med. May 1994;12(3):376-9. [Medline].
• Pentel PR, Keyler DE. Clinical Management of Poisoning and Drug Overdose. 3rd ed. Philadelphia:. WB Saunders Co;1998:437-49.
• Pimentel L, Trommer L. Cyclic antidepressant overdoses. A review. Emerg Med Clin North Am. May 1994;12(2):533-47. [Medline].
• Reith D, Fountain J, Tilyard M, McDowell R. Antidepressant poisoning deaths in New Zealand for 2001. N Z Med J. Oct 24 2003;116(1184):U646. [Medline].
• Teba L, Schiebel F, Dedhia HV, Lazzell VA. Beneficial effect of norepinephrine in the treatment of circulatory shock caused by tricyclic antidepressant overdose. Am J Emerg Med. Nov 1988;6(6):566-8. [Medline].
• Tenenbein M. Position statement: whole bowel irrigation. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1997;35(7):753-62. [Medline].
• Vale JA. Position statement: gastric lavage. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1997;35(7):711-9. [Medline].
• Watson WA, Litovitz TL, Rodgers GC. 2004 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Toxicology. 2005;589-666.
• Weisman RS, Goldfrank LR, Flomenbaum NE, eds. Goldfrank's Toxicologic Emergencies. 6th ed. McGraw-Hill Professional Publ;1998:925-33.

Article Last Updated: Nov 3, 2006