Tricyclic Antidepressant Toxicity in Pediatrics 

Updated: Apr 22, 2016
Author: Derrick Lung, MD, MPH; Chief Editor: Timothy E Corden, MD 

Overview

Background

Cyclic antidepressants (CAs) have been used in the treatment of major depression since the late 1950s. Originally termed tricyclic antidepressants (TCAs), they are more accurately called cyclic antidepressants because some newer members of this class have a four-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 the following:

The most commonly prescribed cyclic antidepressants include the following:

  • Amitriptyline
  • Desipramine
  • Imipramine
  • Nortriptyline
  • Doxepin
  • Clomipramine

Cyclic antidepressants have a narrow therapeutic window, which increases 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 few decades, the prescription of selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression has far surpassed that of cyclic antidepressants. However, the decreased use of cyclic antidepressants for depression has in part been attenuated by expanded applications for these agents, such as treatment of chronic pain syndromes.

In fact, according to poison center data, cyclic antidepressants continue to contribute disproportionately to mortality for antidepressant overdoses. For example, the American Association of Poison Control Centers reported that in 2014, tetracyclic and tricyclic antidepressants accounted for 5724 of the 46,517 single exposures to antidepressants (12%), but for 13 of the 32 deaths (41%).[1]

Pathophysiology

Cyclic antidepressants are named for their three-ring or four-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 toxic effects of cyclic antidepressants are related to the following four 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 dysrhythmias 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.

Epidemiology

United States

The 2013 American Association of Poison Control Centers (AAPCC) annual report on toxic exposures in the United States included 46,517 single exposures to antidepressants and 111,985 case mentions. Of single exposures, 5724 were due to tetracyclic and tricyclic antidepressants, with 13 related deaths. Single exposures to cyclic antidepressants were reported in 1819 pediatric patients. Of cases in which the patient's age was known, 799 occurred in children younger than 6 years, 242 in those 6 to 12 years old, and 776 occurred in teenagers.[1]

Mortality/Morbidity

According to poison center data, cyclic antidepressants toxicity contribute disproportionately to mortality from antidepressant exposures. Although cyclic antidepressants accounted for approximately 12% of reported single exposures to antidepressants in 2013, they accounted for approximately 49% of deaths (20 of 41 total deaths).[1] Cyclic antidepressants were the most common cause of overdose-related fatalities until the 1990s, 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.

 

Presentation

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 (not available in the United States) and amitriptyline have been shown to have greater toxicity than the other cyclic antidepressants.[6]

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 Examination

Physical examination findings relate to the anticholinergic, cardiovascular, and central nervous system (CNS) effects of cyclic antidepressants. Anticholinergic effects are typically the first to appear and should raise clinical suspicion of cyclic antidepressant overdose. One suggested aid to help identify and recall severe CA toxicity is the mnemonic "S-A-L-T" (ie, shock, altered mental status, long-QRS interval duration, terminal R wave in aVR).[7]

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 QRS and QT intervals

  • Heart block

  • Peripheral vasodilatation

  • Hypotension

  • Cardiogenic shock

  • Ventricular dysrhythmias

  • Asystole

CNS effects may include the following:

  • Drowsiness

  • Extrapyramidal signs

  • Rigidity

  • Ophthalmoplegia

  • Respiratory depression

  • Delirium

  • Seizure

  • Coma

 

DDx

 

Workup

Laboratory Studies

As in all patients with potential overdose, the following should be routinely monitored in cases of cyclic antidepressant (CA) poisoning:

  • Complete blood cell count (CBC)

  • Electrolyte levels (with determination of anion gap)

  • Urinalysis (UA)

  • Urine or serum pregnancy test (in females of childbearing age)

Arterial blood gas (ABG) testing is also indicated. Cyclic antidepressant toxicity usually results in mixed acidosis due to respiratory depression coupled with hypotension from 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 pH is a primary target of therapy in cyclic antidepressant overdose.

In addition, because of the ubiquity of cyclic antidepressants and the lack of acute symptoms associated with cyclic antidepressant toxicity, serum acetaminophen and salicylate levels should be routinely checked. Further serum and/or urine toxicology screening for other potential co-ingestants (eg, ethanol) may be performed if indicated based on the clinical picture.

Serum cyclic antidepressant level

Serum cyclic antidepressant levels are typically available through reference and research laboratories only, and thus are not available for at least several days, well after the peak of toxicity. Therefore, levels may only be used to retrospectively confirm suspected poisoning or give a rough estimate of overdose.

However, serum levels do not correlate with toxic effects. This is due to the highly lipophilic nature of cyclic antidepressants and high degree of protein binding. Because of the large volume of distribution, tissue levels of cyclic antidepressant are often much higher than serum levels of free drug.

In fact, a meta-analysis of 18 studies of prognostic indicators in cyclic antidepressant overdose found that prolongation of the QRS interval on the electrocardiogram had pooled sensitivity and specificity similar to that of serum cyclic antidepressant concentrations in predicting dysrhythmias, seizures, and death. Both measures had relatively poor predictive performance, however.[8]

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.

Electrocardiography

An electrocardiogram (ECG) is useful as both a screening tool for cyclic antidepressant exposure and as a prognostic indicator in cyclic antidepressant poisoning.[9] See the image below.

Toxicity, antidepressant. ECG shows the terminal R 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. Early ECG changes that suggest significant, evolving toxicity include prolongation of the QRS complex and QT interval; terminal 40-millisecond (msec) right-axis deviation of the QRS in aVR; and the Brugada pattern, including right bundle branch block (RBBB) and a downsloping ST segment elevation in V1-V3. Later ECG changes can include atrioventricular (AV) blocks, ectopy, and ventricular dysrhythmias.

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 dysrhythmias, 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 msec are unlikely to develop seizures and dysrhythmias. When the QRS is more than 100 msec, patients have a 34% chance of seizure and a 14% chance of serious dysrhythmia. Patients with QRS complexes of more than 160 msec have a 50% chance of developing ventricular dysrhythmias.

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 aVR. A large R wave in aVR is a highly sensitive screening tool for cyclic antidepressant exposure. Liebelt et al found that the finding of a large R wave in aVR had better test characteristics than any particular QRS length. In this study, an R wave of more than 3 mm in aVR was 81% sensitive and 73% specific for the development of seizures and dysrhythmias.[10]

 

Treatment

Medical Care

During initial evaluation and stabilization, clinicians should bear in mind that symptoms of cyclic antidepressant (CA) toxicity generally appear within 2 hours of ingestion. Severe signs of toxicity, such as seizures and dysrhythmias, usually occur within the first 6 hours after ingestion.

As with any overdose, good supportive care is the mainstay of treatment in patients with cyclic antidepressant poisoning, and the first priority is to assess and treat any abnormalities in airway, breathing, and circulation (the ABCs). Early intubation for patients with significant signs of toxicity, including seizures and central nervous system (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 dysrhythmias. An electrocardiogram (ECG) should be performed early to look for a large terminal R wave in aVR, and for prolongation of the QRS and QT intervals, which confirm significant cyclic antidepressant exposure and consequent risk for seizures and dysrhythmias. If seizures do occur, they should be initially treated with benzodiazepines.

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, which is a sign of cyclic antidepressant drug effect that is not necessarily indicative of toxicity, and for prolongation of the QRS and QT intervals, which is more ominous and is possibly indicative of toxin-induced sodium channel blockade.

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 6 hours.

Decontamination

Decontamination measures include activated charcoal administration and possibly gastric lavage.[48]

Activated charcoal

If the patient's airway protective reflexes are intact, 1 g/kg of activated charcoal should be administered as soon as possible. Multidose charcoal may enhance elimination and should be considered. Charcoal should be withheld in patients who are obtunded or seizing because the risk of aspiration may outweigh the benefits of charcoal.[47]

Gastric lavage

Consider gastric lavage if the patient has a known or suspected significant ingestion that occurred within 1 hour of presentation.[11] However, a 2013 position paper by the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists notes that only weak evidence supports gastric lavage as a beneficial treatment, even in special situations.[12]

In addition, the potential benefit of gastric lavage needs to be weighed against its potential adverse events, such as vomiting, aspiration, and esophageal perforation. Also, the position paper advises that in the rare instances in which lavage is indicated, it should be performed only by personnel with proper training and expertise[12] —and as the use of gastric lavage has precipitously decreased over the last two decades, there are likely very few health care personnel with experience and comfort performing the procedure.

Management of Seizures

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 be used as a long-acting anticonvulsant. Phenytoin and other electrolyte-channel modulating antiepileptics have traditionally been considered third-line for drug-induced seizures.

Management of Cardiovascular Toxicity

Hypotension should be initially treated with intravenous fluid boluses. Vasopressors should be started for refractory hypotension. Agents with alpha-adrenergic effects should be chosen.

Dopamine is not usually effective in these patients because its mechanism of action partially depends on the release of endogenous norepinephrine. Cyclic antidepressants block reuptake of norepinephrine, and stores may be depleted in overdose. Animal studies have suggested that epinephrine may cause fewer dysrhythmias than norepinephrine in this setting.

Sodium bicarbonate, given in boluses of 1-2 mEq/kg, is the first-line treatment for severe cardiotoxicity (eg dysrhythmia, conduction disturbance), in order to overcome cardiac sodium channel blockade. Sodium bicarbonate should also be given when the QRS duration is >120 msec, since a prolonged QRS is a portent of severe cardiotoxicity. An adequate dose will result in rapid shortening of the QRS duration. There is no absolute maximum dose threshold.

The ECG should be monitored for the desired effect of QRS narrowing during and immediately after bolus therapy, and then subsequent QRS widening for ongoing or recrudescent cardiotoxicity. 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.

Serum alkalinization with sodium bicarbonate is adjunctive 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 dysrhythmias, and increase blood pressure in patients with cyclic antidepressant poisoning. Caution is advised, as some patients may not be able to tolerate the fluid load.

Hypertonic saline may be carefully considered as an alternative to sodium bicarbonate. Animal studies and some human case reports of treatment with hypertonic saline (without serum alkalinization) have shown similar effects on myocardial conduction parameters.[13] 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.

Adjunctive treatment of cardiac dysrhythmias

Cardiac dysrhythmias should be treated according to the hemodynamic stability of the patient. Correction of hypoxia, hypotension, and acidosis should be attempted in conjunction with other pharmacologic interventions. Sodium bicarbonate therapy should be initiated in such patients (see above).

Lidocaine is the only recommended antiarrhythmic.[14] As a class Ib antiarrhythmic, it exhibits fast on-off sodium channel binding, in contrast to class Ia and Ic antiarrhythmics. Cardiac sodium channel recovery time for class Ib antiarrhythmics is rapid (< 1 second), compared to class Ia (1-10 seconds) and class Ic (>10 seconds) antiarrhythmics. Competitive binding at cardiac sodium channels by lidocaine against cyclic antidepressants (believed to exhibit class Ia effects) is thought to mitigate cardiac toxicity and dysrhythmias.

Magnesium has also been suggested as an adjunct for refractory ventricular dysrhythmias.[37, 15]

Other antiarrhythmic medications are less ideal. Like cyclic antidepressants, class Ia and Ic drugs block sodium channels and prolong depolarization and, therefore, may exacerbate the effects of cyclic antidepressants on the myocardium. Beta-blockers and calcium-channel blockers (class II and IV) 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 dysrhythmia.

All patients should be monitored for dysrhythmias for at least 12 hours. Patients with signs of severe toxicity (eg altered mental status, hypotension, prolonged QRS duration, seizures, etc) should be admitted to an intensive care unit setting.

Enhanced Elimination

Dialysis has no known role for dialysis except for patients with renal failure. Cyclic antidepressants are lipophilic and exhibit high protein-binding, thus are generally poor candidates for extracoporal removal. However, successful use of charcoal hemoperfusion for life-threatening amitriptyline poisoning has been reported.[16]

Lipid Emulsion Therapy

There is increasing enthusiasm for use of lipid emulsion therapy (LET) as a potential nonspecific antidote for poisonings due to lipophilic toxicants. Originally established as an antidote for local anesthetic toxicity, LET has been reportedly used with variable success in some published cases of CA toxicity.[17] In particular, there are two published pediatric cases (an intentional, self-harm ingestion of amitriptyline by a 13-year-old, and a large exploratory ingestion of dothiepin by a 20-month-old) in which ventricular tachycardia was converted to sinus tachycardia within minutes of instituting LET.[18, 19]

Current dosing recommendations have been provided by the American College of Medical Toxicologists.[20] A 20% lipid emulsion is administered as a 1.5 ml/kg bolus over 2-3 minutes. This is followed by a continuous infusion at 0.25 ml/kg/min, which should be discontinued when the patient’s condition has stabilized.

Published experience indicates that if LET is going to be effective, then rapid and noticeable clinical improvement (eg, return of spontaneous circulation, termination of malignant dysrhythmia) should follow the initial bolus. If no effect is noted, an immediate second bolus may be considered. If there is still no observable response, further doses should not be considered unless the patient is in extremis.

LET does have several major drawbacks. For one, its mechanism of action is unclear. The most popular explanation is the “lipid sink” theory, which proposes that by introducing a new intravascular lipid “compartment,” lipophilic drugs will be attracted to the intravascular space and pulled away from target sites (eg, brain, heart).

Early reports that demonstrate rather marked increases in blood levels of drugs after receiving LET supported this theory.[21] However, animals models show that LET is more accurately a “conduit for redistribution.” Animal models demonstrate that toxicants are redistributed among body sites.[22]

Thus, the logical, unanswered question is, Can LET cause harmful, rather than therapeutic, drug redistribution? The potential effects of redistribution of a toxicant into a more problematic end-organ site ought to be considered. Also, providers must weigh the potential effects of redistribution of therapeutic medications that critical patients are actively receiving. Fortunately, vasopressors have little lipophilicity and so should be minimally affected by LET. However, other common resuscitative medications (eg, amiodarone) are very lipophilic, and the possibility of reversing their therapeutic effects must be considered.[23]

Secondly, a number of case series and registries have suggested a range of possible adverse reactions.[24, 25] Clearly, LET causes a hypertriglyceridemia that can sometimes render laboratory blood/serum measurements uninterpretable for up to 12 hours. Some patients sustain a pancreatitis (by elevated lipase and amylase measurements) of unclear clinical significance. Other reported possible adverse effects (eg, acute respiratory distress syndrome [ARDS]) are not clearly distinct from patients’ critical illness.

Finally, optimal (for therapy and safety) dosing is unknown. The original dosing strategy for local anesthetic toxicity continues to be used universally. It is unknown whether (and if so, how) age, body weight, toxicant, or other factors should modify dosing.

Consultations

Recommended consultations are as follows:

  • The regional 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

Medication Summary

Activated charcoal is used to prevent drug absorption. Pharmacologic therapy in patients with cyclic antidepressant (CA) toxicity is directed toward cardiac and central nervous system (CNS) effects of these drugs.

Cardiotoxicity

Sodium bicarbonate therapy is the cornerstone of treatment for cyclic antidepressant–induced conduction disturbances, ventricular dysrhythmias, and hypotension. The sodium load increases extracellular sodium concentration, improving the gradient across the sodium channel, and serum alkalinization to a pH of 7.45-7.55 appears to uncouple cyclic antidepressants from myocardial sodium channels.

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 dysrhythmias that are refractory to sodium bicarbonate may require treatment with lidocaine (class Ib), magnesium sulfate, or both. Class Ia antidysrhythmic drugs (eg, quinidine, procainamide, disopyramide) and class Ic drugs (eg, flecainide, propafenone) are contraindicated because they may worsen sodium channel inhibition.

Class III drugs (eg, amiodarone, sotalol) are contraindicated because they can further prolong the QT interval, leading to ventricular dysrhythmia. 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

Benzodiazepines are the agents of choice for treatment of CNS toxicity from cyclic antidepressants. Phenobarbital may also be used as a long-acting anticonvulsant. Phenytoin and other electrolyte-channel modulating antiepileptics have traditionally been considered third-line for drug-induced seizures.

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 patients with 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

Class Summary

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.

Alkalinizing agents

Class Summary

Sodium bicarbonate remains the first-line therapy for cyclic antidepressant-induced cardiotoxicity (eg dysrhythmia, conduction disturbance). 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.

Vasopressors

Class Summary

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.

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.

Inotropic agents

Class Summary

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.

Dobutamine (Dobutrex)

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

Antiarrhythmic agents

Class Summary

Sodium bicarbonate is the initial and most effective drug for the treatment of cyclic antidepressant-induced conduction disturbances and dysrhythmias. Lidocaine and magnesium sulfate should be reserved for dysrhythmias 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.

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.

Anticonvulsant agents

Class Summary

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.

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.

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.

 

Follow-up

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.

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.

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 the following:

  • 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

  • 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 patient education information, see the First Aid and Injuries Center and Mental Health Center, as well as Poisoning, Drug Overdose, Activated Charcoal, and Poison Proofing Your Home.