Tricyclic Antidepressant Toxicity in Pediatrics

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Practice Essentials

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. Cyclic antidepressants have a narrow therapeutic window, which increases their likelihood for toxicity.[1]

In 2018, the US Food and Drug Administration (FDA) issued a public health advisory that directed manufacturers of all antidepressant drugs, including TCAs, to revise the labeling for their products to include a boxed warning and expanded warning statements alerting health care providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents.[2]

The risk of suicidality associated with these drugs was identified based on a combined analysis of short-term (up to 4mo), placebo-controlled trials of 9 antidepressant drugs in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients on drug therapy was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.[2]

On the basis of those data, the FDA determined that the following points are appropriate for inclusion in the boxed warning[2] :

Only fluoxetine (Prozac) is FDA approved for use in treating major depressive disorder (MDD) in pediatric patients. The selective serotonin reuptake inhibitors (SSRIs) Prozac, sertraline (Zoloft), and fluvoxamine (Luvox) and the cyclic antidepressant clomipramine (Anafranil) are approved for OCD in pediatric patients. None of the drugs is approved for other psychiatric indications in children.[2]

In the past few decades, the prescription of 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 the pediatric population, they are commonly prescribed for the treatment of the following:

The most commonly prescribed cyclic antidepressants include the following:

Onset of symptoms of cyclic antidepressant toxicity typically occurs within 2 hours and typically begins with antimuscarinic effects. Major cardiovascular and central nervous system (CNS)  complications typically occur within the first 6 hours after exposure. See Presentation and Workup. Pharmacologic therapy in patients with CA toxicity is directed toward the cardiac and CNS effects. Sodium bicarbonate therapy is the cornerstone of treatment for cyclic antidepressant–induced conduction disturbances, ventricular dysrhythmias, and hypotension. See Treatment and Medication.

For patient education information, see First Aid for Poisoning in Children and Child Safety Proofing.

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 antimuscarinic 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:

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 antimuscarinic 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.  Fast sodium channel blockade may also contribute to development of seizures.

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

The 2018 annual report of the American Association of Poison Control Centers National Poison Data System(AAPCC-NPDS) reported 1521 tetracyclic and 3969 tricyclic antidepressant exposures (from a total of 56,891 antidepressant single exposures). Of tetracyclic and tricyclic antidepressant exposures combined, 3500 occurred in adults age 20 years and older; 915 occurred in adolescents aged 13-19 years, and 675 ocurred in children younger than 6 years. The lowest number of exposures (228) were seen in children aged 6-12.[4]

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. 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.

Prognosis

Cyclic antidepressants contribute disproportionately to mortality for antidepressant overdoses. The American Association of Poison Control Centers reported that in 2018, tetracyclic and tricyclic antidepressants accounted for 5490 of the 56,891 single exposures to antidepressants (10%), but for 25 of the 50 deaths (50%).[4]

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.

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,[5]  and skin hyperpigmentation.[6]  Some of these ADRs may be responsible for the increased risk of falls, with associated morbidity, seen among elderly patients taking cyclic antidepressants. A prospective cohort study noted an association between cyclic antidepressant use and an increased risk of coronary heart disease.[7]

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.[8]

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. Onset of symptoms typically occurs within 2 hours, and major complications typically occur within the first 6 hours after exposure. 

A history can be taken from the patient, if possible, witnesses, or family members. Details about the possible source of ingestion, past medical history, and co-ingestion of alcohol or illicit drugs should be elicited. [9]  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.[10]

 

Physical Examination

Physical examination findings relate to the antimuscarinic, cardiovascular, and central nervous system (CNS) effects of cyclic antidepressants. Antimuscarinic 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).[3]

A targeted physical examination should assess the patient’s vital signs, and a brief neurologic assessment should include pupillary response and a gross motor and sensory examination. Classic symptoms of antimuscarinic syndrome include mydriasis, delirium, dry skin, fever, and flushing. Other antimuscarinic effects may include the following[9] :

Cardiorespiratory assessment and evaluation of the skin for temperature, moisture, and track marks can be done. Cardiovascular effects may include the following[9] :

CNS effects may include the following[9] :

Laboratory Studies

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

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 to serum acetaminophen levels, obtaining serum salicylate levels can also be considered. Further serum and/or urine toxicology screening for other potential co-ingestants (eg, ethanol) may be performed if indicated based on the clinical picture. Urine drug screens should not be routeinly obtained as they do not change clinical management. Serum and urine cyclic antidepressant screens are available but are notorious for false positives, including from cyclobenzaprine and diphenhydramine, and have not been shown to have clinical utility.[31]

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.[11]

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.[12] See the image below.



View Image

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 antimuscarinic 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.[13]

Approach Considerations

As with any overdose, good supportive care is the mainstay of treatment and the first priority is to assess and treat any abnormalities in airway, breathing, and circulation (the ABCs). The rapid onset of toxicity from cyclic antidepressant exposures can not be overstated. 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.

During initial evaluation and stabilization, clinicians should bear in mind that symptoms of cyclic antidepressant 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. 

All patients with suspected cyclic antidepressant ingestion should undergo cardiac monitoring for a minimum of 6 hours. Monitoring should continue in symptomatic patients such as those with electrocardiogram (ECG) changes, tachycardia, or mental status changes until the clinical findings have returned to baseline and ECG changes have resolved. Patients may be admitted to a non-ICU ward for telemetry monitoring if they have persistent signs of mild-to-moderate antimuscarinic toxicity (ie, resting tachycardia, mydriasis, behavioral changes, hyperthermia) without serious CNS or cardiac manifestations.

An ECG is 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. Prolongation of the QRS and development of an R wave in avR are concerning findings and indicative of toxin-induced sodium channel blockade. These changes confirm significant cyclic antidepressant exposure and consequent risk for seizures and dysrhythmias. If seizures do occur, they should be initially treated with benzodiazepines with consideration for sodium bicarbonate therapy.

Patients with severe CNS toxicity or any cardiotoxicity should be admitted to an ICU setting. Patients should be monitored for at least 24 hours until the ECG findings normalize and alkalinization therapy is stopped. Patients with suspected intentional overdose should be screened for suicidal behavior and admitted to a psychiatric facility, if indicated, once they are medically cleared.

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. Patients may be discharged from the emergency department (ED) if they meet all of the following criteria:

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. Children with unintentional overdose should be admitted if inadequate supervision in the home is suspected or if adequate follow-up cannot be assured.

 

Medical Care

Decontamination

Decontamination measures, such as activated charcoal administration and possibly gastric lavage, may have theoretical benefit but the rapid onset of cyclic antidepressant toxicity limits real-life utility.[14]

Activated charcoal

While theoretically beneifical,  activated charcoal should not routinely be used due to the risk of rapid onset of toxicity and aspiration.[15]   It should be administerd only under direct supervision of a medical toxicologist or a poison control center, with assurance of airway control.

Gastric lavage

Gastric lavage should never be used routinely and should only be considered under direct supervision of a medical toxicologists or poison control center.  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.[17]

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 cyclic antidepressant toxicity.[18]  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 (dosulepin; a tricyclic antidepresssant available in a number of countries outside the United States) by a 20-month-old—in which ventricular tachycardia was converted to sinus tachycardia within minutes of instituting LET.[19, 20]

Current dosing recommendations have been provided by the American College of Medical Toxicologists as follows[21] : 

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.[22]  However, animals models show that LET is more accurately a “conduit for redistribution.” Animal models demonstrate that toxicants are redistributed among body sites.[23]

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.[24]

Secondly, a number of case series and registries have suggested a range of possible adverse reactions.[25, 26]  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.

 

Management of Complications

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.  Intravenous sodium bicarbonate therapy may be considered as an adjunct to benzodiazepine or barbiturates. Phenytoin should be avoided owing to possible interaction.[9]  

Management of cardiovascular complications

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 1-3 mEq/kg, is the first-line treatment for severe cardiotoxicity (eg dysrhythmia, conduction disturbance), in order to overcome cardiac sodium channel blockade.[1] Sodium bicarbonate should also be given when the QRS duration is >120 msec or the R wave in aVR is greater than 3 mm, as these are markers 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.[27] 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). Temporary pacemakers have been used to treat refractory symptomatic bradycardias not responsive to sodium bicarbonate.[1]  

Lidocaine is the only recommended antiarrhythmic.[28] 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.[29, 30]

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.

Serotonin syndrome

Serotonin syndrome, characterized by mental status changes, neuromuscular dysfunction, and autonomic instability, is thought to be secondary to excessive serotonin activity in the spinal cord and brain. Myoclonus is the most common finding in serotonin syndrome and is rare in other conditions that can mimic this condition.

The risk of serotonin syndrome is increased by the addition of a second serotonergic agent, especially agents with monoamine oxidase inhibition property. Therefore, clinicians need to be more vigilant in cases of concomitant ingestion of cyclic antidepressants and SSRIs or SNRIs or MOAI. Accidental ingestion by toddlers and illicit drug use in adolescents (methylenedioxymethamphetamine [MDMA], or ecstasy) are important pediatric considerations.

Most patients with serotonin syndrome return to baseline in 24 hours with supportive care, removal of the precipitating drug, and treatment with benzodiazepines.[9]

Consultations

The regional poison control center or a medical 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.

Prevention

Prevention remains the first line of defense against all pediatric ingestions. Important prevention measures include the following:

Medication Summary

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 1-3 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 widely practiced but not supported by medical evidence.

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. Sodium bicarbonate therapy may also have benefit as the fast sodium channel blockade is thought to contribute to developement of seizures. Phenytoin and other electrolyte-channel modulating antiepileptics have traditionally been considered third-line for drug-induced seizures.

Physostigmine is an acetylcholinesterase inhibitor who use in patients with cyclic antidepressant overdoses in controversial. Although physostigmine is very effective in treating the antimuscarinic effects of the cyclic antidepressants it has no benefit for the life threatening cardiac complications.  It should only be used under direct supervision of a medical toxicologists or poison control center.

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

Activated charcoal (Actidose-Aqua, Liqui-Char)

Clinical Context:  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.

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.

Sodium bicarbonate

Clinical Context:  DOC in limiting cardiovascular morbidity in TCA overdoses.

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.

Norepinephrine (Levophed)

Clinical Context:  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)

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

Class Summary

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

Dopamine

Clinical Context:  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)

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

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.

Lidocaine (Xylocaine)

Clinical Context:  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

Clinical Context:  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.

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.

Lorazepam (Ativan)

Clinical Context:  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)

Clinical Context:  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)

Clinical Context:  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.

Class Summary

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

Author

Derrick Lung, MD, MPH, Physician, Department of Emergency Medicine, San Mateo Medical Center; Assistant Clinical Professor, Division of Clinical Pharmacology, Department of Medicine, San Francisco General Hospital; Assistant Medical Director, California Poison Control System, San Francisco Division

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Jeffrey R Tucker, MD, Assistant Professor, Department of Pediatrics, Division of Emergency Medicine, University of Connecticut School of Medicine, Connecticut Children's Medical Center

Disclosure: Received salary from Merck for employment.

Chief Editor

Stephen L Thornton, MD, Associate Clinical Professor, Department of Emergency Medicine (Medical Toxicology), University of Kansas Hospital; Medical Director, University of Kansas Hospital Poison Control Center; Staff Medical Toxicologist, Children’s Mercy Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Michael E Mullins, MD, Assistant Professor, Division of Emergency Medicine, Washington University in St Louis School of Medicine; Attending Physician, Emergency Department, Barnes-Jewish Hospital

Disclosure: Received stock ownership from Johnson & Johnson for none; Received stock ownership from Savient Pharmaceuticals for none.

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

Disclosure: Nothing to disclose.

Acknowledgements

Heidi Connolly, MD Associate Professor of Pediatrics and Psychiatry, University of Rochester School of Medicine and Dentistry; 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.

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, 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; Medical Director, Pediatric Intensive Care Unit, Janet Weis Children's Hospital at Geisinger Health System

Frank A Maffei, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

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.

Rashida Y White-McCrimmon, MD Resident Physician, Department of Emergency Medicine, Kings County Hospital Center, State University of New York Downstate Medical Center

Rashida Y White-McCrimmon, MD is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and Emergency Medicine Residents Association

Disclosure: Nothing to disclose.

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

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