Tricyclic Antidepressant Toxicity in Pediatrics Treatment & Management

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:

• The ingestion was unintentional
• No signs or symptoms of cyclic antidepressant toxicity are evident during observation for a minimum of 6-8 hours
• The parents are reliable
• Appropriate follow-up is assured

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.

 

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] : 

• A 20% lipid emulsion is administered as a 1.5 ml/kg bolus over 2-3 minutes.
• This is followed by an infusion at 0.25 ml/kg/min. After 3 minutes of this infusion rate, response to the bolus and initial infusion should be assessed.
• If there has been a significant response, the infusion rate may be adjusted to 0.025 mL/kg/min (i.e., 1/10 the initial rate). 
• Blood pressure, heart rate, and other available hemodynamic parameters should be recorded at least every 15 minutes during the infusion. 
• If there is an initial response to the bolus followed by the re-emergence of instability during the lowest-dose infusion, the infusion rate could be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated.
• There is no known maximal dose, but other authors have suggested a maximum dose of 10 mL/kg.

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 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]

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 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