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Decisions regarding referral to the emergency department (ED) must take into account factors such as patient age, intent of exposure, symptoms, as well as timing of exposure. All patients with MAOI exposures who display suicidal intent should be referred to an ED for evaluation. Children with exposure to even one adult formulation MAOI tablet or selegiline patch should be referred to the ED due to the potential for late-onset significant toxicity.3 Patients who exhibit more than mild headache or minimal diaphoresis following an acute MAOI ingestion should be referred to an ED. Observation at home is warranted in patients who are asymptomatic and more than 24 hours have elapsed since the time of ingestion. Due to paucity of data at this time, patients with selegiline patch ingestion should be referred to the ED for observation, even if suicidal intent is absent.
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Induction of emesis is not recommended.3 Activated charcoal can be administered to asymptomatic patients who have ingested overdoses of MAOI if no contraindications are present.2 Transportation to the hospital should not be delayed in order to administer activated charcoal. Use of intravenous benzodiazepines for seizures and external cooling measures for severe hyperthermia (> 106°F {> 41.1°C})107 should be performed in consultation or authorization with medical direction from emergency medical services, by a written treatment protocol or policy, or with direct medical oversight.
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Initial Approach in the Emergency Department
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As with any serious ingestion, initial stabilization must include rapid assessment of the airway, breathing, and circulation as well as establishment of intravenous access, supplemental oxygen, and cardiac monitoring. Evidence of hyperthermia or hemodynamic instability following MAOI ingestion may be a manifestation of significant toxicity. Intravenous volume repletion should begin while gastrointestinal decontamination is considered. In any patient with altered mental status who will likely deteriorate progressively, early orotracheal intubation may facilitate safe gastric decontamination measures. Subsequent management should focus on stabilization of hyperthermia, seizures, and muscular rigidity.
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Gastrointestinal Decontamination
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Patients who overdose with MAOIs are more likely to benefit from gastrointestinal decontamination than most other overdose patients because of their high potential for morbidity and mortality.59,89 Orogastric lavage with a large bore orogastric tube (36–40 French) should be considered if a life-threatening ingestion is suspected to have occurred within several hours prior to presentation.39,59,89 Single-dose activated charcoal should be orally administered for ingestions presenting within several hours, unless contraindications are present. Whole bowel irrigation with oral polyethylene glycol electrolyte solution likely has limited utility unless there are coingestions with other sustained-release preparation medications. The lack of early clinical findings of poisoning should not dissuade the use of gastrointestinal decontamination given the potential for delayed clinical deterioration.
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Severe hyperthermia must be treated with aggressive cooling. Use of ice baths (first choice for life-threatening hyperthermia),110 cold water, and fans are the mainstay of treatment (Chap. 30). There is no available evidence to support use of invasive cooling devices (ie, catheter based) or noninvasive devices such as cooling blankets. Indications for ice bath immersion to treat MAOI toxicity include rectal temperature greater than 106°F (41.1°C),107 rigidity, and altered mental status. Benzodiazepines help control muscular rigidity, seizures, and agitation that may contribute to amelioration of hyperthermia and tachycardia. Patients with refractory hyperthermia despite the above measures may require neuromuscular blockade, using nondepolarizing paralytics, in conjunction with tracheal intubation and ventilation. The depolarizing paralytic succinylcholine should be avoided in severe MAOI toxicity due to the risk of precipitating lethal dysrhythmia due to hyperkalemia in the setting of rhabdomyolysis. Neuromuscular blockade eliminates hyperthermia that results from muscular rigidity, and can be employed if first-line treatments are unsuccessful. Antipyretics such as acetaminophen are unlikely to be efficacious because the hyperthermia is not due to alterations in the hypothalamic temperature set point.107
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Blood Pressure Control
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Because there is characteristic fluctuation in vital signs associated with MAOI overdose, hemodynamic monitoring should be instituted even for patients who initially are stable. When supporting the patient’s blood pressure, preference should be given to titratable drugs with a rapid onset and termination of action because of the potential for rapid hemodynamic changes. Use of β-adrenergic antagonists is contraindicated for control of hypertension in MAOI-related toxicity because the action of monoamines (eg, norepinephrine) at the neuronal synapse in the autonomic nervous system could result in refractory hypertension due to unopposed α-adrenergic agonism.95
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Patients who are normotensive at baseline and who experience MAOI-related severe hypertension can be treated with a short-acting α-adrenergic antagonist such as phentolamine (intravenous 2–5 mg) for effective control.12 Other therapies such as nitroprusside and nitroglycerin may be preferred because they allow for titratable blood pressure control.21 Tyramine-related hypertensive crises can successfully be controlled with the dihydropyridine calcium channel blockers such as nifedipine and possibly the oral α-adrenergic antagonists such as terazosin but should be used with caution.20,48 Particular caution must be exercised in patients with baseline hypertension because overly aggressive blood pressure lowering may reduce cerebral perfusion pressure sufficiently to cause cerebral ischemia.
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Patients who are hypotensive may require aggressive support with intravenous fluid resuscitation and vasopressors. Direct-acting sympathetic agents (eg, epinephrine, norepinephrine) can be used safely in patients taking MAOIs.14 Rather than causing release of a stored pool of norepinephrine, these xenobiotics bind directly with postsynaptic α- and β-adrenergic receptors.
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Dopamine is contraindicated in hypotensive patients who have overdosed on MAOIs for several reasons. The indirect action of dopamine administration may produce a synergistic effect with MAOI, resulting in excessive adrenergic activity and exaggerated rises in blood pressure. In addition, most of the α-adrenoceptor mediated vasoconstriction of dopamine is secondary to norepinephrine release; in the presence of MAOIs, norepinephrine synthesis may be impaired from concomitant dopamine-β-hydroxylase inhibition, and dopamine may not reliably raise blood pressure if cytoplasmic and vesicular neuronal stores have been depleted. Finally, in the presence of impaired norepinephrine release or α-adrenergic blockade by any cause, unopposed dopamine-induced vasodilation from action on peripheral dopamine and β adrenoceptors may paradoxically lower blood pressure further.
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Due to the unique pharmacologic and toxicokinetic considerations of MAOI toxicity, adherence to advance cardiac life support protocols may not provide optimal results.4 In any stable patient, removal of the offending xenobiotic as well as correction of hypoxia, hypokalemia, and hypomagnesemia, if present, is a rational initial step.
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Patients with immediately life-threatening dysrhythmias require rapid cardioversion. In the presence of the nonperfusing dysrhythmias such as ventricular fibrillation, pulseless ventricular tachycardia, and torsade de pointes unsynchronized electrical defibrillation is the treatment of choice.
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Stable patients with ventricular tachycardia may benefit from a trial of antidysrhythmic drugs such as amiodarone or lidocaine. High-quality studies evaluating the use of these xenobiotics in the setting of MAOI overdose are not available.
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Hemodynamically significant supraventricular tachycardia from MAOI toxicity should be corrected to prevent myocardial ischemia or infarction, ventricular dysrhythmia, and high-output heart failure. Benzodiazepines are safe and effective to treat sinus tachycardia, as long as respiratory status remains monitored. Adenosine and synchronized cardioversion are unlikely to be useful in the setting of ongoing presence of the MAOI, but may be considered in rare cases that are unresponsive to benzodiazepines. In patients with borderline hypotension, nondihydropyridine calcium-channel antagonists such as diltiazem and verapamil are relatively contraindicated because they may further lower blood pressure.
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Hemodynamically significant bradycardia from MAOI toxicity may be refractory to standard advance cardiac life support protocols. An initial approach with intravenous fluid and atropine is a rational first-line therapy to temporize the patient with bradycardia and hypotension. Epinephrine and isoproterenol may also be administered while a pacemaker (transcutaneous or transvenous) is considered.
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Management of CNS Manifestations
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In acute altered mental status, hypoglycemia should be rapidly excluded.15,102 Mild to moderate CNS excitation may be treated with small incremental doses of parenteral diazepam. Seizures should be treated with benzodiazepines such as lorazepam in standard incremental doses. Empiric administration of pyridoxine (vitamin B6), intravenously at 70 mg/kg, up to 5 g in adults should be considered in patients with status epilepticus, particularly following massive ingestions of hydrazide-derived MAOIs such as phenelzine which may deplete endogenous pyridoxine stores (Antidotes in Depth: A14).115 Theoretically, phenytoin is not likely to be useful for treatment of MAOI-induced seizures because there is no distinct seizure focus, but rather generalized neuronal dysfunction in the presence of MAOI (and metabolites) in the CNS.
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Cyproheptadine is a nonselective serotonin antagonist that is recommended as third-line therapy (after benzodiazepine administration and cooling measures) for MAOI-induced serotonin toxicity.13 Cyproheptadine prevents lethality in animal models of serotonin toxicity79 and reportedly is beneficial in humans although its efficacy has not been rigorously established.38,44 It should be strongly considered when the diagnosis of serotonin toxicity is likely, especially if incomplete response has been achieved with aggressive cooling and benzodiazepine therapy.62 In addition, its use to treat neuromuscular rigidity and hyperthermia associated with MAOI overdose has been reported.10,25
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The recommended initial dose in adults is 12 mg orally, to be followed by 2 mg every 2 hours while symptoms continue.13 A dose of 12 to 32 mg will bind 85% to 95% of serotonin receptors.54 The dose of cyproheptadine used to treat the serotonin toxicity may cause sedation, but this effect is a goal of therapy and should not deter clinicians from using the drug. Relative contraindications to its use include acute asthma exacerbation, GI obstruction, and age less than 2 years (due to lack of safety information for this age group).
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Use of dantrolene in patients with serotonin toxicity is not recommended (Antidotes in Depth: A21). Case reports citing its utility with off-label usage probably involved misdiagnosis.13,53 Malignant hyperthermia, for which dantrolene is actually indicated, is a disease that is completely unrelated to serotonin toxicity. In animal models of serotonin toxicity, dantrolene administration has no effect on survival.51,79 In addition, dantrolene has been implicated in the fatality of one case of serotonin toxicity.56
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Extracorporeal Elimination
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The utility of extracorporeal measures, such as hemodialysis, to treat MAOI toxicity remains to be demonstrated. The ability to dialyze a xenobiotic depends largely on its protein binding the volume of distribution. Unfortunately, data regarding protein binding and volumes of distribution of the first-generation MAOI drugs such as isocarboxazid are not well characterized. Use of peritoneal dialysis67 and hemodialysis71 to treat MAOI overdose has been reported in the literature. However, time to resolution of symptoms for all cases did not differ (~ 24 hours) from those in which hemodialysis was not employed. Therefore, extracorporeal elimination is not recommended in the management of MAOI overdose unless other indications are present such as severe acidemia or life-threatening hyperkalemia, or the need to eliminate dialyzable toxic coingestions.
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Recommendations for the ideal time frame for observation of patients with suspected MAOI overdose are limited by a paucity of relevant studies in the clinical toxicology literature. Patients with presumed MAOI (selective or nonselective) overdose should be observed with telemetry monitoring, preferably in an intensive care unit, for at least 24 hours regardless of the initial clinical findings. This recommendation takes into account the potential for delayed-onset of clinical toxicity as well as the potential for severe morbidity and mortality.70,72,96 However, patients with MAOI–food or MAOI–xenobiotic interactions may not require hospital admission if the interaction is mild, resolution of symptoms is complete, and the patient has been observed for 4 to 8 hours.