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SEROTONIN SYNDROME

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Serotonin syndrome is a disorder that can be caused by the use of drugs or combinations of drugs that increase serotonin availability. It most often occurs when 2 or more drugs that increase serotonin availability by different mechanisms are used simultaneously. Similarly, the more severe cases tend to result from drug interactions, especially when an MAOI is involved. The syndrome may develop after therapeutic use or overdose.

Specific Substances

    A) GENERAL TERMS
    1) AMPHETAMINES, HALLUCINOGENIC
    2) AMPHETAMINES, METHOXY DERIVATIVES
    3) AMPHETAMINES, METHYLENEDIOXY DERIVATIVES
    4) C & M (SLANG FOR COCAINE AND HEROIN)
    5) C & M (SLANG FOR COCAINE AND MORPHINE)
    6) CARBAMAZEPINA (MEXICAN)
    7) CG 315 E
    8) DIBENZ(B,F)-AZEPINE-5-CARBOXAMIDE (ANTICONVULSANT)
    9) DROPERIDOL
    10) DU-2300
    11) K-315
    12) LAEVO-DOPA
    13) LU-10-171
    14) LYSERGIC ACID DIETHYLAMIDE (LSD)
    15) METHOXYLATED AMPHETAMINES
    16) NIH 7958
    17) NITALAPRAM
    18) NITALOPRAM
    19) NSC 107438
    20) PENTAZOCINE (WITH TRIPELENNAMINE)
    21) SYNDROME, SEROTONIN
    22) TRAMADOL HYDROCHLORIDE
    23) U-26225A
    24) WATER (SLANG FOR METHEDRINE, IN SOLUTION, USED INTRAVENOUSLY)
    25) WIN 20228
    DRUGS THAT INCREASE SEROTONIN SYNTHESIS
    1) L-tryptophan
    DRUGS THAT DECREASE SEROTONIN METABOLISM - MONAMINE OXIDASE INHIBITORS
    1) Moclobemide (reversible inhibitor)
    2) Isocarboxazid
    3) Linezolid
    4) Phenelzine
    5) Selegiline (selective for MAO-B)
    6) Tranylcypromine
    DRUGS THAT INCREASE SEROTONIN RELEASE
    1) Amphetamine
    2) Cocaine
    3) Dexfenfluramine
    4) Fenfluramine
    5) Methylenedioxymethamphetamine (MDMA)
    6) Mirtazapine
    7) Phentermine
    8) Reserpine
    DRUGS THAT INHIBIT SEROTONIN REUPTAKE - SELECTIVE SEROTONIN REUPTAKE INHIBITORS
    1) Citalopram
    2) Fluoxetine
    3) Fluvoxamine
    4) Paroxetine
    5) Sertraline
    DRUGS THAT INHIBIT SEROTONIN REUPTAKE - TRICYCLIC ANTIDEPRESSANTS
    1) Amitriptyline
    2) Clomipramine
    3) Desipramine
    4) Doxepin
    5) Imipramine
    6) Nortriptyline
    7) Protriptyline
    OTHER SEROTONIN UPTAKE INHIBITORS
    1) Amphetamine
    2) Cocaine
    3) Dextromethorphan
    4) Duloxetine
    5) Meperidine (pethidine)
    6) Methylenedioxymethamphetamine (MDMA)
    7) Nefazodone
    8) Tramadol
    9) Trazodone
    10) Venlafaxine
    DIRECT SEROTONIN RECEPTOR AGONISTS
    1) Buspirone
    2) Lysergic acid diethylamide
    3) Hallucinogenic amphetamines such as:
    4) 4-Methyl-2,5-dimethoxyamphetamine (DOM)
    5) 4-Bromo-2,5-dimethyoxyamphetamine (DOB)
    6) Almotriptan
    7) Avitriptan
    8) Eletriptan
    9) Frovatriptan
    10) Naratriptan
    11) Rizatriptan
    12) Sumatriptan
    13) Zolmitriptan
    NONSPECIFIC INCREASE IN SEROTONIN ACTIVITY
    1) Electroconvulsive Therapy
    2) Lithium
    DOPAMINE AGONISTS
    1) Amantadine
    2) Bromocriptine
    3) Bupropion
    4) REFERENCES: (Bergeron et al, 2005; Fisher & David, 2002; Demers & Malone, 2001; Chan et al, 1998; Roxanas & Machado, 1998; Dike, 1997; Kudo et al, 1997; Richard et al, 1997; Reynolds, 1996; Levy et al, 1996; Bastani et al, 1996; Benazzi, 1996; Fink, 1996; Fischer, 1995; Mills, 1995; Price et al, 1992; Sandyk, 1986)
    OTHER DRUGS WHICH HAVE BEEN IMPLICATED IN SEROTONIN SYNDROME
    1) Ademetionine
    2) Brompheniramine
    3) Carbamazepine
    4) Carisoprodol
    5) Codeine
    6) Dextropropoxyphene
    7) Dihydroergotamine
    8) Droperidol
    9) Fentanyl
    10) Levodopa
    11) Metaxalone (infrequent)
    12) Methadone
    13) Methylene Blue
    14) Metoclopramide
    15) Pentazocine
    16) Phenylpropanolamine
    17) Sumatriptan
    18) REFERENCES: (Surmaitis et al, 2015; Ramsay et al, 2007; Bramness et al, 2005; Fisher & David, 2002; Demers & Malone, 2001; Egsieker et al, 2000; Mason et al, 2000; Heard et al, 1999; Mason & Blackburn, 1997; John et al, 1997; Rao, 1997; Brazelton et al, 1997; Dike, 1997; Mathew et al, 1996; Fink, 1996; Sporer, 1995; Reeves & Bullen, 1995; Gillman, 1995)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) BACKGROUND: Serotonin syndrome is a potentially lethal adverse drug reaction that results from excessive central and peripheral serotonergic activity and is characterized by a triad of altered mental status, neuromuscular abnormalities, and autonomic instability, such as hyperthermia. Up to 60% of patients with serotonin syndrome develop symptoms and present for care within 6 hours of initial medical use, overdose, or change in dosing.
    B) PHARMACOLOGY: Serotonin syndrome results from excessive stimulation of central and peripheral nervous system serotonin receptors, namely 5-hydroxytryptamine (HT)-1A and 5-HT-2A. It may occur with drug interactions, therapeutic dosing, or deliberate self-harm.
    C) TOXICOLOGY: Pro-serotonergic drugs interact in at least 4 ways to account for excessive serotonin activation at 5-HT-1A and 5-HT-2A receptors: 1) deceased serotonin breakdown (eg, MAOIs); 2) decreased serotonin reuptake (eg, SSRIs, cocaine, dextromethorphan, meperidine, and serotonin norepinephrine reuptake inhibitors); 3) increased serotonin precursors or agonists (eg, L-tryptophan, LSD); and 4) increased serotonin release (eg, amphetamines, ecstasy, buspirone, lithium).
    D) EPIDEMIOLOGY: Serotonin syndrome occurs in approximately 15% to 20% of patients who overdose on SSRIs as single agents and may occur more commonly with serotonergic drug interactions.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Serotonin syndrome has been reported uncommonly in overdose of single agents (eg, fluvoxamine, venlafaxine, citalopram, and escitalopram) but usually occurs following interaction of 2 or more pro-serotonergic drugs. Serotonin drug effects may be seen in approximately 30% of patients starting SSRIs. Symptoms are milder than the full serotonin syndrome and may include jitteriness or anxiety syndrome (ie, agitation, anxiety, hyperactivity, irritability, and mania or hypomania).
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Serotonin syndrome comprises a continuum of clinical manifestations ranging from mild to life-threatening. Common manifestations are akathisia, tremor, altered mental status, inducible clonus, sustained clonus, muscular hypertonicity, and hyperthermia. The classic clinical triad is altered mental status, neuromuscular abnormalities (rigidity), and autonomic instability (eg, hypertension, tachycardia, hyperthermia). A patient with serotonin syndrome is more likely to present with hyperreflexia and myoclonus rather than "lead pipe" rigidity that develops in neuroleptic malignant syndrome. MILD cases may show subtle findings, such as tachycardia, shivering, diaphoresis, mydriasis, and no fever. MODERATE cases may show tachycardia, hypertension, hyperthermia (up to 40 degrees C), hyperactive bowel sounds, diaphoresis, hyperreflexia, clonus (greater in the lower extremities than upper), horizontal ocular clonus, and mild agitation.
    2) SEVERE POISONING: Severe cases may manifest shock, marked hypertension and tachycardia, agitated delirium, and rigidity (greater in the lower extremities). Other findings include severe hyperthermia (greater than 41.1 degrees C), acidosis, rhabdomyolysis, seizures, renal failure, and rarely, disseminated intravascular coagulopathy.
    0.2.3) VITAL SIGNS
    A) Hyperthermia is characteristic; tachycardia, hypertension, and tachypnea are common. Hypotension and respiratory failure may develop in severe cases.
    0.2.4) HEENT
    A) Nystagmus, mydriasis, and hypersalivation are common.
    0.2.5) CARDIOVASCULAR
    A) Hypertension and tachycardia are common. Hypotension, dysrhythmias, and ECG changes may develop in severe cases.
    0.2.6) RESPIRATORY
    A) Tachypnea is common. Respiratory failure, trismus, and adult respiratory distress syndrome may develop in severe cases.
    0.2.7) NEUROLOGIC
    A) CNS effects are common and include confusion, disorientation, agitation, CNS depression, coma, and hallucinations. Seizures may develop in severe cases.
    B) Neuromuscular effects include myoclonus, tremor, hyperreflexia, rigidity, hyperactivity, ataxia, shivering, teeth chattering, opisthotonus, and abnormal Babinski reflexes.
    0.2.8) GASTROINTESTINAL
    A) Diarrhea is common; abdominal pain may also develop.
    0.2.9) HEPATIC
    A) Hepatocellular injury may develop in severe cases.
    0.2.10) GENITOURINARY
    A) Acute renal failure may develop in severe cases.
    0.2.11) ACID-BASE
    A) Mild metabolic acidosis is common; respiratory acidosis may develop in severe cases.
    0.2.13) HEMATOLOGIC
    A) Leukocytosis is common. DIC may develop in severe cases.
    0.2.14) DERMATOLOGIC
    A) Diaphoresis is common, and skin may be flushed.
    0.2.15) MUSCULOSKELETAL
    A) Rhabdomyolysis may develop in severe cases.

Laboratory Monitoring

    A) Serotonin syndrome is a clinical diagnosis. Drug levels do not assist in the diagnosis or management. Serum electrolytes, glucose, creatinine, CPK, arterial blood gases, and ECG may be helpful in moderate to severe cases.
    B) Other studies may include liver function tests, prothrombin time, partial thromboplastin time or INR, and platelets in patients experiencing severe hyperthermia or hypotension, or as indicated.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Discontinue the precipitating agent; the main treatment is benzodiazepines. Other treatments are cyproheptadine and supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Provide therapy as above, but patients with severe toxicity may need immediate aggressive sedation, intubation, and neuromuscular paralysis. Control agitation with aggressive benzodiazepine use. Administer fluids and direct-acting vasopressors (eg, norepinephrine, epinephrine, phenylephrine) for hypotension. Use nitroprusside or esmolol for hypertension that is refractory to benzodiazepines. Manage hyperthermia by controlling muscle hyperactivity with benzodiazepines and nondepolarizing paralytics as well as external cooling.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal may be given if the patient is alert, the airway is protected, and the patient has ingested a potentially dangerous coingestant (eg, tricyclic antidepressants). Avoid activated charcoal if mental status is altered.
    2) HOSPITAL: Activated charcoal may be given for recent ingestions if the patient is intubated or able to protect their airway. There is no role for whole bowel irrigation or lavage because these drugs are absorbed rapidly.
    D) AIRWAY MANAGEMENT
    1) Severe serotonin syndrome requires intubation, sedation, and paralysis.
    E) ANTIDOTE
    1) CYPROHEPTADINE is an oral antihistamine with serotonin antagonism at 5-hydroxytryptamine (HT)-1A and 5-HT-2A receptors. It is used to improve mild to moderate symptoms of serotonin syndrome (eg, core temperature greater than 38.5 degrees C or severe muscle rigidity requiring neuromuscular paralysis). DOSE: ADULT: Administer an initial dose of 12 mg, then 2 mg every 2 hours if the patient remains symptomatic. Maintenance: 8 mg every 6 hours. Maximum dose: 32 mg in 24 hours. CHILD: 0.25 mg/kg/day divided every 6 hours, maximum 12 mg/day. It may be crushed and administered via a nasogastric tube.
    F) AGITATION
    1) DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed; CHILD: 0.25 mg/kg IV every 5 to 10 minutes. Monitor for respiratory depression and need for intubation. Nondepolarizing paralytics may be used in severe cases.
    G) HYPOTENSION
    1) Administer 10 to 20 mL/kg 0.9% saline, and control hyperthermia. Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct-acting agents (eg, norepinephrine, epinephrine, phentolamine) are preferred.
    H) HYPERTENSION
    1) Monitor vital signs regularly. For severe hypertension, nitroprusside may be necessary.
    I) ENHANCED ELIMINATION
    1) There is no role for enhanced elimination. Discontinuation of the offending agents, aggressive benzodiazepine use, and meticulous supportive care are the mainstays of treatment.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients with suspected serotonin syndrome should be referred to a healthcare facility for evaluation.
    2) OBSERVATION CRITERIA: Patients with suspected serotonin syndrome should be evaluated in a healthcare facility. Mild cases that resolve with benzodiazepines and supportive care may be observed in a monitored setting until asymptomatic.
    3) ADMISSION CRITERIA: Symptomatic patients requiring aggressive benzodiazepines, airway management, and vasopressors should be admitted to an ICU. Discharge may occur when symptoms resolve.
    4) CONSULT CRITERIA: Consult a medical toxicologist if moderate to severe serotonin syndrome is suspected because symptoms may progress rapidly.
    K) PITFALLS
    1) Fail to recognize symptoms and how quickly a patient may deteriorate. Realize that severe muscle rigidity may mask clonus and hyperreflexia.
    2) Inadequate benzodiazepine administration can result in all of the following: persistent overstimulation, hyperthermia, rhabdomyolysis, and further injury. Hyperthermia requires aggressive sedation and cooling measures and should NOT be treated with other medications (eg, antipyretics, dantrolene, or bromocriptine).
    3) Avoid use of physical restraints instead of chemical restraints (eg, adequate benzodiazepine therapy).
    L) PREDISPOSING CONDITIONS
    1) Pro-serotonergic drug interactions usually result in serotonin syndrome. Classic examples include MAOIs, tricyclic antidepressants, SSRIs, opiates, dextromethorphan, antibiotics, weight-loss agents, sympathomimetic agents of abuse, and herbals. Drugs that inhibit the cytochrome P450 system (CYP2D6 and CYP314) may lead to serotonin syndrome when coadministered with SSRIs.
    M) DIFFERENTIAL DIAGNOSIS
    1) Eliminate neuroleptic malignant syndrome; anticholinergic toxicity; sympathomimetic overdose (eg, cocaine, amphetamines); or ethanol, benzodiazepine, barbiturate, or baclofen withdrawal.

Range Of Toxicity

    A) Serotonin syndrome occurs with both therapeutic dosing as well as overdose, but it usually results from the interaction of more than one proserotonergic agent.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: Serotonin syndrome is a potentially lethal adverse drug reaction that results from excessive central and peripheral serotonergic activity and is characterized by a triad of altered mental status, neuromuscular abnormalities, and autonomic instability, such as hyperthermia. Up to 60% of patients with serotonin syndrome develop symptoms and present for care within 6 hours of initial medical use, overdose, or change in dosing.
    B) PHARMACOLOGY: Serotonin syndrome results from excessive stimulation of central and peripheral nervous system serotonin receptors, namely 5-hydroxytryptamine (HT)-1A and 5-HT-2A. It may occur with drug interactions, therapeutic dosing, or deliberate self-harm.
    C) TOXICOLOGY: Pro-serotonergic drugs interact in at least 4 ways to account for excessive serotonin activation at 5-HT-1A and 5-HT-2A receptors: 1) deceased serotonin breakdown (eg, MAOIs); 2) decreased serotonin reuptake (eg, SSRIs, cocaine, dextromethorphan, meperidine, and serotonin norepinephrine reuptake inhibitors); 3) increased serotonin precursors or agonists (eg, L-tryptophan, LSD); and 4) increased serotonin release (eg, amphetamines, ecstasy, buspirone, lithium).
    D) EPIDEMIOLOGY: Serotonin syndrome occurs in approximately 15% to 20% of patients who overdose on SSRIs as single agents and may occur more commonly with serotonergic drug interactions.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: Serotonin syndrome has been reported uncommonly in overdose of single agents (eg, fluvoxamine, venlafaxine, citalopram, and escitalopram) but usually occurs following interaction of 2 or more pro-serotonergic drugs. Serotonin drug effects may be seen in approximately 30% of patients starting SSRIs. Symptoms are milder than the full serotonin syndrome and may include jitteriness or anxiety syndrome (ie, agitation, anxiety, hyperactivity, irritability, and mania or hypomania).
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE POISONING: Serotonin syndrome comprises a continuum of clinical manifestations ranging from mild to life-threatening. Common manifestations are akathisia, tremor, altered mental status, inducible clonus, sustained clonus, muscular hypertonicity, and hyperthermia. The classic clinical triad is altered mental status, neuromuscular abnormalities (rigidity), and autonomic instability (eg, hypertension, tachycardia, hyperthermia). A patient with serotonin syndrome is more likely to present with hyperreflexia and myoclonus rather than "lead pipe" rigidity that develops in neuroleptic malignant syndrome. MILD cases may show subtle findings, such as tachycardia, shivering, diaphoresis, mydriasis, and no fever. MODERATE cases may show tachycardia, hypertension, hyperthermia (up to 40 degrees C), hyperactive bowel sounds, diaphoresis, hyperreflexia, clonus (greater in the lower extremities than upper), horizontal ocular clonus, and mild agitation.
    2) SEVERE POISONING: Severe cases may manifest shock, marked hypertension and tachycardia, agitated delirium, and rigidity (greater in the lower extremities). Other findings include severe hyperthermia (greater than 41.1 degrees C), acidosis, rhabdomyolysis, seizures, renal failure, and rarely, disseminated intravascular coagulopathy.

Vital Signs

    3.3.1) SUMMARY
    A) Hyperthermia is characteristic; tachycardia, hypertension, and tachypnea are common. Hypotension and respiratory failure may develop in severe cases.
    3.3.2) RESPIRATIONS
    A) TACHYPNEA is common in patients with serotonin syndrome (Radomski et al, 2000; Power et al, 1995; Price et al, 1986; Weiss, 1995; Nijhawan et al, 1996; Roxanas & Machado, 1998a; Pao & Tipnis, 1997).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, tachypnea was reported in 35 (28%) patients (Mills, 1997).
    B) RESPIRATORY FAILURE may develop in severe cases (Power et al, 1995; Ruiz, 1994; Brubacher et al, 1996).
    3.3.3) TEMPERATURE
    A) HYPERTHERMIA is characteristic of serotonin syndrome. In severe cases, core temperature may exceed 42 degrees C (Fisher & Davis, 2002; Nisijima et al, 2002; Radomski et al, 2000; Power et al, 1995; Kline et al, 1989; Weiss, 1995; Hodgman et al, 1997; Keltner, 1994).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, hyperthermia was reported in 59 (46%) patients (Mills, 1997).
    3.3.4) BLOOD PRESSURE
    A) HYPERTENSION: Mild to moderate hypertension is common in patients with serotonin syndrome (Fink, 1996; Weiss, 1995; Sandyk, 1986).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, hypertension was reported in 42 (33%) patients (Mills, 1997).
    B) HYPOTENSION may develop in severe cases (FitzSimmons & Metha, 1999; Kline et al, 1989; Power et al, 1995; Heisler, 1996; Francois et al, 1997).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, hypotension was reported in 18 (14%) patients (Mills, 1997).
    3.3.5) PULSE
    A) TACHYCARDIA is common with serotonin syndrome (Fisher & Davis, 2002; Radomski et al, 2000; Mason & Blackburn, 1997; Fink, 1996; Mathew et al, 1996a).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, tachycardia was reported in 52 (41%) patients (Mills, 1997).

Heent

    3.4.1) SUMMARY
    A) Nystagmus, mydriasis, and hypersalivation are common.
    3.4.3) EYES
    A) MYDRIASIS: Dilated, sluggishly reactive pupils are common (Radomski et al, 2000; Brubacher et al, 1996; John et al, 1997a; Mathew et al, 1996a).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, dilated pupils were reported in 33 (26%) patients, and unreactive pupils were reported in 23 (18%) patients (Mills, 1997).
    B) NYSTAGMUS has been reported (Fisher & Davis, 2002; Ruiz, 1994).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, nystagmus was reported in 16 (13%) patients (Mills, 1997).
    3.4.6) THROAT
    A) HYPERSALIVATION may occur (Brubacher et al, 1996; Mathew et al, 1996a).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, hypersalivation was reported in 6 (5%) patients (Mills, 1997).
    B) TRISMUS has been reported and may significantly complicate airway management (Kuisma, 1995; Brubacher et al, 1996; Ruiz, 1994; Chan et al, 1998a).
    1) INCIDENCE: In a review of 127 reports of serotonin syndrome, trismus was reported in 8 (6%) patients (Mills, 1997).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypertension and tachycardia are common. Hypotension, dysrhythmias, and ECG changes may develop in severe cases.
    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) Mild to moderate hypertension is common in patients with serotonin syndrome (Fisher & Davis, 2002; Radomski et al, 2000; Fink, 1996; Weiss, 1995; Sandyk, 1986).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, hypertension was reported in 42 (33%) patients (Mills, 1997).
    B) HYPOTENSIVE EPISODE
    1) Hypotension may develop in severe cases (Radomski et al, 2000; FitzSimmons & Metha, 1999; Kline et al, 1989; Power et al, 1995; Heisler, 1996; Francois et al, 1997).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, hypotension was reported in 18 (14%) patients (Mills, 1997).
    C) TACHYARRHYTHMIA
    1) Tachycardia is common with serotonin syndrome (Fisher & Davis, 2002; Nisijima et al, 2002; Radomski et al, 2000; Mason & Blackburn, 1997; Fink, 1996; Mathew et al, 1996a).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, tachycardia was reported in 52 (41%) patients (Mills, 1997).
    D) CONDUCTION DISORDER OF THE HEART
    1) CASE REPORT: A 35-year-old woman developed unifocal ventricular bigeminy during an episode of suspected serotonin syndrome (Insel et al, 1982). Her bigeminy began to abate 2 hours after the onset of her syndrome.
    E) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 31-year-old woman with a history of depression and bipolar disease and who was taking duloxetine, paroxetine, bupropion, and clonazepam became somnolent and confused, with physical findings consistent with serotonin syndrome. Heart rate was 100 beats per minute, and blood pressure was 160/104 mmHg on admission. Laboratory studies included a serum creatine kinase level of 1638 units/L with normal fractionation, and a serum troponin I level of 3.83 mcg/L. Over the next 3 days, the troponin I level decreased, and a repeat ECG showed inverted T-wave leads in I, aVL, II, aVF, and V3 to V6. Echocardiogram revealed septal, anterior, and lateral hypokinesis with an ejection fraction of 0.3. The patient progressed well and was discharged on day 4, to be readmitted 1 week later with pericarditis. A repeat echocardiogram showed an ejection fraction of 0.74, and normal coronary arteries were observed following cardiac catheterization (Ganetsky et al, 2006).
    F) ELECTROCARDIOGRAM ABNORMAL
    1) CASE REPORT: A 42-year-old woman developed sinus tachycardia (ST) to 140 beats/minute and questionable anterolateral ST depression during an episode of suspected serotonin syndrome (Mason & Blackburn, 1997).

Respiratory

    3.6.1) SUMMARY
    A) Tachypnea is common. Respiratory failure, trismus, and adult respiratory distress syndrome may develop in severe cases.
    3.6.2) CLINICAL EFFECTS
    A) HYPERVENTILATION
    1) Tachypnea is common in patients with serotonin syndrome (Fisher & Davis, 2002; Radomski et al, 2000; Power et al, 1995; Price et al, 1986; Weiss, 1995; Nijhawan et al, 1996; Roxanas & Machado, 1998a; Pao & Tipnis, 1997).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, tachypnea was reported in 35 (28%) patients (Mills, 1997).
    B) RESPIRATORY FAILURE
    1) Respiratory failure may develop in severe cases (Power et al, 1995; Ruiz, 1994; Brubacher et al, 1996).
    2) Trismus has been reported and may significantly complicate airway management (Kuisma, 1995; Brubacher et al, 1996; Ruiz, 1994).
    C) ACUTE LUNG INJURY
    1) Acute lung injury may develop in severe cases (Kline et al, 1989; Power et al, 1995).

Neurologic

    3.7.1) SUMMARY
    A) CNS effects are common and include confusion, disorientation, agitation, CNS depression, coma, and hallucinations. Seizures may develop in severe cases.
    B) Neuromuscular effects include myoclonus, tremor, hyperreflexia, rigidity, hyperactivity, ataxia, shivering, teeth chattering, opisthotonus, and abnormal Babinski reflexes.
    3.7.2) CLINICAL EFFECTS
    A) CLOUDED CONSCIOUSNESS
    1) Some degree of confusion is common in patients with serotonin syndrome (Fisher & Davis, 2002; Radomski et al, 2000; Fink, 1996; Ruiz, 1994; Brubacher et al, 1996; Heisler, 1996; Baetz & Malcom, 1995).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, confusion and disorientation were reported in 69 (54%) patients (Mills, 1997).
    B) CENTRAL STIMULANT ADVERSE REACTION
    1) Agitation and hyperactivity are common; hypomania has also been reported (Fisher & Davis, 2002; Nisijima et al, 2002; Radomski et al, 2000; McDaniel, 2001; Fink, 1996; Ruiz, 1994; Alderman & Lee, 1996; Baetz & Malcom, 1995).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, agitation was reported in 44 (35%) patients, and hypomania developed in 19 (15%) patients (Mills, 1997). Insomnia developed in 13 (10%) of the patients in the same review.
    C) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Lethargy is fairly common, and coma may develop in severe cases (Fisher & Davis, 2002; Radomski et al, 2000; John et al, 1997a; Baetz & Malcom, 1995; Power et al, 1995; Roxanas & Machado, 1998a).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, coma or unresponsiveness was reported in 36 (28%) patients, and drowsiness or lethargy developed in 19 (15%) patients (Mills, 1997).
    D) SEIZURE
    1) Seizures may develop in severe cases (Fisher & Davis, 2002; Radomski et al, 2000; Francois et al, 1997; Fink, 1996).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, seizures were reported in 18 (14%) patients (Mills, 1997).
    3) CASE REPORT: A 36-year-old woman with a history of bipolar disorder and depression receiving chronic lithium, venlafaxine, and imipramine therapy developed mydriasis, diaphoresis, tachycardia, hypertension, diarrhea, tremor, and unresponsiveness shortly after receiving linezolid (a serotonergic medication) for an MRSA empyema. Symptoms started within 36 hours. She improved within 24 hours with supportive care (Miller & Lovell, 2008).
    E) HALLUCINATIONS
    1) Hallucinations have been reported (Heisler, 1996; Fink, 1996).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, hallucinations were reported in 8 (6%) patients (Mills, 1997).
    F) MYOCLONUS
    1) Myoclonus is common (Fisher & Davis, 2002; Nisijima et al, 2002; Radomski et al, 2000; Bodner et al, 1995; Brubacher et al, 1996; Heisler, 1996; Baetz & Malcom, 1995).
    2) A patient with serotonin syndrome is more likely to present with hyperreflexia and myoclonus rather than "lead pipe" rigidity that develops in neuroleptic malignant syndrome (Stork, 2002).
    3) INCIDENCE: In a review of 127 reports of serotonin syndrome, myoclonus was reported in 73 (58%) patients (Mills, 1997).
    G) HYPERREFLEXIA
    1) Hyperreflexia is common (Fisher & Davis, 2002; Alderman & Lee, 1996; Power et al, 1995; Cano-Munoz et al, 1995a; Chan et al, 1998a; Fink, 1996). In severe cases, clonus may develop (Weiner et al, 1998).
    2) A patient with serotonin syndrome is more likely to present with hyperreflexia and myoclonus rather than "lead pipe" rigidity that develops in neuroleptic malignant syndrome (Stork, 2002).
    3) INCIDENCE: In a review of 127 reports of serotonin syndrome, hyperreflexia was reported in 70 (55%) patients (Fisher & Davis, 2002; Mills, 1997).
    H) TREMOR
    1) Extremity tremors and muscle rigidity are very common in patients with serotonin syndrome (Radomski et al, 2000; Fink, 1996; Brubacher et al, 1996; Heisler, 1996; John et al, 1997a; Baetz & Malcom, 1995; Cano-Munoz et al, 1995a).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, tremor was reported in 62 (49%) patients, muscle rigidity was reported in 62 (49%) patients, and shivering and chills were reported in 32 (25%) patients (Mills, 1997).
    I) ATAXIA
    1) Ataxia and loss of coordination are common (Mills, 1997).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, ataxia and loss of coordination were reported in 48 (38%) patients (Mills, 1997).
    J) OPISTHOTONUS
    1) Opisthotonos has been reported (Radomski et al, 2000; Power et al, 1995).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, opisthotonos was reported in 7 (6%) patients (Mills, 1997).
    K) ELECTROENCEPHALOGRAM ABNORMAL
    1) EEG abnormalities that have been reported in patients with serotonin syndrome include slow waves, spikes and waves in the delta range, generalized slowing of background activity, and triphasic waves (Dike, 1997a; Miyaoka & Kamijima, 1995; Lejoyeux et al, 1992).
    L) ABNORMAL REFLEX
    1) Babinski reflexes may be abnormal (Ruiz, 1994; Roxanas & Machado, 1998a).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, 18 (14%) patients had extensor Babinski reflexes (Mills, 1997).
    M) CSF: EXAMINATION ABNORMAL
    1) CASE REPORT: In 1 patient with serotonin syndrome, cerebrospinal fluid levels of 5-HT acid (a serotonin metabolite) were lower than in controls (12.2 nanograms [ng]/mL compared with 20.8 +/- 3 ng/mL). Levels of homovanillic acid (a dopamine metabolite) were also lower than controls (12.9 ng/mL compared with 52.9 +/- 9.9 ng/mL). Yet levels of noradrenaline were higher than controls (0.17 ng/mL compared with 0.07 ng/mL). On repeat examination after recovery, the levels were similar to controls (Nisijima, 2000).
    N) EXTRAPYRAMIDAL SIGN
    1) In 2 patients, concomitant use of sertraline or venlafaxine with metoclopramide resulted in serotonin syndrome with serious dystonic/dyskinetic reactions. The authors suggest that increased serotonin activity inhibits the dopaminergic system at the level of basal ganglia (in particular, the nigrostriatal dopaminergic pathway), resulting in extrapyramidal reactions (Fisher & Davis, 2002).
    O) CATATONIC REACTION
    1) CASE REPORT: One study describes a case of toxic serotonin syndrome with catatonic symptoms, including motor rigidity and negativism, induced by nortriptyline and levodopa, which was treated with electroconvulsive therapy and lorazepam (Fink, 1996). The authors believe that these acute neurotoxic syndromes also met criteria for catatonia, and neuroleptic malignant syndrome and toxic serotonin syndrome are subtypes of catatonia.

Gastrointestinal

    3.8.1) SUMMARY
    A) Diarrhea is common; abdominal pain may also develop.
    3.8.2) CLINICAL EFFECTS
    A) DIARRHEA
    1) Diarrhea is a common finding (George & Godleski, 1996; Fink, 1996; Gitlin, 1997).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, diarrhea was reported in 15 (12%) patients (Mills, 1997).
    B) ABDOMINAL PAIN
    1) Abdominal pain develops in some patients.
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, abdominal cramps were reported in 6 (5%) patients (Mills, 1997).

Hepatic

    3.9.1) SUMMARY
    A) Hepatocellular injury may develop in severe cases.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) Hepatocellular injury may develop in patients with severe hyperthermia (Mason et al, 2000; Kline et al, 1989; Francois et al, 1997; Power et al, 1995; Keltner, 1994).
    2) CASE REPORT: Serum liver enzyme elevation, with an AST of 3560 units/L and an ALT of 2680 units/L, was reported in a 60-year-old female who developed serotonin syndrome after taking clomipramine for 8 months (Rosebush & Margetts, 1999).

Genitourinary

    3.10.1) SUMMARY
    A) Acute renal failure may develop in severe cases.
    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) Acute tubular necrosis and renal failure may develop in patients with prolonged hypotension or severe rhabdomyolysis (Kline et al, 1989; Power et al, 1995; Francois et al, 1997; Rosebush & Margetts, 1999).

Acid-Base

    3.11.1) SUMMARY
    A) Mild metabolic acidosis is common; respiratory acidosis may develop in severe cases.
    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Mild metabolic acidosis is fairly common (Nijhawan et al, 1996; Keltner, 1994).
    2) Respiratory acidosis may develop in severe cases (Hodgman et al, 1997; Ruiz, 1994; Brubacher et al, 1996a).

Hematologic

    3.13.1) SUMMARY
    A) Leukocytosis is common. DIC may develop in severe cases.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) Leukocytosis is a common finding (13%) (Fisher & Davis, 2002; Cano-Munoz et al, 1995; Nisijima et al, 1996).
    B) DISSEMINATED INTRAVASCULAR COAGULATION
    1) DIC may develop in severe cases (Francois et al, 1997; Power et al, 1995; Kline et al, 1989).
    C) THROMBOCYTOPENIC DISORDER
    1) CASE REPORT: A 60-year-old woman with serotonin syndrome because of clomipramine monotherapy developed thrombocytopenia, with platelets decreasing from 269,000 on admission to 44,000 within 24 hours. She also developed evidence of DIC (Rosebush & Margetts, 1999).

Dermatologic

    3.14.1) SUMMARY
    A) Diaphoresis is common, and skin may be flushed.
    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) Diaphoresis is a common finding (Fisher & Davis, 2002; Radomski et al, 2000; Fink, 1996; George & Godleski, 1996; Gitlin, 1997).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, diaphoresis was reported in 59 (46%) patients (Mills, 1997).
    B) FLUSHING
    1) Flushing is common (Corkeron, 1995).
    2) INCIDENCE: In a review of 127 reports of serotonin syndrome, flushed skin was reported in 18 (14%) patients (Mills, 1997).

Musculoskeletal

    3.15.1) SUMMARY
    A) Rhabdomyolysis may develop in severe cases.
    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) Rhabdomyolysis may develop in patients with prolonged tremors or rigidity (John et al, 1997a; Roxanas & Machado, 1998a; Weiner et al, 1998).
    2) CASE REPORT: A 60-year-old woman developed serotonin syndrome and rhabdomyolysis after clomipramine monotherapy. The patient presented with a CPK of 4300 units/L, which rose to 39,900 units/L over the next 72 hours. Rhabdomyolysis led to acute renal failure requiring dialysis; the patient died 4 weeks after admission because of infection (Rosebush & Margetts, 1999).
    3) Increased creatine kinase (CK) has been reported in 18% of patients with serotonin syndrome (Fisher & Davis, 2002).
    4) CASE REPORT: Elevated serum CK (957 units/mL; normal range 19 to 150) was reported in a 56-year-old man with toxic serotonin syndrome (Nisijima et al, 2002).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serotonin syndrome is a clinical diagnosis. Drug levels do not assist in the diagnosis or management. Serum electrolytes, glucose, creatinine, CPK, arterial blood gases, and ECG may be helpful in moderate to severe cases.
    B) Other studies may include liver function tests, prothrombin time, partial thromboplastin time or INR, and platelets in patients experiencing severe hyperthermia or hypotension, or as indicated.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, glucose, renal function, and creatine kinase (CK) in all patients with suspected serotonin syndrome.
    2) Monitor hepatic function tests in patients with severe hyperthermia or other serious effects.
    B) ACID/BASE
    1) Monitor arterial blood gases in patients with pulmonary symptoms, severe hyperthermia or hypotension, or other serious effects.
    C) COAGULATION STUDIES
    1) Monitor prothrombin time, partial thromboplastin time or INR and platelet count in patients with severe hyperthermia, hypotension, or other severe effects.
    4.1.3) URINE
    A) URINALYSIS
    1) Monitor urinalysis and urine output in patients with rhabdomyolysis.
    B) URINARY SEROTONIN AND 5-HYDROXYINDOLEACETIC ACID LEVELS
    1) Urinary serotonin concentrations were increased following an intentional MAOI and SSRI ingestion. These may be a potential biomarker of serotonin syndrome.
    a) CASE REPORT: Following an intentional overdose of moclobemide, sertraline, and citalopram, a 35-year-old woman showed signs of serotonin syndrome 3 hours after ingestion. Initial laboratory studies were normal, including a normal serum serotonin level. However, the urinary serotonin level (1533 mcg/L) was increased on admission. An increased urinary serotonin:creatinine ratio of 1 mg/g was observed, which gradually fell during 16 hours (normal value: 0.2 mg/g). As the urinary serotonin levels declined, it was noted that the symptoms of serotonin syndrome had resolved. A urinary 5-hydroxyindoleacetic acid (5-HIAA) was also measured, and the 5-HIAA:creatinine ratio was 10 mg/g, which was below the average daily value. The authors suggest that urinary serotonin concentrations could be used as biochemical markers for serotonin syndrome, but further study is indicated (Brvar et al, 2007).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG and institute continuous cardiac monitoring in all patients with suspected serotonin syndrome.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a chest radiograph in patients with CNS depression or hypoxia.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Symptomatic patients requiring aggressive benzodiazepines, airway management, and vasopressors should be admitted to an ICU. Discharge may occur when symptoms resolve.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients with suspected serotonin syndrome should be referred to a healthcare facility for evaluation.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist if moderate to severe serotonin syndrome is suspected because symptoms may progress rapidly.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with suspected serotonin syndrome should be evaluated in a healthcare facility. Mild cases that resolve with benzodiazepines and supportive care may be observed in a monitored setting until asymptomatic.

Monitoring

    A) Serotonin syndrome is a clinical diagnosis. Drug levels do not assist in the diagnosis or management. Serum electrolytes, glucose, creatinine, CPK, arterial blood gases, and ECG may be helpful in moderate to severe cases.
    B) Other studies may include liver function tests, prothrombin time, partial thromboplastin time or INR, and platelets in patients experiencing severe hyperthermia or hypotension, or as indicated.

Oral Exposure

    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Gastric decontamination may be useful if serotonin syndrome develops in the setting of recent overdose. Decontamination is generally not indicated if serotonin syndrome develops after therapeutic dosing.
    2) Activated charcoal may be given for recent ingestions if the patient is intubated or able to protect their airway. There is no role for whole bowel irrigation or lavage because these drugs are absorbed rapidly.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) For patients with mild to moderate serotonin-related symptoms, cessation of suspected drug treatments and supportive care is indicated. Severe symptoms (eg, increased temperature [greater than 38.5 degrees C] and muscle rigidity necessitating paralysis) of serotonin toxicity require immediate intervention. In animal models, these events are predominantly mediated by 5-hydroxytryptamine (HT)-2A, and such toxicity may be prevented by administration of 5-HT-2A antagonists to reverse serotonin excess (Isbister & Buckley, 2005).
    B) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Control agitation and muscle activity. Undress the patient, and enhance evaporative heat loss by keeping skin damp and using cooling fans. Administer cyproheptadine to patients with a core temperature greater than 38.5 degrees C or with severe muscle rigidity (Isbister & Buckley, 2005). In severe toxicity, a patient with a temperature greater than 41.1 degrees C requires immediate paralysis with nondepolarizing agents (eg, vecuronium), along with mechanical intubation and ventilation. Succinylcholine should be avoided because of the risk of dysrhythmias secondary to hyperkalemia associated with rhabdomyolysis (Boyer & Shannon, 2005).
    C) CYPROHEPTADINE
    1) ADULT: 12 mg orally initially, followed by 2 mg every 2 hours if symptoms persist. Maintenance: 8 mg every 6 hours. Maximum: 32 mg may be administered in 24 hours (Boyer & Shannon, 2005; Mills, 1997).
    2) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    3) Cyproheptadine is a nonspecific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Horowitz & Mullins, 1999; Goldberg & Huk, 1992; Graudins et al, 1997). Its use may be limited in patients who are unable to tolerate oral administration; however, it may be crushed and administered via a nasogastric tube (Boyer & Shannon, 2005; Isbister & Buckley, 2005). There are no controlled human trials substantiating its efficacy.
    4) One pharmacokinetic study reported that orally administered cyproheptadine (8 mg) resulted in higher serum levels than the same dose administered sublingually. For oral and sublingual routes, mean Cmax was 30 mcg/L and 4 mcg/L, mean Tmax was 4 hours and 9.6 hours, and mean AUC was 209 and 25 mcg/hr/L, respectively. The authors suggest that 8 mg of cyproheptadine administered sublingually is unlikely to be effective in treating serotonin syndrome (Gunja et al, 2004).
    5) Of 5 probable or definite cases of serotonin syndrome treated with cyproheptadine, most cases had either a poor response or no response, with only 1 case having a good response. The authors suggest that the doses of cyproheptadine administered may have been too low to be beneficial because the blockade of brain serotonin receptors occurs at doses between 20 to 30 mg; the cases reported used doses of 4 to 16 mg (Gillman, 1999).
    D) PSYCHOMOTOR AGITATION
    1) Diazepam and other benzodiazepines are useful in the symptomatic treatment of agitation (Isbister & Buckley, 2005).
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    E) HYPERTENSIVE EPISODE
    1) SUMMARY
    a) Monitor vital signs regularly. For mild to moderate asymptomatic hypertension, pharmacologic intervention may not be necessary. For hypertensive emergencies (ie, emergent need to lower mean blood pressure [BP] 30% within 30 minutes and to achieve a diastolic BP of 100 mmHg or less within 1 hour), nitroprusside is preferred.
    2) NITROPRUSSIDE
    a) SODIUM NITROPRUSSIDE/INDICATIONS
    1) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    b) SODIUM NITROPRUSSIDE/DOSE
    1) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    c) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    1) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    d) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    1) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    e) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    1) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    F) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Administer 10 to 20 mL/kg 0.9% saline bolus, and place patient in the Trendelenburg position. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Control hyperthermia.
    c) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct-acting agents (eg, norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    G) SEIZURE
    1) Seizures may develop in severe cases of serotonin syndrome.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    H) ACUTE LUNG INJURY
    1) Acute lung injury may develop in severe case of serotonin syndrome.
    2) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    3) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    4) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    5) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    7) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    8) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    I) EXPERIMENTAL THERAPY
    1) SUMMARY
    a) The following agents or therapies have been used in a limited number of patients in the treatment of serotonin syndrome.
    2) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT-2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Adverse effects may include significant hypotension (Isbister & Buckley, 2005).
    b) In a review of 13 patients, chlorpromazine was relatively efficacious. Of 7 severe cases, 3 patients had good responses, 1 patient had a moderate response, and 3 patients had poor responses; of 4 moderate cases, 3 had good responses, and 1 had a moderate response (Gillman, 1999). Doses used ranged from 50 to 200 mg IM, 10 to 50 mg IV, and 50 mg orally. Chlorpromazine should not be used if neuroleptic malignant syndrome is considered because of further dopaminergic receptor blockade.
    1) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    2) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours, not to exceed 2 mg/kg/day.
    3) PROPOFOL
    a) Propofol has been used only in limited experience. A short-acting gamma-aminobutyric acid receptor agonist and N-methyl-D-asparate receptor antagonist, propofol was used effectively to treat serotonin toxicity in an 18-year-old man who had intentionally ingested 480 mg of dextromethorphan. An initial infusion was started at 10 mcg/kg/minute and increased to 30 mcg/kg/minute for continued agitation. Symptoms returned when the infusion was stopped for 2 hours. The infusion was restarted and continued for several more hours; no further symptoms occurred when the infusion was discontinued (Ganetsky et al, 2007). The authors suggest that propofol may be effective in treating the neuromuscular and autonomic hyperactivity associated with severe serotonin syndrome. However, the exact mechanism is unknown, but the effects may be related to decreased sympathetic outflow from CNS depression via gamma-aminobutyric acid agonism.
    4) KETANSERIN
    a) Ketanserin, a nonselective 5-HT-2 antagonist, may also be effective, but there is limited experience with this agent, and it is not widely available (Isbister & Buckley, 2005). The usual dose of ketanserin in adults with hypertensive emergencies is 5 mg IV infused at 3 mg/min, repeated as needed every 10 minutes to a maximum of 30 mg (AMA Department of Drugs, 1986).
    5) METHYSERGIDE
    a) Other agents that have been used to treat serotonin syndrome are methysergide and mirtazapine(Mills, 1997; Hoes MJAJM, 1996), but there is limited experience with these agents (Isbister & Buckley, 2005).
    6) ELECTROCONVULSIVE THERAPY
    a) In 2 case reports, toxic serotonin syndrome (TSS) was successfully treated with electroconvulsive therapy (ECT) (Nisijima et al, 2002; Fink, 1996). Although one report describes the effectiveness of ECT for TSS with catatonic symptoms, including motor rigidity and negativism(Fink, 1996), another report describes a patient with myoclonus and no catatonic features (Nisijima et al, 2002).
    J) SEDATION
    1) Sedation and neuromuscular blockade with nondepolarizing agents have been used to treat severe serotonin syndrome (Claassen & Gelissen, 2005).
    K) CONTRAINDICATED TREATMENT
    1) BROMOCRIPTINE: This agent has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome because it has serotonergic effects (Gillman, 1997). In one case, the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

    A) SUMMARY
    1) Most agents that have been implicated in serotonin syndrome have large volumes of distribution or high degrees of protein binding or both and are not amenable to extracorporeal methods of enhanced elimination.
    B) HEMODIALYSIS
    1) Hemodialysis may be useful if serotonin syndrome develops in the setting of lithium toxicity.

Abstracts

Case Reports

    A) PEDIATRIC
    1) An 11-year-old boy developed symptoms of serotonin syndrome, including rapidly progressive agitation, unresponsiveness, erratic blood pressure and heart rate changes, myoclonus of the jaw and ankles, diaphoresis, shivering, and hyperreflexia. The symptoms occurred approximately 1 hour after he took a single dose of fluvoxamine 50 mg, given for attention-deficit disorder. Progressive hyperthermia and rhabdomyolysis developed.
    a) The patient was paralyzed with rocuronium and sedated for 24 hours. The patient recovered, and physical exam was normal 48 hours after admission (Gill et al, 1999).

Range Of Toxicity

Summary

    A) Serotonin syndrome occurs with both therapeutic dosing as well as overdose, but it usually results from the interaction of more than one proserotonergic agent.

Pharmacology Toxicology

Toxicologic Mechanism

    A) Serotonin modulates numerous functions in the brain, including mood, appetite, personality, motor function, temperature regulation, sleep, pain perception, and sexual function. Serotonin receptors are complex and diverse; currently, there are 14 known receptor types belonging to 7 families (5-hydroxytryptamine [HT]-1 to 7). Animal experiments suggest that stimulation of postsynaptic 5-HT1A receptors is primarily responsible for serotonin syndrome. However, stimulation of postsynaptic 5-HT2A receptors is also significantly involved. 5-HT2A receptors may play a significant role in inducing hyperthermia. Agonists selective to other serotonin receptors have not been implicated in inducing serotonin syndrome when used in therapeutic doses. An intact dopaminergic system may also be necessary in the development of serotonin syndrome (Nisijima et al, 2001; Barnes & Trevor, 1999). Further research suggests that 5-HT1A has a lesser role in serotonin toxicity in humans by producing hyperactivity and anxiety, whereas hyperthermia and severe hypertonicity are primarily mediated by 5-HT2A receptors. Higher concentrations of serotonin are needed to trigger 5-HT2A as compared with 5-HT1A-mediated effects (Isbister & Buckley, 2005).
    B) Serotonin syndrome most commonly develops when a patient is receiving 2 or more drugs that increase brain serotonin levels by different mechanisms (Isbister & Buckley, 2005).
    C) Pharmacokinetic interactions may also be involved in some cases. Paroxetine is a potent inhibitor of the hepatic P450 isoenzyme CYP2D6, and fluoxetine is to a lesser extent, whereas sertraline and fluvoxamine have minimal effects. Dextromethorphan is metabolized by CYP2D6, predisposing patients taking paroxetine and dextromethorphan to serotonin syndrome (Harvey & Burke, 1995).

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