eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Selective Serotonin Reuptake Inhibitor

Tracy A Cushing, MD, MPH, Instructor in Medicine, Department of Emergency Medicine, Harvard Medical School; Attending Physician, Department of Emergency Medicine, Mount Auburn Hospital
Theodore I Benzer, MD, PhD, Assistant Professor in Medicine, Harvard Medical School; Director of Clinical Operations, Director of Toxicology, Chair of Quality and Safety, Department of Emergency Medicine, Massachusetts General Hospital

Updated: Oct 22, 2009

Introduction

Background

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed medications for the treatment of depression, obsessive-compulsive disorder, bulimia, anorexia nervosa, panic disorder, and social phobia. The majority of all antidepressants prescribed in the United States are from the SSRI family.^1,2 Commonly prescribed SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), escitalopram (Lexapro), and fluvoxamine (Luvox). SSRI toxicity and other adverse drug reactions can occur with overdose, in combination with other medications, or infrequently at therapeutic doses.

SSRIs have a high therapeutic to toxicity ratio and are associated with less toxicity than tricyclic antidepressants (TCAs). However, they are often involved in co-ingestions that can precipitate the potentially lethal "serotonin syndrome" (SS). SS is characterized by mental status changes, neuromuscular hyperactivity, and autonomic instability.^3,4 SS is often caused by combinations of SSRIs with other proserotonergic agents, including monoamine oxidase inhibitors (MAOIs), TCAs, trazodone (Desyrel), lithium, opioids, and amphetamine/stimulants, including methylphenidate (Ritalin), 3,4 methylenedioxymethamphetamine (MDMA, Ecstasy), cocaine, and herbal dietary supplements or nutraceuticals (St. John's wort, ginseng, and S-adenosyl-methionine). All of these affect the production, release, or breakdown of serotonin at the presynaptic cleft, thereby increasing its levels and toxicity. Less frequently, SS can be precipitated by overdose of a single SSRI.

Venlafaxine (Effexor) and duloxetine (Cymbalta) are serotonin-norepinephrine reuptake inhibitors (SNRIs) that are also associated with serotonin toxicity, as is the tetracyclic drug mirtazapine (Remeron), an alpha-2 adrenergic heteroreceptor blocking agent that causes increased norepinephrine and serotonin release in addition to blocking serotonin receptors. Trazodone (Desyrel) is a tetracyclic drug that blocks serotonin reuptake and also has an antagonistic effect at the serotonin 5-HT2 receptor site.

Several opioids are serotonergic and have been associated with SS. These include meperidine (Demerol), tramadol (Ultram), dextromethorphan, and pentazocine. The historically significant Libby Zion medicolegal case involved meperidine, cocaine, and an MAOI and was instrumental in changing the working conditions of postgraduate training programs.

Pathophysiology

Serotonin, or 5-hydroxytryptamine (5HT), is a neurotransmitter found in both the central and peripheral nervous system. Serotonin is produced in the brainstem raphe nucleus from L-tryptophan and is then stored in presynaptic vesicles. Neuronal activation causes release of 5HT into the synapse. Excess serotonin is taken back up into presynaptic vesicles by an active transport mechanism or locally metabolized by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid. Systemic metabolism is through liver mixed function oxidases (MFOs). Inhibition of particular MFOs, by other medications or plant materials (eg, grapefruit), may cause increased drug effect from decreased metabolism.⁵ Seven distinct 5HT receptors with further specific subtypes exist and produce a wide variety of physiologic effects. This diverse activity gives rise to the multiple signs and symptoms of toxicity.^6,7

Excess serotonergic activity can be precipitated through any of the several mechanisms listed below.⁸ Large dosages or combinations of any of these drugs can produce serotonin toxicity or the SS. The physiologic manifestations of serotonin syndrome are largely due to stimulation of 5HT_1a and 5HT₂ receptors.⁹

• Direct 5HT receptor stimulation - Buspirone (BuSpar), triptans (Imitrex, Amerge, Zomig, others), lithium, carbamazepine (Tegretol), lysergic acid diethylamide (LSD), and mescaline-containing cacti (peyote and others)
• Direct 5HT release from stored vesicles - Amphetamines, MDMA, cocaine, reserpine, levodopa, MAOIs, codeine, dextromethorphan, pentazocine
• Increased availability of 5HT precursors - L-tryptophan
• Decreased 5HT reuptake - SSRIs, trazodone (Desyrel), nefazodone, venlafaxine (Effexor), TCAs, dextromethorphan, tramadol, meperidine (Demerol), cocaine, Hypericum species (St. John's wort), amphetamines, carbamazepine (Tegretol), methadone
• Decreased 5HT degradation - MAOIs, St. John's wort

Serotonergic projections to the thalamus and cortex result in effects on sleep-wake cycles, mood, thermoregulation, appetite, pain perception, and sexual function. Excess 5-HT in these pathways causes the mental status changes, confusion, agitation, ataxia, and fever associated with SSRI toxicity and SS. Toxicity of descending pathways to the brainstem and medulla results in hyperreflexia, myoclonus, and tremor.

Autonomic nervous system effects include diaphoresis, mydriasis, hypertension, tachycardia, hyperthermia, piloerection, and muscular rigidity.

Cardiovascular effects most commonly include sinus tachycardia, flushing, hypertension, and in rare cases, hypotension. Citalopram (Celexa) was associated with prolonged QTc in one series.¹⁰

Due to the high levels of serotonin in gastric and intestinal mucosal enterochromaffin cells, the most common minor adverse effects of SSRI therapy are gastrointestinal, eg, abdominal cramping, nausea, and diarrhea. SSRIs have also been shown to moderately increase the risk of upper gastrointestinal bleeding.¹¹

Pharmacokinetics

SSRIs are metabolized in the liver by cytochrome P-450 MFO microsomal enzymes. They are highly bound to plasma proteins and have a large volume of distribution. Peak plasma levels are reached in 2-10 hours. Half-lives are variable, but most SSRIs have half-lives of 20-24 hours.⁵ A notable exception is fluoxetine (Prozac), and its active metabolite, norfluoxetine, which have half-lives of 2-4 days and 8-9 days, respectively. Hence, addition of serotonergic medications to a patient's regimen must not occur until 2-3 weeks after discontinuation of an SSRI (some recommend a 5-week "wash-out" period for fluoxetine prior to initiation of an MAOI).^12,9

Frequency

United States

Data from the 2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (AAPCC-NPDS) showed 2.4 million total toxic exposures in 2007.¹³ Antidepressants (SSRIs, TCAs, and atypicals) accounted for 98,898 exposures and 220 deaths and were the third most common class of drug associated with fatalities. Ten fatalities were related to ingestion of SSRIs alone. Of 220 total antidepressant-related fatalities, SSRIs were involved in 61 deaths, mostly in combination with other medications or illicit substances. Atypical antidepressants such as venlafaxine (Effexor) and bupropion (Wellbutrin) were involved in a significant number of fatalities.¹³

Mortality/Morbidity

AAPCC-NPDS 2007 data showed that, of 98,898 adult antidepressant exposures, 10 deaths were attributable to SSRIs alone. Most exposures were classified as causing mild-to-moderate effects. A significant number of deaths involved ingestions of bupropion (Wellbutrin) or venlafaxine (Effexor), often in combination with alcohol or other prescription medications.¹³

Sex

Incidence of reported SSRI ingestions is higher in women than in men. Incidence of death from antidepressant ingestions is higher in men than in women.

Age

Incidence of SSRI toxicity is highest in persons aged 19-39 years, the age group with the greatest overall number of intentional ingestions. Side effects from SSRIs are not age-specific, but they may occur more in elderly persons who are more likely to be taking several serotonergic agents or other medications that alter MFO CYP metabolism.

Clinical

History

Serotonin toxicity is most likely to develop following the initiation of a new serotonergic medication or the increase in dosage of a previously prescribed SSRI.⁷

Symptom onset from SSRI toxicity presents within 2-8 hours after acute ingestion, or it may occur over several days if SS develops from initiation of new therapy or addition of a second serotonergic agent.

History of mental illness, particularly affective disorders, and prior suicide attempts, should be elicited.

Serotonin syndrome (SS) represents a constellation of signs and symptoms that manifest in the neuromuscular, autonomic nervous, and GI systems in which concentrations of 5HT receptors are the highest. SS represents the most severe end of a spectrum of serotonin excess. Diagnostic criteria were developed in 1991 by Sternbach et al to assist in diagnosis.³ The Sternbach criteria include the following:

• Symptoms coincide temporally with the addition of a serotonergic agent to a patient's regimen or with increasing the dose of a previously prescribed serotonergic agent.
• At least 3 of the following physical findings are present: agitation, ataxia, diaphoresis, diarrhea, hyperreflexia, mental status changes, myoclonus, shivering, tremor, or hyperthermia.
• A neuroleptic agent has not been recently added to the patient's regimen or increased in dose, if previously prescribed.
• Other etiologies such as infection, intoxication, metabolic derangements, substance abuse, or withdrawal have been ruled out.

These criteria have been modified over time to account for symptoms associated with more mild cases, but they provide a framework for important clues in the history and physical examination to aid in diagnosis.

Remember that mild cases of SS due to vague symptomatology may often go unrecognized.

Physical

Signs of excess serotonin can range from subtle tremor to frank coma.¹⁴ Mental status changes, autonomic instability, and neuromuscular agitation are the primary findings used to delineate Sternbach's criteria. However, more specific signs and physical findings have become recognized as reliable predictors of serotonin toxicity; several decision rules have been established to help clinicians identify patients with possible SS.

• Neuromuscular findings, such as clonus, hyperreflexia, muscular rigidity, and ataxia, may be present, as well as myoclonic jerks, teeth chattering, and resting tremor. The clonus is spontaneous, inducible, or ocular. Hyperreflexia is often more pronounced in the lower extremities. Muscular rigidity may mask clonus. Among these findings, clonus is the most important in diagnosing SS.
• Mental status findings may be subtle, such as pressured speech, restlessness, and confusion. More severe cases may manifest with agitation, hypomania, coma, or seizures.
• Autonomic instability includes diaphoresis, hyperthermia, which is exacerbated by prolonged muscular rigidity or seizure activity, tachycardia, mydriasis, and blood pressure variations; both hypertension and hypotension have been observed. Electrocardiographic changes such as QTc prolongation have been reported in citalopram (Celexa) ingestions in particular.
• Peripheral findings may include increased GI motility, eg, diarrhea or hyperactive bowel sounds, coagulopathy (disseminated intravascular coagulation [DIC] in severe cases), and increased vascular tone.

Physical examination findings are helpful when distinguishing serotonin toxicity from other toxic ingestions in the differential diagnosis. Neuroleptic malignant syndrome, associated with dopamine antagonists, has a slower onset of symptoms than SS and is associated with bradykinesia and "lead-pipe" muscular rigidity, rather than hyperkinesias and tremors. Anticholinergic toxicity involves dry erythematous skin, enlarged pupils (mydriasis), decreased bowel sounds, and normal reflexes in contrast to serotonin toxicity, which includes diaphoresis, increased bowel sounds, diarrhea, and hyperreflexia. Ingestion of multiple agents in suicide attempts can make physical findings less reliable.

Causes

Serotonin syndrome is most often caused by simultaneous ingestion of 2 or more proserotonergic medications, which may be associated with therapeutic error, idiopathic response, or intentional overdose. No particular SSRI has been associated with an increased incidence of toxicity.^15,16 A recent increased dose of a chronic medication or a new addition to an extensive medication regimen is an important component of the history that may provide the diagnosis. Use of over-the-counter medications or dietary supplements in addition to prescribed serotonergic medications is also an important etiology.

The physiologic manifestations of serotonin toxicity are due to the locations of 5HT receptors throughout the body. Most CNS 5HT receptors are located in the brainstem raphe nuclei. The neurons of the proximal raphe are involved in regulation of sleep and waking, hunger and satiety, affective and sexual behavior, as well as thermoregulation and emesis. Peripheral effects of serotonin are due to receptors in the gastrointestinal tract that stimulate motility, as well as endovascular effects on blood pressure and coagulation.

Differential Diagnoses

Other Problems to Be Considered

Malignant hyperthermia

Workup

Laboratory Studies

• Diagnosis of serotonin toxicity begins with a detailed history of the patient's medications, changes to regimen, history of suicide attempts, and availability of serotonergic drugs as well as a careful physical examination.
  • Serum and urine toxicology screen - Opiates/opioids (meperidine), salicylates, acetaminophen, TCAs, amphetamines, phencyclidine (detection of dextromethorphan by cross-reactivity), and cocaine
  • Total CPK
  • Urine myoglobin
  • Basic electrolytes, including calcium, magnesium, and phosphorus levels, as well as lactate and ketone levels, to evaluate for metabolic acidosis
  • Blood urea nitrogen (BUN) and creatinine levels
  • Serum pH level
  • Liver function tests
  • Complete blood count and blood cultures if febrile
  • Prothrombin time/activated partial thromboplastin time in severe cases; DIC panels if necessary
  • Pregnancy testing if indicated
• Electrocardiogram, rhythm strips

Imaging Studies

• Chest radiograph after intubation or in any patient with hypoxia or aspiration
• Head CT scan in any patient with suspected trauma, new-onset seizures, or hypertension and localizing neurologic findings

Procedures

• Intubation should be considered in any unstable patient or any patient with altered mental status who cannot protect his or her airway.
• ECG to determine rhythm, morphology, and intervals, particularly in suspected co-ingestions.
• Lumbar puncture is indicated in any patient with fever and altered mental status.

Treatment

Prehospital Care

Prehospital care includes airway management and arrhythmia treatment per ACLS protocols; consider naloxone 2 mg IV, 50 mL of D50W, and thiamine 100 mg IV as well as a fingerstick glucose level for altered mental status. Of prime importance is getting history from any bystanders or family members and collecting ancillary materials, such as pills, empty pill bottles or medication packets, and suicide notes. If given, naloxone should be gradually titrated starting with 0.05 or 0.1 mg, and repeated if needed, to avoid rapid precipitation of opioid withdrawal.

Out-of-hospital management guidelines are available from the American Association of Poison Control Centers.¹⁷

Emergency Department Care

As for all care in the emergency department, the patient needs immediate evaluation and stabilization of the airway, breathing, and circulation, even without knowledge of the ultimate diagnosis. Treatment of serotonin syndrome is primarily supportive. The severity of presentation helps to guide appropriate emergency department care.

• Mild cases: Check laboratory results as indicated, intravenous fluids, benzodiazepines for agitation/restlessness, avoidance of all serotonergic medications.
• Moderate cases: Treat hyperthermia with cooling blankets, fans, ice packs, and intravenous fluids. The role for antipyretics is limited, as the mechanism of temperature alteration is centrally mediated. Administer activated charcoal if a potentially lethal amount has been ingested and if presentation is within 1-2 hours. Treat neuromuscular abnormalities with benzodiazepines.
• Severe cases: Patients with hyperthermia, depressed mental status, and vital sign abnormalities should be treated aggressively. All patients should be treated as above, with the addition of airway protection and ventilation if needed. Paralysis and mechanical ventilation are necessary to avoid worsening muscle rigidity and increasing hyperthermia in any patient with a temperature higher than 41ºC. Patients with severe hyperthermia that is unresponsive to aforementioned measures should be immersed into an ice bath to achieve rapid cooling and to prevent development of DIC and multiorgan failure (MOF). Avoid succinylcholine as a paralytic in any patient with possible rhabdomyolysis to prevent development of hyperkalemia.
• Severely ill patients could be treated pharmacologically with 5HT antagonists, such as cyproheptadine¹⁸ (see dosing information below). Efficacy has not been established in randomized clinical trials; however, it has shown benefit in animal models and case reports. It is available only in oral form, which can be crushed and infused via nasogastric tube. Caution should be exercised in hyperthermic patients, because cyproheptadine has anticholinergic properties and theoretically can worsen hyperthermia.
• Autonomic instability requires treatment with short-acting agents that are amenable to titration, such as nitroprusside and esmolol.
• Treat rhabdomyolysis with aggressive hydration, and alkalinize urine with sodium bicarbonate for renal protection.¹⁹

Consultations

• Medical toxicologist
• Poison Control Center at (800) 222-1222 (US and territories only)
• Psychiatrist

Medication

Pharmacologic treatment of the serotonin syndrome is largely based on anecdotal case reports and on animal models. Supportive care remains the basis of treatment; however, severe cases may benefit from the following interventions.

Adsorbent antidotes

These agents inhibit GI absorption of certain toxic agents or irritants.

Activated charcoal (Liqui-Char)

Emergency treatment used in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal absorbs 100-1000 mg of drug per gram of charcoal. Prevents absorption by adsorbing drug in the intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Theoretically, by constantly bathing the GI tract with charcoal, the intestinal lumen serves as a dialysis membrane for reverse absorption of drug from intestinal villous capillary blood into intestine. Does not dissolve in water.

For maximum effect, administer within 30-60 min after ingesting poison. Addition of sorbitol results in hyperosmotic laxative action causing catharsis, further inhibiting intestinal absorption of toxic substances.

Dosing

Adult

1 g/kg PO or per nasogastric tube mixed with sorbitol or in aqueous solution

Pediatric

1 g/kg PO; 15-30 g/dose maximum

Interactions

May inactivate syrup of ipecac if used concomitantly; effectiveness of other medications decrease with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties of activated charcoal)

Contraindications

Documented hypersensitivity; aspiration risk/unprotected airway; acid or alkali ingestions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check for bowel sounds prior to administering activated charcoal; aspiration of charcoal is highly irritable to lungs; not for administration to anyone without a secured airway; not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before giving activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns will be black

Serotonin antagonists

Cyproheptadine, chlorpromazine, and methylsergide have all been reported to be useful in SS to block postsynaptic serotonin receptors. No formalized dosing regimens have been established; the following recommendations are based on case reports and reviews of serotonin toxicity treatment.

Cyproheptadine (Periactin)

A 5HT (2a) antagonist. Has been shown in animal studies and case reports to reduce symptoms of SS. May be helpful in mild-to-moderate cases of serotonin syndrome.

Dosing

Adult

8-12 mg PO initially, followed by 2-4 mg q2h until symptoms resolve; not to exceed 0.5 mg/kg/d

Pediatric

<2 years: Not recommended
2-6 years: 2 mg PO bid/tid; not to exceed 12 mg/d
7-14 years: 4 mg PO bid/tid; not to exceed 16 mg/d
>14 years: Administer as in adults

Interactions

Potentiates effects of CNS depressants; MAO inhibitors may prolong and intensify anticholinergic and sedative effects of antihistamines

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; stenosing peptic ulcer; symptomatic prostatic hypertrophy; symptomatic BPH; bladder neck obstruction; pyloroduodenal obstruction; lower respiratory tract symptoms

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in patients with a predisposition to urinary retention, history of bronchial asthma, increased intraocular pressure, hyperthyroidism, cardiovascular disease, or hypertension; may thicken bronchial secretions caused by anticholinergic properties and may inhibit expectoration and sinus drainage; antihistamines may cause hallucinations and CNS depression in children, and less often may produce paradoxical excitation

Sedatives and anticonvulsants

Benzodiazepines are considered mainstay treatment in treating SS, particularly neuromuscular symptoms and seizures. They are also excellent for controlling agitated behavior.

Lorazepam (Ativan)

Sedative with rapid onset and relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Anticonvulsant effects last longer than diazepam or midazolam (4-6h).

Dosing

Adult

0.5-2 mg IV over 2-5 min; repeat q10-15min prn

Pediatric

0.05-0.1 mg/kg/dose IV over 2-5 min; not to exceed 4 mg/dose; repeat dose of 0.05 mg/kg q10-15 min prn

Interactions

Toxicity of benzodiazepines in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAO inhibitors

Contraindications

Documented hypersensitivity; CNS depression; hypotension; acute narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with hepatic or renal dysfunction, myasthenia gravis, Parkinson disease, or organic brain syndrome; may cause respiratory depression, especially in combination with other sedatives; patients with significant respiratory/mental status depression may require endotracheal intubation for airway protection

Diazepam (Valium)

Modulates postsynaptic effects of GABA-A transmission, resulting in an increase in presynaptic inhibition. Appears to act on part of the limbic system, thalamus, and hypothalamus to induce a calming effect. Also has been found to be an effective adjunct for the relief of skeletal muscle spasm caused by upper motor neuron disorders.
Rapidly distributes to other body fat stores. Twenty minutes after initial IV infusion, serum concentration drops to 20% of Cmax.
Individualize dosage and increase cautiously to avoid adverse effects.

Dosing

Adult

0.02-0.05 mg/kg IV q10-15min until symptoms resolve; not to exceed 30 mg in 8-h period; some clinicians are comfortable even with the larger cumulative doses; however, risk of respiratory depression increases with doses larger than 30 mg over 8 h

Pediatric

30 days to 5 years: 0.05-0.3 mg/kg/dose IV over 2-3 min q10-15min; not to exceed total dose of 5 mg
>5 years: 1 mg/dose IV over 2-3min q10-15min; not to exceed total dose of 10 mg

Interactions

Phenothiazines, barbiturates, alcohols, and MAO inhibitors increase CNS toxicity when administered concurrently

Contraindications

Documented hypersensitivity; CNS depression; hypotension; acute narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or hepatic or renal dysfunction (may increase toxicity)

Antihypertensives

Used for the treatment of autonomic instability and malignant hypertension as evidenced by end-organ damage of the brain, heart, and/or kidneys.

Nitroprusside (Nitropress)

Produces arterial and venous vasodilation. Decreases afterload and preload and may produce a reflex tachycardia.

Dosing

Adult

0.1-8 mcg/kg/min IV, titrate to effect; not to exceed 10 mcg/kg/min

Pediatric

Administer as in adults

Interactions

Effects are additive when administered with other hypotensive agents

Contraindications

Documented hypersensitivity; subaortic stenosis; decreased cerebral perfusion; arteriovenous shunt or coarctation of aorta (eg, compensatory hypertension); atrial fibrillation or flutter

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in increased intracranial pressure, hepatic failure, severe renal impairment, and hypothyroidism; in renal or hepatic insufficiency, nitroprusside levels may increase and can cause cyanide toxicity; sodium nitroprusside has the ability to lower blood pressure and thus should be used only in patients with mean arterial pressures >70 mm Hg

Neuromuscular Blockade, Paralytic

To control hyperreflexia, clonus, and hyperthermia, total neuromuscular paralysis may be required. Succinylcholine should be avoided in SS given the risk of hyperkalemia secondary to rhabdomyolysis.

Rocuronium (Zemuron)

Nondepolarizing neuromuscular blocking agent with rapid to intermediate onset (depending on dose) and intermediate duration. Competes for cholinergic receptors at motor end-plate to antagonize action of acetylcholine, which in turn blocks neuromuscular transmission. Acetylcholinesterase inhibitors such as neostigmine and edrophonium antagonize action.

Dosing

Adult

0.6 mg/kg IV

Pediatric

Administer as in adults

Interactions

Coadministration with antibiotics (eg, aminoglycosides, vancomycin, tetracyclines, bacitracin, polymyxin, colistin, sodium colistimethate), verapamil, succinylcholine, magnesium sulfate, quinidine, and ketamine, may enhance neuromuscular blocking action of rocuronium; coadministration with azathioprine, carbamazepine, phenytoin, and theophyllines may decrease neuromuscular blocking action

Contraindications

Documented Hypersensitivity; inability to ventilate

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer carefully adjusted dosages by or under supervision of experienced clinicians familiar with drug's actions and possible complications of use; drug should not be administered unless facilities for intubation, artificial respiration, oxygen therapy, and an antagonist are immediately available; recommended that clinicians administering neuromuscular blocking agents such as rocuronium use peripheral nerve stimulator to monitor drug response, need for additional relaxant, and adequacy of spontaneous recovery or antagonism; use caution in patients with pulmonary hypertension or valvular heart disease (may be associated with increased pulmonary vascular resistance)

Vecuronium (Norcuron)

Prototypic, non-depolarizing neuromuscular blocking agent that reliably results in muscular paralysis. For intubation and maintenance of paralysis a continuous infusion may be used.
Infants are more sensitive to neuromuscular blockade activity and although the same dose is used, recovery is prolonged by 50%. Drug is not recommended for use in neonates.

Dosing

Adult

0.08-0.1 mg/kg IV; may reduce to 0.05 mg/kg if patient has been treated with succinylcholine
Maintenance for paralysis: 0.025-0.1 mg/kg/h IV, and can be titrated to desired train-of-four response (commonly 2 of 4 twitches)

Pediatric

<7 weeks: Not established
7 weeks to 1 year: 0.08-0.1 mg/kg/dose IV followed by maintenance dose of 0.05-0.1 mg/kg q1h prn
1-10 years: May require higher initial dose and more frequent supplementation
>10 years: Administer as in adults

Interactions

When vecuronium is used concurrently with inhalational anesthetics, neuromuscular blockade is enhanced; renal or hepatic failure, as well as, concomitant administration of steroids, may result in prolonged blockade despite withdrawal of the agent

Contraindications

Documented hypersensitivity; myasthenia gravis or related syndromes

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In myasthenia gravis or myasthenic syndrome, small doses of vecuronium may have profound effects

Follow-up

Further Inpatient Care

• All patients with significant ingestions requiring intubation or vasopressors or those with a temperature higher than 40ºC or ECG changes/dysrhythmias should be admitted to an intensive care unit. Moderate toxicity can be safely observed in the hospital for 24 hours, and mild cases can be safely discharged (if asymptomatic) from the emergency department once cleared by psychiatry in cases of intentional overdose and after 6-8 hours of observation.
• Inpatient care should include ongoing fluid resuscitation, appropriate treatment of rhabdomyolysis, DIC, and renal or hepatic dysfunction, as well as psychiatric evaluation.

Transfer

• Transfer any patient who requires a level of care that is not available (eg, an intensive care unit).

Deterrence/Prevention

• Patients taking SSRIs and MAOIs should be cautioned about taking over-the-counter medications or supplements with serotonergic activity. They should be closely monitored if dosages are adjusted or medications are added to their regimen.

Complications

• Seizures
• Aspiration pneumonia
• Rhabdomyolysis
• Disseminated intravascular coagulation
• Acute renal failure
• Respiratory failure

Prognosis

• Most cases will fully resolve without residual deficits if supportive care has been provided. The prognosis is generally favorable.
• Most fatalities occur within the first 24 hours.
• Patients who remain asymptomatic for 6-8 hours after ingestion are unlikely to require further treatment.

Patient Education

• Patients should be counseled about potential interactions among any medications they take and over-the-counter drugs and so-called herbal supplements that may precipitate SS. They should be restarted on, or introduced to, serotonergic medications very gradually in the future (after "wash-out" period). They should report this reaction to all health care providers in the future.
• All patients started on SSRIs by psychiatrists or primary care physicians should be educated about symptoms of serotonin toxicity and SS.
• A minimum of 2 weeks should elapse between termination of an SSRI or MAOI and initiation of a new one. Drugs with a longer half-life (ie, fluoxetine) require up to 5 weeks of wash-out. Elderly patients and those taking liver MFOs may require an extended wash-out period as well.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose SS and institute proper treatment
• Failure to obtain a complete history of a patient's medications, resulting in prescribing serotonergic medications to patients already taking SSRIs or MAOIs
• Failure to counsel patients with regard to over-the-counter medications (particularly dextromethorphan-containing cold remedies), illicit drugs (especially amphetamines, MDMA, cocaine, and mescaline), and herbal dietary supplements/nutraceuticals (eg, St. John's wort, ginseng, and S-adenosyl-methionine) that might affect the patient's tissue concentrations of serotonin
• Symptomatic patients with citalopram/escitalopram overdose may require admission to the monitored bed for 24 hours because of the risk of delayed toxicity that can cause prolonged QTc interval and consequent cardiac dysrhythmias (eg, torsades de pointes).

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Keywords

selective serotonin reuptake inhibitor toxicity, SSRIs, SSRI overdose, serotonin syndrome, SS, SSRI toxicity, fluoxetine, Prozac, sertraline, Zoloft, paroxetine, Paxil, citalopram, Celexa, escitalopram, Lexapro, fluvoxamine, Luvox, SSRI toxicity, serotonin overdose, serotonin syndrome, SS, 5-hydroxytryptamine, 5HT

Contributor Information and Disclosures

Author

Tracy A Cushing, MD, MPH, Instructor in Medicine, Department of Emergency Medicine, Harvard Medical School; Attending Physician, Department of Emergency Medicine, Mount Auburn Hospital
Tracy A Cushing, MD, MPH is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Coauthor(s)

Theodore I Benzer, MD, PhD, Assistant Professor in Medicine, Harvard Medical School; Director of Clinical Operations, Director of Toxicology, Chair of Quality and Safety, Department of Emergency Medicine, Massachusetts General Hospital
Theodore I Benzer, MD, PhD is a member of the following medical societies: Alpha Omega Alpha and American College of Emergency Physicians
Disclosure: Nothing to disclose.

Medical Editor

Miguel C Fernández, MD, FAAEM, FACEP, FACMT, FACCT, Associate Clinical Professor; Medical and Managing Director, South Texas Poison Center, Department of Surgery/Emergency Medicine and Toxicology, University of Texas Health Science Center at San Antonio
Miguel C Fernández, MD, FAAEM, FACEP, FACMT, FACCT is a member of the following medical societies: American Academy of Emergency Medicine, American College of Clinical Toxicologists, American College of Emergency Physicians, American College of Medical Toxicology, American College of Occupational and Environmental Medicine, Society for Academic Emergency Medicine, and Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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