Serotonin Syndrome 

Updated: Sep 19, 2018
  • Author: Sameer S Khan, MD; Chief Editor: Sheela Pai Cole, MD  more...
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Practice Essentials

Serotonin syndrome is classically described as involving a combination of autonomic hyperactivity, hemodynamic changes, neuromuscular derangements, and changes in mental status. This article is aimed at providing a general understanding of this condition, describing its presentation in the perioperative setting, outlining how to manage it, and illustrating some different scenarios in which it may arise. 

Serotonin syndrome can be precipitated by pharmaceuticals, botanicals, and recreational drugs. The diagnosis is based on clinical symptoms rather than on any particular laboratory studies; the Hunter criteria are most often used for this purpose. The utility of these criteria notwithstanding, diagnosis of serotonin syndrome can be challenging, particularly in the perioperative setting.

It is important to obtain an accurate and thorough history of medications and recent ingestions so that the symptoms of this syndrome can be distinguished from those of other disease processes that present similarly. Serotonin syndrome can have a variety of clinical presentations, but the majority of cases manifest within 24 hours of a change of dose or initiation of a drug.

Treatment of serotonin syndrome involves the following measures:

  • Discontinuance of all serotoninergic agents
  • Supportive care with the goal of normalizing vital signs
  • Sedation with benzodiazepines
  • Administration of serotonin antagonists (eg, cyproheptadine)

The prognosis is generally good.

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Problem

Serotonin syndrome can manifest with findings that range from benign to fatal. [1, 2, 3] About 7300 diagnosed cases of serotonin syndrome occur each year, and about 100 of these cases result in death.

Drugs with serotoninergic properties have the ability to increase the level of serotonin or to act as direct agonists of postsynaptic serotonin receptors in the central nervous system (CNS). An excess of serotoninergic neurotransmission can produce the following:

  • Altered mental status - This can manifest as agitation, excitement, confusion, or coma
  • Altered neuromuscular excitability - This can manifest as clonus, hyperreflexia, myoclonus, tremor, or pyramidal rigidity
  • Autonomic instability - This can manifest as hyperthermia, tachypnea, tachycardia, diaphoresis, or mydriasis

In the perioperative setting, it may prove challenging to differentiate serotonin toxicity from other syndromes that have similar manifestations. Such syndromes include, but are not limited to, neuroleptic malignant syndrome (NMS), malignant hyperthermia (MH), anticholinergic toxicity, and infectious diseases such as meningitis and encephalitis (see Table 1 below). [1]

Table 1. Differentiation of Serotonin Syndrome From Similarly Presenting Conditions (Open Table in a new window)

Clinical Feature Serotonin Syndrome Anticholinergic "Toxidrome" Neuroleptic Malignant Syndrome Malignant Hyperthermia
Medication history Serotoninergic drug Anticholinergic agent Dopamine agonist Inhalational anesthetic
Average onset time < 12 hr < 12 hr 1-3 days 0.5-24 hr
Vital signs Hypertension, tachycardia, tachypnea, fever (> 41ºC) Hypertension, tachypnea, tachycardia, fever (< 39ºC) Hypertension, tachycardia, tachypnea, fever (> 41ºC) Hypertension, tachycardia, tachypnea, hyperthermia
Pupils Mydriasis Mydriasis Normal Normal
Bowel sounds Hyperactive Decreased or absent Normal or decreased Decreased
Tone Increased in lower extremities Normal "Lead-pipe" rigidity in all muscle groups Rigor mortis–like rigidity
Reflexes Hyperreflexia clonus Normal Bradyreflexia Hyporeflexia
Mental status Agitation, coma Agitation, delirium Stupor, alert, mutism, coma Agitation
Adapted from Boyer et al. [1]

NMS is the condition most commonly cited in the differential diagnosis when serotonin syndrome is a concern. NMS involves exposure to or withdrawal from a dopamine antagonist; it is related to an inherited genetic mutation in skeletal muscle and is provoked in the presence of certain neuroleptics (eg, haloperidol). [4]

Compared with serotonin syndrome, which presents within 24 hours of exposure, NMS usually has a more gradual onset, generally presenting in days to weeks. The altered mental status in serotonin syndrome often manifests in the form of global symptoms such as agitation and delirium, whereas in NMS, symptoms are more localized (eg, dysphagia, incontinence, and increased secretions).

In addition, NMS often has extrapyramidal side effects, including muscle rigidity and rhabdomyolysis, which can lead to leukocytosis, increased creatinine kinase and hepatic transaminase levels, and metabolic acidosis. Finally, unlike serotonin syndrome, NMS is rarely associated with hyperreflexia and myoclonus. It must be noted, however, that in cases involving both serotonergic and dopaminergic drugs, differentiation between serotonin syndrome and NMS can be very difficult. 

Serotonin syndrome is diagnosed on the basis of clinical manifestations, as well as a comprehensive medication review. Perioperative diagnosis of serotonin syndrome can be facilitated by the use of the Hunter serotonin toxicity criteria, which are based on a specific set of clinical features in specific combinations and which have a sensitivity of 84% and a specificity of 97%.

According to the Hunter criteria, the patient must have taken a serotoninergic agent within the preceding 5 weeks and must also have one of the following [1] :

  • Muscle rigidity plus temperature higher than 38ºC plus ocular clonus/inducible clonus
  • Ocular clonus plus agitation/diaphoresis
  • Inducible clonus  plus agitation/diaphoresis
  • Spontaneous clonus
  • Tremor plus hyperreflexia
  • Hypertonia

As mentioned earlier, serotonin syndrome typically manifests within 24 hours of exposure to the offending agent. Early manifestations and symptoms of mild serotonin syndrome include the following:

  • Tachycardia
  • Diaphoresis
  • Dilated pupils
  • Myoclonus
  • Increased deep tendon reflexes
  • Restlessness
  • Anxiety
  • Gait abnormalities
  • Difficulty concentrating
  • Sleep disturbances
  • Shivering
  • Muscle twitching

Late manifestations and symptoms of moderate-to-severe serotonin syndrome include the following:

Rhabdomyolysis is the most common and serious complication, occurring in 25% of cases. Generalized seizures occur in approximately 10% of cases. Early diagnosis of serotonin toxicity is vital because the condition can progress and become fatal.

There is no laboratory test that specifically confirms the diagnosis of serotonin syndrome; however, there are some nonspecific laboratory findings associated with the syndrome, including the following:

  • Increased white blood cell (WBC) count
  • Increased creatine phosphokinase (CPK) level
  • Decreased bicarbonate level

Additionally, case reports have found several electroencephalographic (EEG) abnormalities to be associated with serotonin syndrome, [5] including the following:

  • Delta range activity
  • Slow waves
  • Spike and waves
  • Polyspike and waves
  • Triphasic waves 
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Management

When serotonin toxicity is suspected, the most important initial step is to remove the offending agent. The best-known serotoninergic agents are antidepressants, [6, 7, 8] as follows:

  • Monoamine oxidase inhibitors (MAOIs; eg, MAO-A [isocarboxazid, phenelzine, tranylcypromine] or MAO-B [rasagiline, safinamide, selegiline])
  • Tricyclic antidepressants (TCAs; eg, amitriptyline, amoxapine, clomipramine, cyclobenzaprine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine)
  • Selective serotonin reuptake inhibitors (SSRIs; eg, citalopram, escitalopram, fluoxetine, paroxetine, fluvoxamine, sertraline, vortioxetine)
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) (eg, desvenlafaxine, duloxetine, levomilnacipran, milnacipran, venlafaxine)
  • Bupropion

However, there are many other pharmaceuticals of which practitioners should also be aware as potential offending agents, including various common perioperative and labor medications, as follows:

  • Opioids (eg, fentanyl, meperidine, oxycodone, hydrocodone, tramadol)
  • 5-hydroxytryptamine (5-HT; ie, serotonin) antagonists (eg, ondansetron, granisetron, dolasetron, palonosetron)
  • Triptans (eg, sumatriptan, eletriptan, frovatriptan, rizatriptan)
  • Stimulants (eg, amphetamine, dexmethylphenidate, dextroamphetamine, diethylpropion, lisdexamfetamine, methylphenidate)
  • Metoclopramide
  • Trazodone
  • Mirtazapine
  • Methylene blue
  • Linezolid

For the intensivist, it is important to know that antipsychotics (eg, olanzapine, risperidone, and quetiapine) and antibiotics (eg, linezolid) are also often implicated. Additionally, recreational drugs and over-the-counter (OTC) drugs (eg, 3,4-methylenedioxy-methamphetamine [MDMA; ecstasy], bath salts, and St John's wort) have been associated with serotonin syndrome. Patients taking high doses of a serotoninergic drug are particularly vulnerable. [9] A list of commonly implicated drugs is provided in Table 2 below.

Table 2. Serotoninergic Drugs Commonly Encountered in Perioperative Settings (Open Table in a new window)

Home Prescriptions Drugs of Abuse OTC/Herbal Agents Agents Used in OR Agents Used in PACU Agents Used in ICU

Antianxietals/antidepressants

  • Buspirone
  • MAOIs
  • TCAs
  • SSRIs
  • SNRIs
  • Bupropion

 

Stimulants for ADHD or obesity

  • Diethylproprion

Amphetamine

 

Cocaine (crack)

 

MDMA (ecstasy)

 

Methamphetamine (meth, crystal)

Dextromethorphan

 

Chlorpheniramine

 

St John's Wort

 

Syrian rue

 

Panax ginseng

 

Nutmeg

 

Yohimbe

Opioids

 

5-HT antagonists

 

Metoclopramide

 

Methylene blue

Opioids

 

5-HT antagonists

 

Antipsychotics (data limited

 

Chronic pain/headaches

  • Tramadol
  • Buprenorphine
  • Triptans

Sleep-wake cycle

  • Stimulants

Antibiotics

  • Linezolid

Adapted from Boyer et al. [1]

ADHD = attention deficit hyperativity disorder; 5-HT = 5-hydroxytryptamine (serotonin); ICU = intensive care unit; MAOI = monoamine oxidase inhibitor; MDMA = 3,4-methylenedioxy-methamphetamine; OR = operating room; OTC = over-the-counter; PACU = postanesthesia care unit; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.

Once serotonin syndrome has been diagnosed, and after the offending agent has been removed, supportive care is the mainstay of treatment. The syndrome often resolves within 24 hours after discontinuance of the serotoninergic agent and initiation of supportive care. More often than not, these patients will need intensive care unit (ICU) monitoring, including the following:

  • Oxygen administration
  • Intravenous (IV) fluids
  • Continuous cardiac monitoring (including QTc and QRS duration monitoring)
  • Airway support/intubation

In the setting of recent ingestion, the use of activated charcoal to assist with gastrointestinal (GI) decontamination may be considered.

One of the most important components of treatment is administration of benzodiazepines, which can alleviate numerous symptoms, especially agitation.

If the patient is hyperthermic (especially > 40ºC), it is important to begin active external cooling. Because the rise in temperature is of muscular origin, antipyretics are of no use, and paralytics are indicated when fever is high.

For both hemodynamic instability and agitation, there is some evidence to suggest that dexmedetomidine may be useful to treat these symptoms of serotonin toxicity. [10]

For severe hypertension, easily titratable medications (eg, clevidipine or esmolol), should be employed. In cases of refractory hypotension, vasopressors should be used.

Finally, the serotonin antagonist cyproheptadine has been recommended for the treatment of serotonin syndrome. [11]  Mirtazapine, a 5-HTand 5-HTantagonist, has also been used in a small number of cases; however, multiple studies have suggested that this agent does not change outcomes.

Although many different agents have been used in the care of patients with serotonin syndrome, there are a number that are not recommended, including olanzapine, chlorpromazine, propanolol, bromocriptine, and dantrolene.

Typically, serotonin syndrome starts usually within hours after initiation of a medication regimen, increase of the dosage, or overdose. It will continue as long as the serotoninergic agents remain in the system. The prognosis for patients with serotonin syndrome is generally favorable, provided that the syndrome is promptly recognized and that its associated complications are treated appropriately.

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Case Example 1

Clinical scenario

An 86-year-old woman weighing 76 kg is scheduled to undergo aortic valve replacement. She has a history of aortic valve disease, atrial fibrillation (AF), hypertension, osteoporosis, hypothyroidism, and acid reflux. Her medications include losartan, levothyroxine, pantoprazole, bisoprolol, furosemide, warfarin, citalopram, and nitroglycerin.

The anesthetic induction is standard: propofol, fentanyl and rocuronium. After the patient's cardiac operation, methylene blue (100 mg twice) is given as a vasopressor. In the ICU, the patient develops a generalized tonic-clonic seizure, lateral nystagmus, muscle rigidity, and coma for 30 hours, as well as hyperthermia (to 42ºC). 

Resolution

Methylene blue (methylthioninium chloride) is a redox dye that has been used for various clinical situations, including, but are not limited to, staining of tissue, treatment of methemoglobinemia, and treatment of cyanide poisoning. It is also used as a vasopressor to treat vasoplegic syndrome, especially after cardiac bypass. It is important to note here that methylene blue has powerful MAOI activity and is likely the cause of this patient's serotonin toxicity, especially given that the patient had been taking citalopram on an outpatient basis.

Altered mental status is very common in the ICU setting, and these altered mental states are usually diagnosed as delirium. In the context of serotonin toxicity, delirium can be caused by the excess serotoninergic neurotransmission. Because delirium is so common in the ICU, serotonin toxicity is often not recognized immediately.

In general, critically ill patients are predisposed to toxicities as a consequence of altered pharmacokinetics and changes in distribution volumes, protein binding, and the blood-brain barrier. The ICU drugs commonly implicated in serotonin toxicity include antipsychotics, opioid analgesics, antiemetics, antibiotics (linezolid), and, as seen in this case, methylene blue. [12, 13, 14, 15] Toxicity can result from therapeutic drug use or, more commonly, from inadvertent interactions between drugs.

In ICU patients, it is important to distinguish serotonin syndrome from other syndromes that have similar presentations: NMS, MH, anticholinergic toxicity, meningitis, and encephalitis. In high-volume cardiac surgery centers, these unexplained comas can be secondary to perioperative microemboli or low cardiac output syndrome.

Treatment, as mentioned earlier, requires recognition and discontinuance of the offending agents and initiation of supportive care. Serotonergic toxicity, in and of itself, is generally associated with a favorable prognosis, especially if diagnosed early. In this case, the toxicity resolved within 48 hours with supportive care and discontinuance of all serotoninergic agents. 

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Case Example 2

Clinical scenario

A 23-year-old man with a history of posttraumatic stress disorder (PTSD) and depression is in the postanesthesia care unit (PACU) after undergoing arthroscopy. When examined, the patient is found to be agitated with pressured tangential speech. Upon review of his chart, you note that he had been discharged from a psychiatric hospital several weeks previously, after intentionally overdosing on clonazepam. He admits to you that before the arthroscopic procedure, he took 40 pills of prescribed sertraline (100-mg tabs) to calm down his nerves. He denies any suicidal intent.

The patient's vital signs are as follows: heart rate (HR), 137 beats/min; blood pressure (BP), 152/89 mm Hg; respiratory rate (RR), 22 breaths/min; and temperature, 98.5ºF. On physical examination, his pupils are 8 mm bilaterally, and he has ankle clonus, as well as hyperreflexia on his patellar deep tendon reflexes. Urine drug screening is positive for amphetamines, as well as benzodiazepines. Finally, electrocardiography (ECG) shows sinus tachycardia with a QTc of 457. 

Resolution

In addition to pharmaceuticals, various botanicals and recreational drugs (including amphetamines) can be serotoninergic; this effect typically manifests within 24 hours of exposure to one of these agents.

This patient exhibited the three categories of symptom presentation: cognitive, autonomic, and neuromuscular. It is important to note the emergency department (ED) presentation and to be aware that these symptoms can vary considerably with regard to clinical severity, as follows:

  • Cognitive changes can range from restlessness and anxiety and agitation to altered mental status
  • Autonomic changes can range from tachycardia, mydriasis, and hypertension to hypotension, hyperthermia, and diaphoresis
  • Neuromuscular changes can range from akathisia to muscle rigidity, hyperreflexia, and myoclonus

The other important note for the PACU diagnosis of serotonin syndrome, beyond the consideration of offending agents and clinical manifestations, is differentiation from NMS (provoked usually in the presence of neuroleptics such as haloperidol) on the basis not only of the symptoms noted but also of the chronicity of clinical presentation: NMS is usually more delayed, developing about 5-7 days after exposure to a neuroleptic agent.

The patient was admitted to the ICU for removal of all exposure to serotoninergic drugs and for initiation of continuous cardiac monitoring. His symptoms resolved within 24 hours with benzodiazepine administration as needed for both agitation and hemodynamic instability. 

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Case Example 3

Clinical scenario

A 32-year-old woman who is now G2P2 is in recovery after delivery. Her prenatal course was unremarkable. Her first childbirth, 3 years ago, was a cesarean section done because of failure to progress; her current birth was an elective repeat cesarean. She experienced significant postpartum depression after her first birth and has been on sertraline 50 mg/day since that birth and throughout her second pregnancy. She has also been taking prenatal vitamins and the occasional acetaminophen.

During recovery, the patient complains of 7/10 pain and receives a prescription for fentanyl 50 μg IV hourly when she is transferred to the postpartum unit. After two fentanyl doses, a family member comes to the desk saying that the patient seems confused. The provider finds her agitated, restless, and slightly disoriented. Vital signs are as follows: HR, 120 beats/min; BP, 180/120 mm Hg; RR, 24 breaths/min, and temperature, 100.5ºF. Deep tendon reflexes are 4+ bilaterally in the patella, with two beats of clonus bilaterally.

Over the following 30 minutes, the patient becomes progressively more disoriented, and restraints are used. Her family denies any recreational drug use or psychiatric history (except for the aforementioned postpartum depression). 

Resolution

Many of the drugs used in obstetric settings can be implicated in the development of serotonin syndrome. [16, 17, 18] This patient exhibited the classic trio of symptoms: mental status changes, autonomic stimulation, and neuromuscular hyperactivity. She was admitted to the ICU, and all serotoninergic agents were eliminated.

It is relevant to note here that only limited data are available regarding the use of cyproheptadine, a serotonin antagonist, in pregnancy; thus, in view of its minimal proven efficacy, this agent is best avoided in this setting, if possible. In cases where there is concern about preeclampsia, providers should know that preeclamptic patients exhibit a 10-fold increase in serotonin, with a correlation between disease severity and serotonin concentration.

For the intrapartum or postpartum patient, several important factors must be considered, including the physiologic effects of serotonin, specifically those related to pregnancy. Such effects include the following:

  • Suppression or intensification of pain perception
  • Decreased emesis
  • Decreased urinary urge
  • Bronchoconstriction
  • Vasodilation and vasoconstriction (depending on the receptors)
  • Regulation of uterine contractility
  • Promotion of uterine involution

Patients taking SSRIs, in particular, specifically, are known to have decreased platelet aggregation with a theoretical hemorrhage risk. For the intraoperative cesarean patient, an anesthesiologist can use the fact that inhaled anesthetics can decrease serotonin levels.

In the antepartum patient, concerns exist regarding the impact on the CNS of the developing fetus. However, little conclusive research is available to answer these questions. It is known that significant vasoconstriction of the umbilical arteries is observed with serotonin, and this can reduce blood flow, potentially leading to adverse outcomes such as prematurity and intrauterine growth restriction. The capacity for many serotoninergic agents to cross the placental barrier is still unknown.

Finally, SSRI administration, particularly in the second and third trimester, has been linked to newborn pulmonary hypertension; the etiology is unknown. 

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Case Example 4

Clinical scenario

A 36-year-old man with a past medical history of congenital heart disease, who underwent ventricular septal defect closure and pulmonary artery banding as an infant, presents to an outside hospital with progressive right-lower-extremity stiffness, swelling, and pain. Workup reveals extensive ileal deep vein thromboses involving the internal iliac vein, external iliac vein, and common iliac vein bilaterally with abnormal narrowing of the inferior vena cava (IVC).

The patient is started on a heparin drip and treated with tissue plasminogen activator (tPA), which resolves the clot on the left and yields marginal improvement of the clot on the right. Additional relevant medical history is significant for anxiety and depression, for which the patient has been taking sertraline and aripiprazole. The patient is then transferred to the author's facility for surgical intervention.

Upon admission, the patient is taken for bilateral femoroiliac thrombectomy and IVC stent placement. His intraoperative course is complicated by an aspiration event, acute hypoxemia upon completion of thrombolysis, and by the subsequent development of acute respiratory distress syndrome (ARDS). He is placed on emergency venovenous extracorporeal membrane oxygenation (ECMO) and transferred to the cardiovascular ICU.

On postoperative day 5, the patient's ICU course is complicated by worsening hypoxia, episodes of hyper- and hypotension and tachycardia, rigors, and fevers and chills. He is receiving sertraline and aripiprazole for his anxiety and depression, and sedation is being continued with propofol, midazolam, and hydromorphone. Laboratory values are significant for elevated WBC count, elevated CPK, and elevated bilirubin. Meperidine is given to address shivering, and shortly thereafter, the patient develops new-onset clonus, rigidity, and tremors. 

Resolution

This is a complex case. In the ICU, there can be many etiologies for each criterion within the Hunter clinical classification for serotonin syndrome. Furthermore, in this case, the patient's vital sign abnormalities, including fever, tachycardia, and autonomic instability, occurred before meperidine was administered, and therefore, his symptoms could have been attributed to many other causes. For example, his shaking could have been attributed to a seizure or an acute intracranial insult.

The neurocritical care team was consulted and diagnosed the patient with serotonin syndrome. The patient’s serotoninergic medications were held, midazolam was restarted, and cyproheptadine was started. His symptoms resolved within 36 hours.

Although laboratory abnormalities alone are not definitively diagnostic of serotonin syndrome, they can certainly support the diagnosis. An elevated CPK can be suggestive of hypermetabolism, which is seen in serotonin syndrome. Also, as noted earlier, elevations in WBC counts and bilirubin levels, as well as decreases in bicarbonate levels, can be associated with serotonin syndrome.

Furthermore, EEG may be useful in supporting the diagnosis of serotonin syndrome. Case reports of serotonin syndrome have shown the following EEG abnormalities: delta range activity, slow waves, spike and waves, polyspike and waves, and triphasic waves. These are not typically expected in NMS or tardive dyskinesia.

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