CONTENTS

• Rapid Reference 🚀
• Overview
• Causes of serotonin syndrome
• Clinical presentation
• Differential diagnosis
• Lab evaluation
• Diagnostic criteria
• Treatment
  • Cyproheptadine?
  • Dexmedetomidine
  • Overall treatment strategy
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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diagnosis

• Hunter diagnostic criteria are shown below.
• ⚠️ Criteria are not 100% specific, so you also need to pay attention to the differential diagnosis.📖

management of serotonin syndrome ✅

• Exhaustive review of medication list; D/C all contributory medications. 📖
• Monitor core temperature & manage as needed with physical cooling. 📖
  • Temp >41C is dangerous, consider intubation & paralysis.
• Control agitation (schema below).📖
• Check creatinine kinase and treat rhabdomyolysis if necessary.📖

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overview

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• Most cases are mild-moderate, and will improve in about a day following cessation of medications.  However, serotonin syndrome can be severe and may require ICU admission.
• The main challenge is recognition:  If serotonin syndrome is recognized early and causative drugs are stopped immediately, then patients will generally do very well.
• Roughly two forms of serotonin syndrome will be seen in the ICU:
  • (1) Patients presenting to the hospital with serotonin syndrome (e.g., due to illicit intoxication or outpatient polypharmacy).
  • (2) Nosocomial serotonin syndrome.  ICU patients who are continued on their outpatient psychiatric medications may easily be exposed to one or more serotonergic medications, creating a risk of serotonin syndrome.  Many housekeeping medications that we don't think about much can promote serotonin syndrome (e.g., ondansetron, fentanyl, metoclopramide).

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pathophysiology

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• There are seven classes of serotonin (5-HT) receptors: 5-HT-1 through 5-HT-7. There are further subdivisions within classes (e.g., 5-HT-1a through 5-HT-1f).
• Based on animal models, 5-HT-2a receptors seem to be involved in the more dangerous symptoms of serotonin syndrome (e.g., hyperthermia and increased muscle tone). Alternatively, 5-HT-1a receptors may contribute to some of the milder symptoms, such as anxiety and hyperactivity.(31523132)
• Ondansetron triggers serotonin syndrome despite the fact that it blocks 5-HT-3 receptors. This might be explained because due to blockade of 5-HT-3 receptors, there may be more serotonin available to stimulate 5-HT1a and 5-HT2a receptors.(33456910)

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causes of serotonin syndrome

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medications that cause or promote serotonin syndrome

• Psychiatric:
  • SSRIs & SNRIs (including trazodone; note fluoxetine's half-life of 1-2 weeks).
  • Tricyclic and tetracyclic antidepressants (including mirtazapine).
  • MAO inhibitors (especially dangerous; including rasagiline and selegiline).
  • Buspirone.
  • Bupropion.
  • Lithium.
  • Antipsychotics that are strong antagonists at 5-HT2A receptors 📖 might indirectly activate 5-HT1A receptors and thereby promote serotonin syndrome (e.g., risperdal, olanzapine).(20884828)
• Antiepileptics:
  • Carbamazepine.
  • Valproate.
• Antiemetics
  • Ondansetron, granisetron,
  • Metoclopramide.
• Triptans.
• Ergot derivatives (ergotamine, methylergonovine).
• Opioids (Meperidine, fentanyl, tramadol, dextromethorphan, methadone, oxycodone, tapentadol, levorphanol, pentazocine, pethidine). (29916050) Opioids alone don't cause serotonin syndrome, but they may promote it in combination with other agents. (33456910)
• Substance use (cocaine, amphetamine, methamphetamine, MDMA, LSD, cathinones).📄
• Miscellaneous:
  • Chlorpheniramine (an over-the-counter antihistamine).
  • Cyclobenzaprine.
  • Linezolid 💉
  • Methylene blue (inhibits MAO).
  • Saint John's Wort.
• (*Purple indicates medications commonly used within the ICU.)

CYP inhibitors

• In some cases, serotonin syndrome can be precipitated by non-serotonergic drugs which inhibit the metabolism of other serotonergic medications!
• Examples:
  • CYP3A4
    • Inhibited by: ciprofloxacin or ritonavir.
    • Metabolizes: methadone, venlafaxine, oxycodone.
  • CYP2C19
    • Inhibited by: fluconazole.
    • Metabolizes: sertraline.

overall architecture of serotonin syndrome

• Serotonin syndrome can occur for a variety of reasons:
  • (1) Overdose of a serotonergic medication (e.g., SSRI or illicits).
    • Serotonin syndrome occurs in ~15% of SSRI overdoses.(30743298)
  • (2) Inadvertent interaction between several serotonergic medications:
    • 2a) Addition of drugs which are directly serotonergic.
    • 2b) Addition of drugs which cause drug-drug interactions, increasing the levels of other serotonergic medications (i.e. the “new” medication doesn't necessarily need to directly affect serotonin signaling).
  • (3) Renal dysfunction may cause accumulation of serotonergic medications (e.g., sertraline).(31523132)
• In practice, most episodes of serotonin syndrome result from multiple drugs interacting together. When in doubt, enter the whole medication list into a program such as the Medscape drug interaction program; this may reveal unexpected interactions.
• Some examples of combinations reported to cause serotonin syndrome are listed below.

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clinical presentation

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chronology

• Usually occurs promptly following medication exposure or dose adjustment (within 12-24 hours).
• It will generally resolve within 24 hours following discontinuation of causative medications.
• Rapid onset & resolution can be helpful diagnostically to distinguish from many other disorders (e.g., neuroleptic malignant syndrome, thyrotoxicosis).

overall presentation: triad of findings

(#1/3) Mental status change 🧠

• Anxiety, agitated delirium.
• Seizure, coma.

(#2/3) Sympathetic hyperactivity 🥵

• Hyperthermia.
• Hypertension, tachycardia.
• Diaphoresis, flushing.
• Mydriasis.
• Nausea/vomiting, diarrhea (may occur early, as a prodrome).

(#3/3) Neuromuscular hyperactivity 💪

• Hyperreflexia.
• Clonus:
  • Most common: elicited by dorsiflexion of foot.
  • Ocular clonus (ping-pong gaze).
  • Spontaneous clonus in the most severe cases (can mimic seizure).
• Hyperkinesis, including myoclonus 📖 and tremor.
• Akathisia (inability to stay still).
• Ultimately rigidity may occur (one of the most severe and dangerous manifestation).

key finding: clonus

• Serotonin syndrome is strongly suggested by the following constellation:
  • (1) Bilateral ankle clonus and hyperreflexia.
  • (2) Lack of another obvious explanation of clonus (no known chronic neurologic abnormality).
• Lack of clonus argues strongly against the diagnosis of serotonin syndrome. However, serotonin syndrome can occur in the absence of clonus under the following circumstances:
  • (1) In a patient with tremor, it may be difficult to discern the presence of clonus.
  • (2) In severe cases of serotonin syndrome, clonus may progress to rigidity.
  • (3) Patients with underlying neurologic disease (e.g., peripheral neuropathy) may not manifest with clonus. (29207768)
• A broader discussion discussion of clonus is here: 📖

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differential diagnosis

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The differential diagnosis will depend on the particular presenting symptoms. The following are the most common considerations:

other toxidromes (usually the closest mimics)

• Sympathomimetic intoxication may be indistinguishable from serotonin syndrome (and these may be largely the same thing, because many sympathomimetics increase serotonin levels).
• Alcohol, benzodiazepine, or barbiturate withdrawal.
• Baclofen withdrawal.
• Anticholinergic toxicity.

sepsis

• Serotonin syndrome can be a sepsis mimic (e.g. can cause fever, elevated lactate, tachycardia).
• Meningitis or encephalitis may look a lot like serotonin syndrome.

hyperthermia syndromes

• Neuroleptic malignant syndrome.
• Malignant hyperthermia.
• Brainstem stroke causing hyperthermia.
• Heat stroke.

other

• Thyrotoxicosis.
• Sympathetic Storm.

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lab evaluation

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Labs don't directly diagnose serotonin syndrome. However, they may be useful in excluding alternative diagnoses and in evaluating complications of serotonin syndrome.

lab abnormalities in serotonin syndrome may include:

• Leukocytosis.
• Lactic acidosis.
• Elevated creatine kinase (rhabdomyolysis).
• Disseminated intravascular coagulation.
• Renal failure.
• Liver function abnormalities.
• Hyponatremia, hypomagnesemia.

tests to consider (evaluation depends on presentation, but consider the following)

• EKG
• Labs:
  • Fingerstick glucose.
  • Chemistries, including Ca/Mg/Phos.
  • Creatinine kinase.
  • Liver function tests.
  • Coagulation studies.
  • Salicylate & acetaminophen levels.
  • Infectious workup (blood & urine cultures).
  • CSF analysis if concern for meningitis/encephalitis.
• Imaging:
  • Chest X-ray
  • CT head, possibly MRI

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diagnostic criteria

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Hunter criteria

• Among various criteria, the Hunter Criteria seem to be the best. Compared to evaluation by a medical toxicologist, these criteria are 84% sensitive and 97% specific.
  • Of course, rigid application of criteria should never supersede clinical judgement.
• These criteria place clonus at the center of the diagnosis (as discussed above). Unfortunately, clonus may be masked among patients with an underlying peripheral neuropathy.(31523132)
• Defining precisely whether or not a patient has serotonin syndrome is tough because this is a spectrum disorder that ranges from mild to severe. Very mild serotonin syndrome might not meet the Hunter Criteria (which are more specific than sensitive).

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cyproheptadine

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cyproheptadine basics

• Cyproheptadine is a first-generation “sedating” antihistamine with anti-serotonin activity (including activity against the 5HT-2A receptor most closely related to serotonin syndrome). (31075831)
• Contraindications: Narrow-angle glaucoma, bladder obstruction.
• Drawbacks:
  • Only available orally.
  • Absorption may take some hours.
  • Side effects include sedation, hypotension, and anticholinergic effects (e.g., tachycardia, urinary retention). Anticholinergic effects could exacerbate hyperthermia.

cyproheptadine use in serotonin syndrome?

• This currently remains controversial. 🌊  🌊
• Cyproheptadine hasn't been proven to work in any RCT (no drug has been).
• Remember that the goal of therapy is primarily symptomatic improvement – so if the patient doesn't have bothersome symptoms, there is unlikely to be any benefit from cyproheptadine.
• The gradual onset of cyproheptadine limits its use in initial control of severe serotonin syndrome.
• For an intubated patient with severe agitation, cyproheptadine could theoretically be used to wean off intravenous sedatives. However, prolonged sedation often isn't necessary, because serotonin syndrome will generally resolve rapidly on its own (due to metabolism of serotonergic agents).
• Bottom Line: Textbooks (such as this one) will obligatorily include a discussion of the use of cyproheptadine. However, in clinical practice, cyproheptadine is generally not very useful. Standard supportive care and behavioral control may be superior (e.g., benzodiazepines and/or dexmedetomidine titrated to clinical effect – more on this below).

cyproheptadine dose

• (1) Loading dose of ~12 mg.
• (2) Maintenance dose of 4-8 mg q6hr (16-24 mg total daily dose).
• For comparison, the dose of cyproheptadine used for urticaria is 4 mg q8hr (12 mg total daily dose).
• Can be crushed and administered via nasogastric tube.(33456910)

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dexmedetomidine

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mechanisms of action

• Two mechanisms may explain efficacy in serotonin syndrome:
  • (1) Dexmedetomidine stimulates alpha-2C receptors in the striatum, thereby modulating serotonin levels. (23117910) It appears that alpha-2 receptors located on serotonergic terminal axons may inhibit serotonin release.(25596946)
  • (2) Dexmedetomidine stimulates alpha-2A receptors in the prefrontal cortex and locus coeruleus, which causes sedation and reduced sympathetic tone.
• Thus, in addition to simply acting as a sedative agent, dexmedetomidine seems to treat the underlying pathophysiology (serotonin excess). This has been demonstrated in an animal model of serotonin syndrome, wherein dexmedetomidine was more effective than midazolam.(25596946)

potential advantages of dexmedetomidine over benzodiazepines

• Traditionally, benzodiazepines have been the sedative agent used in serotonin syndrome. However, dexmedetomidine has several potential advantages over benzodiazepines:
• (1) As explored above, dexmedetomidine may better address the underlying pathophysiology.
• (2) Some case reports describe success with dexmedetomidine in cases which were refractory to other sedatives (including benzodiazepines).(23117910, 25169248)
• (3) Dexmedetomidine doesn't suppress respiration, so it is less likely to precipitate intubation.
• (4) Dexmedetomidine can be titrated to effect, thereby avoiding over-sedation or under-sedation.
• (5) Some authors have suggested that there may be an increased risk of paradoxical agitation when using benzodiazepines in the treatment of serotonin syndrome.(23117910) This isn't a problem with dexmedetomidine.
• (6) Dexmedetomidine is less likely than benzodiazepines to exacerbate delirium.
• (7) Dexmedetomidine can be a good choice when the diagnosis is unclear and you don't want to muddy the waters. If it is ineffective or causes adverse events, it's easily withdrawn.

potential disadvantages of dexmedetomidine compared to benzodiazepines

• (1) Dexmedetomidine may be more expensive.
• (2) Up-titration of dexmedetomidine takes some time, so it may not be an ideal agent for the patient with profoundly dangerous agitation.
• (3) Dexmedetomidine lacks anti-epileptic activity, so it would be less desirable in patients who have had a seizure.

bottom line on dexmedetomidine in serotonin syndrome?

• There is no solid evidence to establish the front-line IV sedative in serotonin syndrome.
• Limited mechanistic and clinical evidence suggests that dexmedetomidine could be superior to benzodiazepines.
• The ideal candidate for dexmedetomidine would have the following characteristics:
  • Sick enough to require IV sedation, yet not so sick as to need immediate intubation.
  • No prior seizure (benzodiazepine probably superior in that situation).
  • Not bradycardic (not really an issue here, however, as patients with serotonin syndrome are often tachycardic).
• The strength of dexmedetomidine is that it may achieve symptom control and avoid the requirement for intubation.

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treatment overview

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basic principles of treatment

• Key principles:
  • (1) The natural history of serotonin syndrome is that once causative medications are stopped, patients will improve rapidly (usually within a day). Most patients don't require anything more than high-quality supportive care. All you need to do is stop the offensive drugs and keep the patients safe, and they will recover.
  • (2) The pathway whereby serotonin syndrome leads to death is hyperthermia. Hyperthermia may promote seizures, leading to a seizure-coma-death spiral.
• Primary goals of treatment:
  • (1) Monitor temperature and treat/avoid hyperthermia.
  • (2) Treat agitation as needed to keep patient comfortable.

agitation control

• Sedation should be used only if the patient is dangerously/uncomfortably agitated or hyperthermic.
  • (Note, however, that physical restraints should be avoided if at all possible or rapidly discontinued. Straining against restraints may increase fever and rhabdomyolysis.)
• From a mechanistic standpoint, front-line agents are theoretically cyproheptadine and dexmedetomidine. Benzodiazepines have historically been used extensively and these are also a solid choice (particularly in a patient with seizure). For patients who are intubated, propofol might be superior to benzodiazepines (similar mechanism of action, with superior titratability).
• A potential schema for how these medications might be utilized is shown above. For example:
  • For patients with very mild agitation who can take oral medication, cyproheptadine may be trialed (with the understanding that it takes a while to work).
  • For patients who are unable to take oral medication or need more immediate sedation, dexmedetomidine may be preferable.
  • For patients with seizure who aren't intubated, benzodiazepines make sense.
  • For an intubated patient, dexmedetomidine or propofol could be used.
• Additionally, if the patient has a source of pain (e.g., trauma), then this should be treated with appropriate analgesia.
  • Avoid opioids which may increase serotonin levels (including fentanyl and oxycodone).

hyperthermia control

• Key treatments:
  • (1) Hyperthermia needs to be controlled with physical cooling techniques (e.g., cooling blanket, Arctic Sun, fan).
  • (2) Agitation should be controlled as discussed above, to prevent muscular activity that could worsen hyperthermia.
• Antipyretics won't work (these patients don't have hypothalamically mediated fever).
• Extreme hyperthermia (e.g., temperature over ~41.1 C) poses an immediate life-threat, since this may lead to rhabdomyolysis, seizure, metabolic acidosis, and disseminated intravascular coagulation.(33456910) Intubation with non-depolarizing paralysis may be considered as the fastest way to control temperature. (24358002, 31523132)
• More on physical cooling techniques.📖

hypertension

• Control agitation and pain first. Often management of these problems will eliminate hypertension.
• For ongoing severe hypertension, an esmolol or nitroglycerine infusion could be utilized. Hemodynamics may be labile, so short-acting agents are preferred.(33456910)
• Avoid hydralazine, as this may increase serotonin levels.

intubation

• Intubation may occasionally be required for the following reasons:
  • (1) In extreme cases, chest wall rigidity may interfere with ventilation.
  • (2) Profound hyperthermia.
  • (3) Uncontrollable agitation.
  • (4) Status epilepticus.
• ⚠️ Succinylcholine is contraindicated as this may theoretically worsen rhabdomyolysis. Nondepolarizing agents are preferred (e.g., rocuronium).
• ⚠️ Fentanyl should be avoided, given that it may promote serotonin syndrome. Hydromorphone may be a safer agent.
• Ongoing paralysis may be useful initially, to gain control of hyperthermia. Core temperature should be closely monitored, because hyperthermia may recrudesce after paralysis is lifted.

rhabdomyolysis

• It this occurs, treat as described here.📖

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to look for inducible ankle clonus in a patient with intoxication.
• Labeling patients with multifactorial delirium as having “serotonin syndrome,” without paying attention to diagnostic criteria.
• Insufficiently aggressive management of hyperthermia in patients with severe hyperthermia that poses a threat to vital organs.
• Use of physical restraints, which may lead to increased muscular activity that could worsen hyperthermia and rhabdomyolysis.
• Over-aggressive treatment of patients with mild serotonin syndrome who aren't hyperthermic (and who will generally improve rapidly with supportive care and cessation of serotonergic medications).

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• 📄 = Link to open-access journal article.
• = Link to supplemental media.