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Serotonin syndrome

June 13, 2019 by Josh Farkas

CONTENTS

Overview (#overview)

Causes of serotonin syndrome (#causes_of_serotonin_syndrome)

Clinical presentation (#clinical_presentation)

Differential diagnosis (#differential_diagnosis)

Lab evaluation (#lab_evaluation)

Diagnostic criteria (#diagnostic_criteria)

TreatmentCyproheptadine (#cyproheptadine)

Dexmedetomidine (#dexmedetomidine)

Overall treatment strategy (#treatment_overview)

Algorithms (#algorithms)

Podcast (#podcast)

Questions & discussion (#questions_&_discussion)

Pitfalls (#pitfalls)

overview(back to contents) (#top)

Serotonin syndrome usually results from inadvertent interaction of several serotonergic medications.Most cases are mild-moderate, and will improve in about a day following cessation of medications.  However, serotonin syndrome can besevere and may require ICU admission.The main challenge is recognition:  If serotonin syndrome is recognized early and causative drugs are stopped immediately, then patients willgenerally do very well.

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causes of serotonin syndrome(back to contents) (#top)

overall architecture of serotonin syndrome

Serotonin syndrome can occur one of two ways:(1) Overdose of a serotonergic medication (e.g. SSRI or illicits)(2) Inadvertent interaction between several serotonergic medications

2a) Addition of drugs which are directly serotonergic2b) 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).

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(http://reference.medscape.com/drug-interactionchecker) ; this may reveal unexpected interactions.

Drugs which more commonly promote serotonin syndrome are as follows…

antidepressants & psychiatric medications

SSRIs, SNRIs (including trazodone)Serotonin syndrome occurs in ~15% of SSRI overdosesFluoxetine has a half-life of ~1-2 weeks, so can participate in serotonin syndrome even after discontinued.

Cyclic antidepressants (including mirtazepine)MAO inhibitors (may cause greater disease severity)BuspironeSaint John's WortLithium

illicits & opioids

Cocaine, amphetamine, methamphetamineMDMA (Ecstasy)LSDOpioids:  meperidine, fentanyl, tramadol, dextromethorphan, methadone, possibly oxycodone (29916050(https://www.ncbi.nlm.nih.gov/pubmed/29916059) )

CYP inhibitors

In some cases, serotonin syndrome can be precipitated by non-serotonergic drugs which inhibit the metabolism of other serotonergicmedications!Examples:

CYP3A4inhibited by:  cipro�oxacin or ritonavirmetabolizes:  methadone, venlafaxine, oxycodone

CYP2C19inhibited by:  �uconazolemetabolizes:  sertraline

miscellaneous

Linezolid (discussed further in the antibiotics chapter (https://emcrit.org/ibcc/antibiotics/#linezolid) )TriptansMethylene blueAnti-epileptics (carbamazepine, valproate)Anti-emetics (ondansetron, granisetron, metoclopramide)Chlorpheniramine (an over-the-counter antihistamine)

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clinical presentation(back to contents) (#top)

chronology

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

overall presentation: triad of �ndings

(1) Mental status changeAnxiety, agitated deliriumSeizure, coma

(2) Sympathetic hyperactivityhyperthermiahypertension, tachycardiadiaphoresis, �ushingmydriasisNausea/vomiting, diarrhea (may occur early, as a prodrome)

(3) Neuromuscular excitationHyperre�exiaClonus

Most common:  elicited by dorsi�exion of footOcular clonus (ping-pong gaze)Spontaneous clonus in most severe cases (can mimic seizure)

TremorRigidity (one of the most severe and dangerous manifestation)Akathisia (inability to stay still)

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Ankle clonus: This is elicited by rapidly dorsi�exing the foot.  One or two beats may be normal.   Prolonged clonus is a hallmark of serotoninsyndrome.

key �nding:  ankle clonus 

Clonus may be conceptualized as a form of profound hyperre�exia, wherein each muscle contraction triggers another re�exive contraction.Causes of clonus include:

Upper motor neuron dysfunction (e.g. due to stroke, trauma, cerebral palsy, or multiple sclerosis).Serotonin syndromeAnticholinergic toxicityBaclofen withdrawal

The hallmark �nding in serotonin syndrome is clonus and hyperre�exia, generally most prominent in the legs.Clonus is usually inducible, meaning that it is triggered by the examiner (video above).In severe cases, clonus may occur spontaneously.  This can resemble a seizure.

Serotonin syndrome is strongly suggested by the following constellation:(1) Bilateral ankle clonus and hyperre�exia.(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 ofclonus under the following circumstances:

(1) In a patient with tremor, it may be di�cult 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(https://www.ncbi.nlm.nih.gov/pubmed/29207768) ).

di�erential diagnosis(back to contents) (#top)

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

Ankle clonusAnkle clonus

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(https://emcrit.org/ibcc/serotonin/) other toxidromes (usually the closest mimics)

Serotonin syndrome can be indistinguishable from sympathomimetic intoxication (and these may be largely the same thing, becausesympathomimetics increase serotonin levels)Alcohol or 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 syndromeMalignant hyperthermiaBrainstem stroke causing hyperthermiaHeat stroke

other

ThyrotoxicosisSympathetic Storm

lab evaluation(back to contents) (#top)

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

lab abnormalities may include:

LeukocytosisLactic acidosisElevated creatine kinase (rhabdomyolysis)Disseminated intravascular coagulation

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Renal failureLiver function abnormalitiesHyponatremia, hypomagnesemia

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

EKGLabs

Fingerstick glucoseChemistries, including Ca/Mg/PhosCreatinine kinaseLiver function testsCoagulation studiesSalicylate & acetaminophen levelsInfectious workup (blood & urine cultures)CSF analysis if concern for meningitis/encephalitis

ImagingChest X-rayCT head, possibly MRI

diagnostic criteria(back to contents) (#top)

Hunter criteria

NEJM@NEJM

Images in Clinical Medicine: Ocular Flutter in the Serotonin Syndrome nej.md/2eUV1Qj

109 1:15 PM - Nov 4, 2016

123 people are talking about this

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Meets criteria for serotonin syndrome

On serotonergic medication(s)

SpontaneousClonus

Is there clonus?

No clonus

Yes

Tremor-PLUS-

Hyperreflexia?

Inducible –or- ocular clonus

YesYesYes

Agitation? Diaphoresis?Hypertonia

-PLUS-Temp >38C?

Hunter Criteria for Serotonin Syndrome

Schematic for the various ways to satisfy the Hunter Criteria for serotonin syndrome.

-Internet Book of Critical Care by @PulmCrit

(https://emcrit.org/wp-content/uploads/2019/06/huntercriteria.svg)

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% speci�c.

Of course, rigid application of criteria should never supersede clinical judgement.These criteria rightfully place clonus at the center of the diagnosis (as discussed above).De�ning precisely whether or not a patient has serotonin syndrome is tough because this is a spectrum disorder which ranges from mild tosevere.  Very mild serotonin syndrome might not meet the Hunter Criteria (which are more speci�c than sensitive).

cyproheptadine(back to contents) (#top)

basics

Cyproheptadine is a �rst-generation “sedating” antihistamine with anti-serotonin activity (including activity against the 5HT-2A receptor mostclosely related to serotonin syndrome)(31075831 (https://www.ncbi.nlm.nih.gov/pubmed/31075831) ).Contraindications:  narrow-angle glaucoma, bladder obstruction.Potential side-effects:  sedation, anticholinergic effects (e.g. tachycardia, urinary retention), hypotension.

use in serotonin syndrome?

Seems safe and likely effective.  Based also on mechanistic and cost considerations, it's arguably a front-line therapy.   However, availableonly orally and absorption may take some hours.Cyproheptadine could be used in roughly two ways:

(1) For a patient with mild to moderate agitation, oral cyproheptadine could be adequate therapy.(2) A patient with severe agitation may initially require IV therapy (e.g. with dexmedetomidine) and possibly intubation.  In this scenario,cyproheptadine could be started following initial stabilization and could be used to wean off other agents.

However, cyproheptadine doesn't need to be given to every patient with serotonin syndrome.It has never been proven to work in any RCT (no drug has been).The goal of cyproheptadine is primarily symptomatic improvement – so if the patient doesn't have bothersome symptoms, then there isunlikely to be any bene�t from cyproheptadine.

dose

(1) Loading dose of 12 mg(2) Additional PRN doses of 2 mg q2hr until response(3) Maintenance dose of ~8 mg q6hr.

Max daily dose is 32 mgFor the sake of comparison, the dose of cyproheptadine used for urticaria is 4 mg q8hr (12 mg total daily dose).

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dexmedetomidine(back to contents) (#top)

mechanisms of action

Two mechanisms may explain e�cacy in serotonin syndrome:(1) Dexmedetomidine stimulates alpha-2C receptors in the striatum, thereby modulating serotonin levels (23117910(https://www.ncbi.nlm.nih.gov/pubmed/23117910) ).  It appears that alpha-2 receptors located on serotonergic terminal axons may inhibitserotonin release (25596946 (https://www.ncbi.nlm.nih.gov/pubmed/25596946) ).(2) Dexmedetomidine stimulates alpha-2A receptors in the prefrontal cortex and locus ceruleus, which causes sedation and reducedsympathetic 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 (https://www.ncbi.nlm.nih.gov/pubmed/25596946) ).

potential advantages of dexmedetomidine over benzodiazepines

Traditionally, benzodiazepines have been the sedative agent used in serotonin syndrome.  However, dexmedetomidine has several potentialadvantages over benzodizepines:(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 (includingbenzodiazepines)(23117910 (https://www.ncbi.nlm.nih.gov/pubmed/23117910) , 25169248 (https://www.ncbi.nlm.nih.gov/pubmed/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 treatmentof serotonin syndrome (23117910 (https://www.ncbi.nlm.nih.gov/pubmed/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 orcauses 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.

treatment overview(back to contents) (#top)

basic principles of treatment

Key principles:(1) The natural history of serotonin syndrome is that once causative medications are stopped, patients will improve rapidly (usuallywithin a day).  Most patients don't require anything more than high-quality supportive care.  All you need to do is stop the offensivedrugs and keep the patients safe, and they will recover.

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(2) The pathway whereby serotonin syndrome leads to death is hyperthermia.  Hyperthermia may promote seizures, leading to aseizure-coma-death spiral.

Primary goals of treatment:(1) Monitor temperature and treat/avoid hyperthermia.(2) Treat agitation as needed to keep patient comfortable.

Approach to sedation in serotonin syndrome

No sedation needed.Follow clinically.

How severe is agitation & can patient take PO medication?

- Trial PO cyproheptadinemonotherapy Indications for benzodiazepine tx?

- Has the patient had any seizures?- Requirement for immediate sedation?

Once stabilized and able to tolerate PO, add cyproheptadine (and wean off IV sedation)

Trial dexmedetomidine infusion- No bolus- Start high infusion & down-titrate PRN

The Internet Book of Critical Care, by @PulmCrit

No

Yes

Mild-moderate agitationAble to take PO mediation

Severe agitation-OR-

Unable to take PO medication

No

Yes

If unresponsive toone may trial other Trial benzodiazepine

(For intubated patient, consider propofolinstead of benzodiazepine)

If patient worsens & requires tx

If ineffective

Does patient have dangerous oruncomfortable agitation?

(https://emcrit.org/wp-content/uploads/2019/06/seroalgo.svg) 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 mayincrease fever and rhabdomyolysis.)

From a mechanistic standpoint, front-line agents are arguably cyproheptadine and dexmedetomidine.  Benzodiazepines have historicallybeen used extensively and these are also a solid choice (particularly in a patient with seizure).  For patients who are intubated, propofolmight be superior to benzodiazepines (similar mechanism of action, with superior titratability).A general schema for how these medications may be utilized is shown above.

For patients with mild-moderate agitation who can take oral medication, cyproheptadine may be preferred.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).

Antipsychotics (e.g. haloperidol) may be undesirable, as they have anticholinergic properties which may tend to increase the temperature.

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).For extreme hyperthermia (e.g. temperature over ~41.1 C), intubation with non-depolarizing paralysis may be considered as the fastest wayto control temperature (24358002 (https://www.ncbi.nlm.nih.gov/pubmed/24358002) ).

intubation

May occasionally be required for the following reasons:

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(1) In extreme cases, chest wall rigidity may interfere with ventilation(2) Profound hyperthermia(3) Uncontrollable agitation(4) Status epilepticus

Paralysis may be useful initially (especially in the case of profound hyperthermia).

rhabdomyolysis

It this occurs, treat as described in the chapter on rhabdomyolysis (https://emcrit.org/ibcc/rhabdo/) .

algorithms(back to contents) (#top)

(https://emcrit.org/ibcc/serotonin/)

Meets criteria for serotonin syndrome

On serotonergic medication(s)

SpontaneousClonus

Is there clonus?

No clonus

Yes

Tremor-PLUS-

Hyperreflexia?

Inducible –or- ocular clonus

YesYesYes

Agitation? Diaphoresis?Hypertonia

-PLUS-Temp >38C?

Hunter Criteria for Serotonin Syndrome

Schematic for the various ways to satisfy the Hunter Criteria for serotonin syndrome.

-Internet Book of Critical Care by @PulmCrit

(https://emcrit.org/wp-content/uploads/2019/06/huntercriteria.svg)

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Approach to sedation in serotonin syndrome

No sedation needed.Follow clinically.

How severe is agitation & can patient take PO medication?

- Trial PO cyproheptadinemonotherapy Indications for benzodiazepine tx?

- Has the patient had any seizures?- Requirement for immediate sedation?

Once stabilized and able to tolerate PO, add cyproheptadine (and wean off IV sedation)

Trial dexmedetomidine infusion- No bolus- Start high infusion & down-titrate PRN

The Internet Book of Critical Care, by @PulmCrit

No

Yes

Mild-moderate agitationAble to take PO mediation

Severe agitation-OR-

Unable to take PO medication

No

Yes

If unresponsive toone may trial other Trial benzodiazepine

(For intubated patient, consider propofolinstead of benzodiazepine)

If patient worsens & requires tx

If ineffective

Does patient have dangerous oruncomfortable agitation?

(https://emcrit.org/wp-content/uploads/2019/06/seroalgo.svg)

podcast(back to contents) (#top)

(https://i1.wp.com/emcrit.org/wp-content/uploads/2016/11/apps.40518.14127333176902609.7be7b901-15fe-4c27-863c-7c0dbfc26c5c.5c278f58-912b-4af9-

88f8-a65fff2da477.jpg)

Follow us on iTunes (https://itunes.apple.com/ca/podcast/the-internet-book-of-critical-care-podcast/id1435679111)

The Podcast Episode

Want to Download the Episode?Right Click Here and Choose Save-As (http://tra�c.libsyn.com/ibccpodcast/IBCC_Episode_40_Serotonin_Syndrome_Final.mp3)

questions & discussion(back to contents) (#top)

To keep this page small and fast, questions & discussion about this post can be found on another page here (https://emcrit.org/pulmcrit/serotonin/) .

(https://i1.wp.com/emcrit.org/wp-content/uploads/2016/11/pitfalls2.gif)

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.

00:00 00:00 (javascript:void(0);)

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Insu�ciently 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 withsupportive care and cessation of serotonergic medications).

5-minute summary by Jacob Avila (EMin5)

Going further: 

Differentiating serotonin syndrome and neuroleptic malignant syndrome (http://www.emdocs.net/toxcard-differentiating-serotonin-syndrome-neuroleptic-

malignant-syndrome/) (Jenna Otter, emDocs); Serotonin Syndrome and NMS: Pearls & Pitfalls (http://www.emdocs.net/serotonin-syndrome-and-

neuroleptic-malignant-syndrome-pearls-pitfalls/) (Brit Long, emDocs)Serotonin Syndrome (http://www.tamingthesru.com/blog/annals-of-b-pod/spring-2017/serotonin-syndrome) (Taming the SRU)Fentanyl can cause serotonin syndrome (http://www.thepoisonreview.com/2016/07/07/fentanyl-can-cause-serotonin-syndrome/) (The Poison Review); alsoMethylene Blue & Serotonin Syndrome (http://www.thepoisonreview.com/2010/11/24/methylene-blue-and-serotonin-syndrome/)

Serotonin Syndrome Differential Diagnosis (https://lifeinthefastlane.com/book/toxicology/serotonin-syndrome-table/) (Mike Cadogan, LITFL)Hyperthermia Syndromes (https://rebelem.com/hyperthermia-syndromes/) (Anand Swaminathan, RebelEM)

The Internet Book of Critical Care is an online textbook written by Josh Farkas (@PulmCrit), an associate professor ofPulmonary and Critical Care Medicine at the University of Vermont.

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