SEROTONIN SYNDROME - Nurse CEUs Online - … nursece4less.com nursece4less.com nursece4less.com nursece4less.com 3 Course Purpose This course will help nurses identify signs and symptoms

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SEROTONIN SYNDROME

DANA BARTLETT, RN, BSN, MSN, MA

Dana Bartlett is a professional nurse and author. His

clinical experience includes 16 years of ICU and ER

experience and over 20 years of as a poison control

center information specialist. Dana has published

numerous CE and journal articles, written NCLEX

material, written textbook chapters, and done editing

and reviewing for publishers such as Elsevire,

Lippincott, and Thieme. He has written widely on the subject of toxicology and was

recently named a contributing editor, toxicology section, for Critical Care Nurse

journal. He is currently employed at the Connecticut Poison Control Center and is

actively involved in lecturing and mentoring nurses, emergency medical residents

and pharmacy students.

ABSTRACT

Drugs can react to cause the body to have too much serotonin and

lead to serotonin syndrome, which is a potentially life threatening

condition. Serotonin syndrome is caused by therapeutic doses, drug

interactions, or overdoses of medications that directly or indirectly

affect the serotonergic system. An excess stimulation of the

serotonergic receptors is what causes serotonin syndrome. The

stimulation is excitatory and causes symptoms, such as tachycardia,

hypertension, agitation, excessive muscular activity. There is no

proven antidote for serotonin syndrome that is effective and safe. The

best treatment is supportive care. Health care professionals must

consider the possibility of serotonin syndrome in the setting of

serotonergic medications where mental status changes and

neurological hyperexcitability occur.


Continuing Nursing Education Course Planners

William A. Cook, PhD, Director, Douglas Lawrence, MA, Webmaster,

Susan DePasquale, CGRN, MSN, FPMHNP-BC, Lead Nurse Planner

Policy Statement

This activity has been planned and implemented in accordance with

the policies of NurseCe4Less.com and the continuing nursing education

requirements of the American Nurses Credentialing Center's

Commission on Accreditation for registered nurses. It is the policy of

NurseCe4Less.com to ensure objectivity, transparency, and best

practice in clinical education for all continuing nursing education (CNE)

activities.

Continuing Education Credit Designation

This educational activity is credited for 2 hours. Nurses may only claim

credit commensurate with the credit awarded for completion of this

course activity.

Pharmacology content is 30 minutes.

Statement of Learning Need

Nursing knowledge to identify serotonin syndrome and to help patients

avoid it is imperative to avoid complications. Patients that are

prescribed serotonergic medications need to be educated and warned

about the possibility of serotonin syndrome and subtle changes that

could lead to severe adverse outcomes.


Course Purpose

This course will help nurses identify signs and symptoms of

serotonin syndrome and recommended treatment.

Target Audience

Advanced Practice Registered Nurses and Registered Nurses

(Interdisciplinary Health Team Members, including Vocational Nurses

and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Dana Bartlett, RN, BSN, MSN, MA, William S. Cook, PhD,

Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC –

All have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Activity Review Information

Reviewed by Susan DePasquale, MSN, FPMHNP-BC.

Release Date: 2/15/2016 Termination Date: 3/3/2017

Please take time to complete a self-assessment of knowledge,

on page 4, sample questions before reading the article.

Opportunity to complete a self-assessment of knowledge

learned will be provided at the end of the course.


1. Which of the following is the correct definition of serotonin

syndrome? a. Signs and symptoms caused by excessive stimulation of the

serotonergic system.

b. Signs/symptoms caused by serotonergic drug overdose.

c. A clinical condition that closely resembles neuroleptic

malignant syndrome.

d. A clinical condition characterized hyperthermia, clonus, and

agitation.

2. Which of these classes of drugs that inhibits the reuptake

of serotonin? a. Common analgesics

b. Illicit drugs

c. Sympathomimetics

d. SSRIs

3. Three illicit drugs that may cause serotonin syndrome are:

a. Methamphetamine, heroin, marijuana

b. Cocaine, LSD, ecstasy

c. Marijuana, ecstasy, cocaine

d. Dextromethorphan, LSD, methamphetamine

4. The criteria used to diagnose serotonin syndrome are:

a. Sternbach’s criteria

b. Hunter’s criteria

c. Modified Glasgow scale

d. Romberg criteria

5. Two clinical conditions that may be mistaken for serotonin

syndrome are: a. Cholinergic syndrome, syndrome, malignant hyperthermia

b. Anticholinergic syndrome, Stevens-Johnson syndrome

c. Neuroleptic malignant syndrome, anticholinergic syndrome

d. Sympathomimetic syndrome, drug-induced hypothermia


Introduction

Serotonin syndrome is a group of signs and symptoms caused by

excessive stimulation of the serotonin receptors. Serotonin syndrome

is caused by therapeutic doses, drug interactions, or overdoses of

medications that directly or indirectly affect the serotonergic system.

The first case of diagnosed serotonin syndrome occurred in the late

1950s, but case reports of unrecognized serotonin syndrome predate

that by at least 20 years. The clinical presentation of serotonin

syndrome can be intense and dramatic, but it can also be mild and

subtle. Serotonin syndrome can be mistaken for an infectious or

metabolic disorder or for the clinical syndromes caused by

anticholinergic or sympathomimetic poisoning, or for the neuroleptic

malignant syndrome or malignant hyperthermia.

Although it is unusual for the serotonin syndrome to cause a fatality, a

severe case of serotonin syndrome is a medical emergency that can

rapidly cause multi-system organ failure. Nurses must be aware of

serotonin syndrome because drugs that can cause it are in common

use, and intentional overdoses with drugs that can cause the serotonin

syndrome are being seen with increasing frequency, which make it

difficult to detect and easily mistaken serotonin syndrome for other

pathologies.

Serotonergic System

Serotonin (also called 5-hydroxytryptamine) is a monoamine

neurotransmitter that acts centrally and peripherally. It is synthesized

in the central nervous system and in enterochromaffin cells in the


gastrointestinal tract. Serotonin has many complex functions, and the

full range and activity of these is not known.

In the brain, serotonin is involved in mood, personality, affect,

appetite, motor function, temperature regulation, sexual activity, pain

perception, and sleep induction. Serotonin also inhibits gastric

secretion, acts as a smooth muscle stimulant, promotes platelet

aggregation, affects vascular tone, and is a central and peripheral

neurotransmitter.

Serotonin is stored in vesicles in presynaptic neurons. It is released

into the synaptic cleft and binds to a serotonin receptor on the

postsynaptic neuron. There are seven families of serotonin receptors

(5-HT1 to 5HT7) and several of these have different subtypes, for

example, 5-HT1A. Serotonin binding to a 5-HT receptor initiates a wide

variety of effects on the post-synaptic neuron (decreasing or

increasing intracellular cAMP levels, causing Na+ and Ca2+ influx and

depolarization action), however the basic effect of serotonin is

excitatory.

After binding to the receptor, serotonin is transported back to the

presynaptic neuron where it reenters the vesicles or is broken down by

monoamine oxidase.1,2


Learning Break:

Neurotransmitters such as serotonin, dopamine, and glycine, function by

binding to receptors on the membranes of post-synaptic neurons. These

receptors are ligand-gated ion channels or G protein receptors. When a

neurotransmitter binds to a ligand-gated ion channel, the channel opens and

ions enter or leave the cell: depending on which ions enter or leave, the effect

of the neurotransmitter can be excitatory (causing cell depolarization) or

inhibitory (preventing cell depolarization). When a neurotransmitter binds to a

G protein, the same effects occur.

Example:

When serotonin binds to G proteins of the 5-HT1 receptors, potassium ions

channels open, potassium leaves the cell – increasing membrane potential and

inhibiting depolarization – and cAMP concentrations are decreased, and the

effect is inhibitory. It is important to remember that the terms inhibition and

excitation refer to how the neurotransmitter affects the cell. The physiological

action produced by excitation may be a decrease in a particular function (i.e.,

decreased peristalsis) and the physiological action produced by inhibition may

be an increase in a particular function (i.e., muscle tremor or hyperreflexia).

Serotonin Syndrome: Epidemiology

Serotonin syndrome is not a recent phenomenon. It was first

recognized in animals, and the first case described in a human was

reported in 19593 The term serotonin syndrome was first used by Insel

et al in 1982 to describe a patient who developed serotonin syndrome

from a combination of an monoamine oxidase (MAO) inhibitor and a

tricyclic antidepressant.4


The exact incidence of serotonin syndrome is not known. One author

noted that 14-16% of all patients who took an overdose of a selective

serotonin reuptake inhibitor (SSRI) had signs and symptoms of

serotonin syndrome.5 Fatality rates have been reported to be between

2-12%, but death from serotonin syndrome is considered to be an

unusual event.6 Serotonin syndrome has been described in all ages

groups, including neonates, children, and the elderly.7-9

Serotonin Syndrome:

How It Happens And The Clinical Presentation

The essential cause of serotonin syndrome is an excess stimulation of

the serotonergic receptors. The stimulation is excitatory and causes

the tachycardia, hypertension, agitation, and excessive muscular

activity. and the other signs and symptoms of the syndrome. The

excess stimulation occurs by one of the following six mechanisms:10-13

Direct stimulation of the serotonergic receptors:

Such as occurs with the medications buspirone, carbamazapine,

lithium, as well as with LSD.

Excessive release of serotonin:

Such as occurs with amphetamines, cocaine, dextromethorphan,

levodopa, monoamine oxidase inhibitors, reserpine, as well as

with ecstasy/MDMA.

Decreased breakdown of serotonin:

Such as occurs with monoamine oxidase inhibitors and St. John’s

wort.


Enzyme inhibition:

Cytochrome P450 enzymes that metabolize certain serotonergic

drugs can be inhibited by these drugs, e.g., dextromethorphan,

methadone, oxycodone, tramadol, venlafaxine.

Increase in serotonin precursors:

The essential amino acid, Tryptophan.

Decreased serotonin reuptake:

Selective serotonin-reuptake inhibitors, such as citalopram,

escitalopram, fluoxetine, fluvoxamine, paroxetine, and

sertraline; as well as, dextromethorphan, monoamine oxidase

inhibitors, methadone, and trazadone.

It is not known exactly which families and subtype of serotonin

receptors are involved in the serotonin syndrome, which could be one

of the factors accounting for the variability of the clinical presentation

of this pathology.14 Some authors, however, have identified the 5-HT1C

and the 5-HT2 receptors as the ones affected in the serotonin

syndrome.15 Although there is a wide range of signs and symptoms

that are possible, serotonin syndrome is definitely characterized and

diagnosed by abnormal autonomic, cognitive, and neuromuscular

changes.16-18 These are further outlined below:

Autonomic:

Autonomic changes include hyperthermia, hypertension,

tachycardia, diaphoresis, flushing, increased bowel sounds,

diarrhea, and mydriasis. The hyperthermia can be very severe

with a body temperature ≥ 38.5° C and higher.


Cognitive:

There are many cognitive changes associated with serotonin

syndrome such as agitation, drowsiness, coma, hypomania,

anxiety, confusion, hallucinations, and delirium.

Neuromuscular:

Akathisia, clonus, hyperreflexia, myoclonus, rigidity, shivering,

and tremor.

Learning Break:

Clonus - inducible, ocular, or spontaneous - is the most reliable finding

when diagnosing serotonin syndrome. Clonus is defined as alternate

muscular contraction and relaxation in rapid succession. This will be

discussed in more detail later in the module.

These are the signs and symptoms that have been observed in

patients who have serotonin syndrome. The clinical presentation and

the severity of signs and symptoms are quite variable: the serotonin

syndrome can be mild and quite subtle in presentation or severe and

life threatening.

Patients with a mild case of serotonin syndrome may feel restless and

anxious, they may have a low-grade fever, and mild, intermittent

tremors, and it is easy to overlook or misdiagnose these types of

cases. A severe case of serotonin syndrome is a medical emergency.

These patients may have a body temperature >41° C. Coma,


metabolic acidosis, renal failure, rhabdomyolysis, and disseminated

intravascular coagulation (DIC) may occur and all of this can develop

very rapidly.19,20

Serotonin syndrome typically begins very quickly: the onset of effects

can be within minutes after exposure. In most cases the patient will

develop signs and symptoms within six hours after exposure to a drug

or drugs,21,22 but a delay of up to 24 hours is possible.23-25 Most cases

resolve within 24 hours, but there have been reports of the serotonin

syndrome lasting for several days.26

Drugs That Cause Serotonin Syndrome

Certain classes of medications have been definitely identified as drugs

that can cause serotonin syndrome, and this makes sense because

their therapeutic effect is based on their action on the serotonergic

system. The SSRIs such as fluoxetine and sertraline, and monoamine

oxidase inhibitors (MAOIs) such as phenelzine and moclobemide, are

common examples of these drugs.

Other drugs may cause serotonin syndrome; however, the connection

between the syndrome and the drug is not as obvious because many

drugs affect uptake or metabolism of multiple neurotransmitters that

does not always translate to a measurable or observable clinical effect.

Two such examples are bromocriptine and tramadol. Both drugs do

have an in vivo effect on the serotenergic system; however, the

therapeutic effect of bromocriptine is caused by dopamine receptor

agonist activity, and the therapeutic effect of tramadol is caused by


agonism of the mu opioid receptors. Yet, both bromocriptine and

tramodol can cause serotonin syndrome.

Drugs and supplements that have been identified as causing, being

associated with, or suspected of causing serotonin syndrome

include:27-32

Sympathomimetics:

Fenfluramine, phentermine, phenylpropanolamine

5-HT1 agonists:

Almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan,

sumatriptan, zolmitriptan

Monoamine oxidase inhibitors: Isocarboxazid, moclobemide,

phenelzine, selegiline, and tranylcypromine

Selective serotonin reuptake inhibitors:

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine,

sertraline

Tricyclic antidepressants:

Amitriptyline, amoxapine, clomipramine, desipramine, doxepin,

imipramine, maprotiline, nortriptyline, protriptyline, trimipramine

Opiates/analgesics:

Buprenorphine, codeine, levomethorphan, levorphanol,

meperidine, methadone, oxycodone, pentazocine, pethidine,

tapentadol, tramadol


Illicit drugs:

Amphetamine, bath salts, cocaine, ecstasy/MDMA, LSD

(unconfirmed)

Antidepressants and anxiolytics:

Bupropion, buspirone, duloxetine, mirtazapine, nefazodone,

trazodone, venlafaxine.

Antiemetics:

Droperidol, granisetron, metoclopramide, ondansetron

Dietary supplements/herbal product:

Ginseng, St. John’s wort, tryptophan, yohimbe

Other drugs:

Amantadine, bromocriptine, carbamazapine, carisoprodol,

chlorpheniramine, dextromethorphan, dihydroergotamine,

fluconazole, levodopa, linezolid, lithium, methylene blue,

olanzapine, reserpine, ritonavir, and 5-

methoxydiisopropyltryptamine (a.k.a. foxy methoxy).

An increased dose of a serotenergic drug, or the addition of a

sertonergic drug to the medication regimen of a patient already taking

a SSRI, MAO, or others (discussed further below) usually causes

serotonin syndrome. It can also be a consequence of overdose.

Serotonin syndrome after a single dose of a serotonergic drug is

unusual, but this has been reported;33-35 and, it is far more common

for serotonin syndrome to be caused by a combination of drugs that

act at different 5-HT receptor sites.


Drug interactions can also be a cause of serotonin syndrome, even if

one of the drugs does not affect the serotonergic system. If a patient

who is taking an SSRI is prescribed a medication that inhibits the

cytochrome P450 enzyme that metabolizes the SSRI, serotonin

syndrome is possible.36

Furthermore, discontinued serotonergic medications can cause

serotonin syndrome if there is an insufficient period of time between

the discontinuation of one medication and beginning therapy with

another.37 An example is Norfluoxetine, which is a metabolite of

fluoxetine that has a half-life of approximately 2.5 weeks. Because of

the long half-life of this drug and its metabolite, fluoxetine may cause

serotonin syndrome if a patient is given another serotonergic drug

within several weeks of the discontinuation of fluoxetine.38

The drug combinations in the list below have been reported to cause,

or be associated with the serotonin syndrome.38-41 It’s important for

health care providers to continuously review an approved drug

database for current information when prescribing or administering

any form of mono- or combination drug therapy. Drug-drug

interactions are one possible cause of serotonin syndrome. Underlying

medical conditions must also be considered. The list below is complete

as of this writing, but there are new reports added all the time in the

medical literature about drug combinations that can cause serotonin

syndrome.

MAOIs and amphetamines, dextromethorphan, meperidine,

SSRIs, TCAs, and serotonin-norepinephrine re-uptake inhibitors

(SNRIs).


SSRIs and amphetamines, buspirone, carbamazapine,

dextromethorphan, fluconazole, MAOIs, opiates, L-tryptophan,

phentermine, SNRIs, other SSRIs, TCAs, or St John’s wort.

Opiates and ciprofloxacin, MAOIs, SSRIs, SNRIs, or tramadol.

Tramadol and mirtazapine, olanzapine, opiates, SSRIS, or

sertraline.

Other anti-depressants: buspirone and SSRIs; mirtazapine and

SSRIs; trazodone and amitriptyline, buspirone, or lithium;

venlafaxine and amitriptyline, ciprofloxacin, fluoxetine or other

SSRIs, linezolid, lithium, meperidine, methadone, moclobemide,

quietiapine, or trazodone.

Atypical anti-psychotics and mood stabilizers: Olanzapine and

citalopram or lithium; Risperidone and dextromethorphan,

fluoxetine, or paroxetine

Linezolid and amitriptyline, citalopram, duloxetine escitalopram,

fentanyl, fluoxetine, meperidine, paroxetine, sertraline, and

venlafaxine.

Severe cases of serotonin syndrome appear to be more common if

multiple drugs are taken than when a single serotonergic drug is taken

in overdose or therapeutically. Monoamine oxidase inhibitors are

particularly dangerous when combined with selective serotonin-

reuptake inhibitors, ecstasy, dextromethorphan, or meperidine.42

Diagnosing Serotonin Syndrome

Serotonin syndrome is a clinical diagnosis. There is no way to confirm

the diagnosis by using laboratory tests. The clinician must make the

diagnosis of serotonin syndrome by including the following: 1) a


physical exam; 2) taking a health and medication history, and; 3)

ruling out other clinical syndromes that can resemble the serotonin

syndrome.

Outlined in that manner, making the diagnosis of serotonin syndrome

might appear to be relatively simple, but it can be difficult to do. Mild

or even moderately symptomatic cases can easily be overlooked or

misdiagnosed43, and there is some evidence that physicians do not

know about the serotonin syndrome or its diagnostic criteria. Mckay, et

al. (1999) found that slightly over 85% of physicians who were

prescribing a medication that could cause serotonin syndrome were

not aware of the serotonin syndrome.44

Diagnostic Criteria

Although making the diagnosis of serotonin syndrome can be

challenging, there are different diagnostic criteria available that can

help.

Sternbach’s criteria:

This was the first set of criteria that was developed for

diagnosing serotonin syndrome.45 Sternbach’s criteria is a list of

10 clinical findings and three clinical situations. The clinical

findings of Sternbach’s criteria are: Ataxia, changes in mental

status (agitation, confusion, hypomania) diaphoresis, diarrhea,

fever, hyperreflexia, myoclonus, restlessness, shivering, and

tremor. The clinical situations are: 1) a recent addition, or

increase in dose of a known serotonergic drug; 2) confirmed

absence of other etiologies that could explain the patient’s


clinical condition such as an infectious disease, metabolic

abnormality, or substance intoxication or withdrawal; and, 3) no

recent addition or increase in dose of a neuroleptic drug.

According to the criteria a patient has serotonin syndrome if the

patient has three or more of the clinical findings and the patient

has been exposed to a serotonergic drug, has not been exposed

to a neuroleptic, and other likely causes of the signs and

symptoms have been ruled out.

Hunter criteria:

The Hunter’s criteria were developed in 2003.46 The authors

were dissatisfied with Sternbach’s criteria, and they reviewed

2222 cases of serotonergic drug overdose. The physical findings

in these patients were noted, and then the ones that were seen

most often in patients who been diagnosed by a clinical

toxicologist as having serotonin syndrome were considered to be

the criteria for diagnosing serotonin syndrome.

The Hunter criteria state that a patient has serotonin syndrome

if: 1) there has been an overdose of a serotonergic drug, or

exposure to a serotonergic drug within the prior five weeks; 2)

the patient has inducible clonus, ocular clonus, or spontaneous

clonus; 3) the temperature is > 38°; 4) The patient is agitated

and/or diaphoretic; and, 4) hyperreflexia and/or tremor are

noted.

Radomski criteria:

The Radomski criteria were developed in 2000 and use many of

the same clinical findings as Sternbach’s criteria and the Hunter


criteria.47 However, the Radomski criteria are intended to

provide diagnostic criteria for establishing the severity of the

serotonin syndrome.

The Hunter criteria (or those criteria, slightly adapted) is the system

that is used most often and is recommended.48 The Sternbach criteria

appear to be biased towards mental status changes, and the Hunter

criteria are felt to be more sensitive and specific and less likely than

the Sternbach criteria to miss incipient or mild cases of serotonin

syndrome.49 The Radomski criteria do not appear to be popular and

although other diagnostic criteria have been developed (i.e., the

serotonin syndrome scale) these do not appear to be in common use.50

THE HUNTER CRITERIA

Ingestion of a serotonergic drug within 5 weeks

or overdose of a serotonergic drug ↓

Spontaneous clonus → Yes → Serotonin syndrome ↓

No ↓

Inducible clonus, ocular clonus → Yes → Agitation,

↓ diaphoresis,

No fever > 38° ↓

Tremor → Yes → Hyperreflexia → Serotonin

Syndrome ↓

No ↓

Not Serotonin Syndrome


Dunkley, et al., (2003) made the point that the term serotonin

syndrome may contribute to the confusion surrounding this syndrome

and the under-diagnosis of serotonin syndrome.51 They suggested that

the diagnostic criteria - or perhaps the physicians using these criteria -

over-emphasize the more dramatic signs of serotonin syndrome. This

may result in milder forms of the syndrome being missed, and the

study by Dunkley, et al., also suggested that serotonin toxicity might

be a better term than serotonin syndrome as a syndrome is typically

thought of as a defined clinical entity. The key point for clinicians to

realize is that serotonin syndrome is a spectrum of toxicity that is

caused by an excess of serotonin; and, serotonin syndrome along the

spectrum can be diagnosed by using the Hunter criteria to look for the

characteristic autonomic, cognitive, and neuromuscular changes.

Taking a Health and Medication History

Taking an accurate health and medication history is very important. It

is fundamental to determine what medications the patient is taking

and has been taking. The clinician must be cognizant of the fact that

some drugs can cause serotonin syndrome even when the patient has

not been taking them for many weeks. Therefore, its good practice to

ask the patient whether doses have recently been changed; ask if the

patient has been taking any dietary or herbal supplements, and

determine if the medication regimen has been changed in the past five

to six weeks. Additionally, the clinician needs to determine the recent

state of the patient’s health; for example, is there any evidence of an

ongoing infectious process? What other medical problems does the

patient have? Each time a patient medication regime is reviewed by a

clinician it’s necessary to include both the existing treatment plan (i.e.,


new medications, and how they have been taking their prescriptions)

and any new organic issues in the patient’s health state.

Clinical Conditions Resembling Serotonin Syndrome

This section covers some clinical conditions that can resemble

serotonin syndrome.52,53 Neonatal considerations for newborns with

conditions resembling serotonin syndrome have been reported,

however, this is outside the scope of this study.

Neuroleptic malignant syndrome:

Neuroleptic malignant syndrome (NMS) is an idiosyncratic drug

reaction to treatment with, or withdrawal from drugs such as levodopa

and antipsychotics that act as dopamine antagonists. Important

differences between serotonin syndrome and NMS are:

The causative agents act on a different neurotransmitter;

NMS develops slowly over several days;

The clinical findings are different than those of the serotonin

syndrome, i.e., the pupils are not mydriatic, the patient will have

normal bowel sounds, and bradyreflexia and a rigid “lead-pipe

like” muscle tone will be noted; and,

NMS is not caused by an overdose.

Anticholinergic syndrome:

The anticholinergic toxidrome is caused by overdose of drugs that act

as antagonists of acetylcholine at peripheral and central muscarinic

receptors: antihistamines, benztropine, and phenothiazines are


examples. Important differences between serotonin syndrome and the

anticholinergic syndrome are:

The causative agents act on a different neurotransmitter

receptor site;

The temperature is usually 38.8°C or less; and,

The patient will have dry mucous membranes, hot, dry, and

flushed skin, decreased or absent bowel sounds, normal

muscular tone and reflexes, and urinary retention.

Malignant hyperthermia:

Malignant hyperthermia is an idiosyncratic response to inhalational

anesthesia. Important differences between the serotonin syndrome

and malignant hyperthermia are:

The causative agent;

Malignant hyperthermia is an idiosyncratic response, but the

serotonin syndrome is a normal physiological response to an

excess of a neurotransmitter; and,

The patient will have hyporeflexia and the temperature is

extremely high, as high as 46°C.

Other clinical conditions that could be mistaken for serotonin syndrome

include acute baclofen overdose, cocaine or ecstasy intoxication, drug

withdrawal, dystonic reactions, encephalitis, meningitis, non-

convulsive seizures, sympathomimetic syndrome caused by a large

dose or an overdose of sympathomimetic drugs), sepsis, serotonin

discontinuation syndrome, thyroid storm, and tetanus.54-56

There are many clinical conditions that can be mistaken for serotonin

syndrome, and trying to remember them all and their distinguishing


features can be difficult for clinicians. However, by far the most

commonly occurring are NMS and the anticholinergic syndrome. To

distinguish between NMS and the anticholinergic syndrome and

serotonin syndrome, the clinician needs to pay special attention to:

The drug ingested.

Body temperature.

Onset and development of the signs and symptoms.

Bowel sounds.

Presence or absence of hyperreflexia.

Presence or absence of clonus.

Serotonin Discontinuation Syndrome

When checking for the presence of the serotonin syndrome, it is

important to know what medications the patient has been taking; this

was previously discussed. However, if a symptomatic patient had been

taking an SSRI or another drug that affects the serotonergic system,

this can confuse the issue of assessment because if these drugs are

not tapered correctly the patient may develop serotonin

discontinuation syndrome. The syndrome occurs in approximately

20%-25% of all patients who stop taking a serotonergic drug.57

The signs and symptoms of serotonin discontinuation syndrome

usually start within one to seven days of decreasing the dose or

discontinuing the drug and they last approximately two weeks.

Somatic signs and symptoms of the serotonin discontinuation

syndrome include: chills, diarrhea, dizziness, fatigue, fever, nausea,

paresthesias, unsteady gait, and vomiting. Mood disturbances such as


agitation, anxiety, insomnia, irritation, and lethargy are common, as

well.58,59 Most cases are mild, but severe effects have been reported.60

Treatment

Most cases of serotonin syndrome will improve dramatically or resolve

with 24 hours61 but if the patient has taken a drug with a long half-life,

a drug with pharmacologically active metabolites, or an extended

release form of a drug, the signs and symptoms can last for

weeks.62.63 Mild cases can be observed for six hours and if the patient

responds well to treatment or improves spontaneously, he/she can be

discharged. Moderate and severe cases should be admitted, and

patients who have ingested an extended release preparation should be

admitted or observed for longer than six hours.

Serotonin syndrome can be caused by an overdose of serotonergic

medications, but what is considered to be an overdose? The amount of

medication that could cause serotonin syndrome cannot be precisely

quantified, but an evidence-based expert consensus published in 2007

provides the following guidelines for the SSRIs:

“Asymptomatic patients or those with mild effects . . . following

isolated unintentional acute SSRI ingestions of up to five times

an initial adult therapeutic dose (i.e., citalopram 100 mg,

escitalopram 50 mg, fluoxetine 100 mg, fluvoxamine 250 mg,

paroxetine 100 mg, sertraline 250 mg) can be observed at home

with instructions to call the poison center back if symptoms

develop. For patients already on an SSRI, those with ingestion of

up to five times their own single therapeutic dose can be


observed at home with instructions to call the poison center back

if symptoms develop.”64

Death from serotonin syndrome is unusual, but severe cases do occur

and the condition of patients who have severe serotonin syndrome

deteriorates very quickly. Patients who have severe serotonin

syndrome should be admitted to intensive care. The use of the drugs

suspected of causing the serotonin syndrome must be immediately

stopped: in mild cases this may be enough to allow the patient to

recover.

In order to avoid serious harm and to successfully treat serotonin

syndrome, it is critical to quickly identify serotonin syndrome and

aggressively provide supportive care. Antidotal therapies have been

tried, but supportive care is the keystone of caring for a patient who

has serotonin syndrome.65-66

Supportive Care

The mainstay of treatment for serotonin syndrome is supportive care.

It includes the following diagnostic tests and therapy.

Laboratory tests:

If the diagnosis of serotonin syndrome is thought to be likely or

the diagnosis seems certain, BUN and creatinine, coagulation

studies, complete blood count, creatine phosphokinase, and

serum transaminases should be obtained.

Other tests that may be needed for making the diagnosis of

serotonin syndrome would be blood cultures, urinalysis and urine


culture, cerebrospinal fluid analysis and culture, chest x-ray, and

CT of the head.

Aggressive cooling:

Aggressive cooling should be used for patients who are

hyperthermic. Acetaminophen will not help because

hyperthermia in serotonin syndrome is caused by excessive

muscular activity, not by a change in central thermoregulation.

Intubation and neuromuscular paralysis:

This will treat the hyperthermia and also treat the basic cause of

hyperthermia. Do not use the neuromuscular blocker

succinylcholine during the intubation process. Use a

nondepolarzing drug such as vercuronium.

Patients who are hyperthermic often have rhabdomyolysis.

Rhabdomyolysis increases serum potassium and increases the

risk of arrhythmias, and succinylcholine can cause hyperkalemia.

Benzodiazepines:

Benzodiazpines are one of the mainstays of treatment for

serotonin syndrome, and in animal models they have been

shown to increase survival rates.67-69 They decrease muscular

rigidity, provide sedation and their use alone may be all that is

needed for a mild to moderate case of serotonin syndrome.

Direct-acting sympathomimetics:

If the patient is hypotensive, use the direct-acting

sympathomimetics epinephrine, norepinephrine, or


phenylephrine. Dopamine acts indirectly. It must be metabolized

to epinephrine and norepinephrine before it can work and in

cases of serotonin syndrome the metabolizing enzyme

(monoamine oxidase) may be inhibited.

Nitroprusside:

Nitroprusside is a good drug to use for treating hypertension

caused by serotonin syndrome because its effects are very

short-acting: the half-life of nitroprusside is two to three

minutes. The autonomic instability in severe cases of serotonin

syndrome means that blood pressure can be very unstable and

unpredictable so using a drug that can tightly controlled is a big

advantage.70

Fluids:

Hydration is a very important treatment for serotonin syndrome.

Intravenous infusion for severe volume depletion is

recommended.

Monitor for complications:

The complications of serotonin syndrome are coma, DIC,

metabolic acidosis, renal failure, and rhabomyolysis.

Special Therapies

There is no antidote for serotonin syndrome that has been proven to

be effective and safe or for which there is extensive clinical

experience. Bromocriptine, chlorpromazine, cyproheptadine,

dantrolene, intravenous lipid, olanzapine, propranolol, and other

drugs/therapies have been used. However, the evidence that supports


or does not support the use of these drugs can be categorized as Level

II, and there are no controlled studies that compare these drugs or

truly determine how effective they are. For example, there are case

reports that suggest use of chlorpromazine, cyproheptadine, and

olanzapine helped control and shorten the duration of the signs and

symptoms of serotonin syndrome, but it may simply be that these

cases represented a natural process of recovery and the drugs had no

effect.

The drugs used in the treatment of serotonin syndrome are discussed

in greater detail below:

Chlorpromazine:

Chlorpromazine (commonly known as Thorazine®) is an

antipsychotic. The therapeutic effect of chlorpromazine is due to

its action as a centrally acting dopamine antagonist. But

chlorpromazine also blocks serotonin binding to 5-HT2A receptors

and there are several case reports of chlorpromazine being an

effective drug for treating serotonin syndrome.70-72 However,

chlorpromazine can cause hypotension, it can cause dystonias,

and it may aggravate hyperthermia, so it should be used

cautiously when treating serotonin syndrome. Chlorpomazine is

contraindicated for treating NMS because it is a dopamine

antagonist.

Cyproheptadine:

Cyproheptadine (Periactin®) is an antihistamine that acts as a

5-HT2A antagonist, and it has been successfully used to treat

cases of serotonin syndrome,73-79 and, in some of these case


reports, the resolution of the signs and symptoms was rapid and

considerable. However, treatment failures have been noted,80

and several authors point out that although cyproheptadine may

be helpful it does not shorten the time course of serotonin

syndrome.81,82 Boyer, E.W. (2005) and Cooper, B.E. (2013) note

there are no controlled studies that have evaluated the use of

cyproheptadine for the treatment of serotonin syndrome, the

evidence for its efficacy is all from case reports, and these case

reports described mild to moderate cases of serotonin

syndrome.83,84 Despite these uncertainties, cyproheptadine is

still recommended as an adjunct, as it is a serotonin receptor

antagonist, and it has sedative properties, as well.

Cyproheptadine is given orally, and if the patient cannot tolerate

oral intake it can be crushed and given via a nasogastric tube.

The dose is 12 mg followed by 2 mg doses every two hours if the

symptoms persist. The maintenance dose is 8 mg every six

hours.85,86 The pediatric dosing is 0.25 mg/kg/day, every two

hours until improvement of symptoms.87

Olanzapine:

Olanzapine (Zyprexa®) is an atypical antipsychotic. One of its

actions is 5-HT2 receptor antagonism, and sublingual olanzapine

has been used successfully to treat cases of serotonin syndrome.

Although most of the patients in these studies had a very quick

and complete resolution of the signs and symptoms, the clinical

experience with using olanzapine to treat these cases so far

consists of eight patients.88,89


Bromocriptine:

Bromocriptine has been used to treat serotonin syndrome.

However, it has serotonergic effects and its use has caused one

fatality.90,91 The drug should not be used to treat serotonin

syndrome.

Dantrolene:

Dantrolene is a skeletal muscle relaxant that is used to treat

malignant hyperthermia. It should not be used to treat serotonin

syndrome. There is no clinical evidence that it is effective, and,

animal studies showed that it is not effective. Dantrolene may

actually cause serotonin syndrome, and its use in a suspected

case of serotonin syndrome was associated with a fatality.92-94

Propranolol:

Propranolol acts as a 5-HT1A antagonist but it can cause

hypotension. It also decreases heart rate, making it difficult to

assess the patient’s condition. It should not be used to treat

serotonin syndrome.95

Intravenous lipid:

There is one case report of intravenous lipid being used for the

treatment of serotonin syndrome. The authors noted that there

was a temporal association between administration of the lipid

therapy and a decrease in hyperreflexia and rigidity.96


Summary

Serotonin syndrome is a group of signs and symptoms caused by

excessive stimulation of serotonin receptors. Serotonin syndrome is

caused by therapeutic doses, overdoses, or drug interactions between

medications that directly or indirectly affect the serotonergic system.

Direct stimulation of serotonin receptors, decreased breakdown of

serotonin, increased inhibition of serotonin reuptake, an increase in

serotonin precursors, or an excessive release of serotonin cause

serotonin syndrome.

Medications that can cause serotonin syndrome include SSRIS, MAOIs,

illicit drugs such as cocaine and amphetamines, atypical

antipsychotics, and analgesics such as fentanyl, meperidine, and

tramadol, and dextromethorphan. The incidence and severity of

serotonin syndrome are greatest when multiple drugs have been

ingested. A particularly dangerous drug combination is the MAOIs

combined with SSRIs, dextromethorphan, ecstasy, or meperidine.

The syndrome is characterized by autonomic, cognitive, and

neuromuscular derangements. Agitation, tachycardia, hypertension,

hyperthermia, muscle rigidity, clonus, hyperreflexia, diaphoresis,

diarrhea are commonly seen. Signs and symptoms usually start within

six hours, and typically last 24 hours. Clonus, inducible, spontaneous

or ocular, is the most reliable clinical finding for diagnosing serotonin

syndrome. Other clinical conditions resemble serotonin syndrome. To

distinguish serotonin syndrome, determine what drug was ingested,

determine when the signs and symptom started, the clinician should


observe for clonus and hyperreflexia, and check body temperature and

bowel sounds. The findings will be specific for serotonin syndrome.

A severe case of serotonin syndrome is a medical emergency: patients

who have severe serotonin syndrome should be admitted to intensive

care. The patient’s condition can deteriorate rapidly and dramatically.

The complications of serotonin syndrome are coma, DIC, metabolic

acidosis, renal failure, and rhabodomyolysis. Medications used to treat

serotonin syndrome, such as, chlorpromazine, cyproheptadine, and

olanzapine may be effective, but there is no conclusive evidence that

these drugs are useful therapies for treating serotonin syndrome. In

particular, drugs that should not be used to treat serotonin syndrome

include Bromocriptine, dantrolene, propranolol, and succinylcholine.

The best treatment for serotonin syndrome is supportive care.

Considerations covered in this study included the use of activated

charcoal if the patient arrives within an hour of the ingestion.

Epinephrine, norepinephrine, or phenylephrine is recommended to

treat hypotension; alternatively, nitroprusside is recommended to

control hypertension. Additionally, aggressive cooling, neuromuscular

paralysis and intubation, benzodiazepines, and IV hydration were

raised as the most important and effective therapies.

Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the

self-assessment of Knowledge Questions after reading the

article, and providing feedback in the online course evaluation.

Completing the study questions is optional and is NOT a course requirement.


1. Which of the following is the correct definition of serotonin

syndrome?

a. Signs and symptoms caused by excessive stimulation of the

serotonergic system.

b. Signs and symptoms caused by an overdose of serotonergic

drugs.

c. A clinical condition that closely resembles neuroleptic malignant

syndrome.

d. A clinical condition characterized hyperthermia, clonus, and

agitation.

2. The causes of serotonin syndrome are:

a. Prolonged use of drugs that affect the serotonergic system.

b. Therapeutic use, overdose, or drug interaction

c. Improper tapering of medications that affect the serotonergic

system.

d. It is an inevitable consequence for some people who take

serotonergic drugs.

3. Which of these classes of drugs that inhibits the reuptake of

serotonin?

a. Common analgesics

b. Illicit drugs

c. Sympathomimetics

d. SSRIs


4. Three illicit drugs that may cause serotonin syndrome are:

a. Methamphetamine, heroin, marijuana

b. Cocaine, LSD, ecstasy

c. Marijuana, ecstasy, cocaine

d. Dextromethorphan, LSD, methamphetamine

5. The three categories of signs/symptoms that are diagnostic

of serotonin syndrome are:

a. Cardiovascular, autonomic, cognitive

a. Metabolic, neuromuscular, cognitive

b. Cognitive, neuromuscular, autonomic

c. Psychiatric, metabolic, cardiovascular

6. The diagnostic signs that is most reliably noted in cases of

serotonin syndrome is:

a. Hyperthermia

b. Hallucinations

c. Tremor

d. Clonus

7. The criteria used to diagnose serotonin syndrome are:

a. Sternbach’s criteria

b. Hunter’s criteria

c. Modified Glasgow scale

d. Romberg criteria


8. Two clinical conditions that may be mistaken for serotonin

syndrome are:

a. Cholinergic syndrome, syndrome, malignant hyperthermia

b. Anticholinergic syndrome, Stevens-Johnson syndrome

c. Neuroleptic malignant syndrome, anticholinergic syndrome

d. Sympathomimetic syndrome, drug-induced hypothermia

9. The best therapy for serotonin syndrome and three specific

treatments include:

a. Supportive care: intubation, fluids, dantrolene

b. Supportive care: aggressive cooling, benzodiazepines,

cyproheptadine

c. Antidotal therapy: cyproheptadine, chlorpromazine

d. Discontinuation of the drug: supportive care

10. Drugs that should not be used to treat serotonin

syndrome are:

a. Cyproheptadine, bromocriptine, acetaminophen, propranolol

b. Dopamine, succinylcholine, epinephrine, chlorpromazine

c. Olanzapine, tramadol, phenylephrine

d. Bromocriptine, dantrolene, propranolol, succinylcholine


Correct Answers:

1) Which of the following is the correct definition of serotonin

syndrome?

*Signs and symptoms caused by excessive stimulation of the

serotonergic system

2) The causes of serotonin syndrome are: *Therapeutic use, overdose, or drug interaction

3) Which of these classes of drugs inhibits the reuptake of serotonin?

*SSRIs.

4) Three illicit drugs that may cause serotonin syndrome are: *Cocaine, LSD, ecstasy.

5) The three categories of signs/symptoms that are diagnostic of

serotonin syndrome are: *Cognitive, neuromuscular, autonomic,

6) The diagnostic signs that is most reliably noted in cases of serotonin syndrome is:

*Clonus.

7) The criteria used to diagnose serotonin syndrome are: *Hunter’s criteria.

8) Two clinical conditions that may be mistaken for serotonin

syndrome are: *Neuroleptic malignant syndrome, anticholinergic syndrome.

9) The best therapy for serotonin syndrome and three specific

treatments include: *Supportive care: aggressive cooling, benzodiazepines,

cyproheptadine.

10) Drugs that should not be used to treat serotonin syndrome are:

*Bromocriptine, dantrolene, propranolol, succinylcholine


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SEROTONIN SYNDROME - Nurse CEUs Online - … nursece4less.com nursece4less.com nursece4less.com nursece4less.com 3 Course Purpose This course will help nurses identify signs and symptoms