DANA BARTLETT, RN, MA, MSN

Transcription

1 SEROTONIN SYNDROME DANA BARTLETT, RN, MA, MSN 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1

2 Continuing Nursing Education Course Director & Planners William A. Cook, PhD, Director, Douglas Lawrence, MS, Webmaster Susan DePasquale, CGRN, MSN, FPMHNP-BC, Lead Nurse Planner Accreditation Statement NurseCe4Less.com is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. Credit Designation This educational activity is credited for 2 hours. Pharmacology content 30 minutes. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Course Author & Planner Disclosure Policy Statements It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities. All authors and course planners participating in the planning or implementation of a CNE activity are expected to disclose to course participants any relevant conflict of interest that may arise. Statement of 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 2

3 Course Purpose This course will help nurses identify signs and symptoms of serotonin syndrome and recommended treatment. Learning Objectives 1. Provide a basic definition of serotonin syndrome. 2. Correctly identify the causes of serotonin syndrome. 3. Name two drug classes that inhibit serotonin reuptake; and, two drugs that can cause excessive release serotonin. 4. List three illicit drugs that may cause serotonin syndrome. 5. List the three categories of signs/symptoms that are diagnostic of serotonin syndrome. 6. Identify the diagnostic sign that is most reliably noted in cases of serotonin syndrome. 7. Identify autonomic, cognitive, and neuromuscular changes seen in serotonin syndrome. 8. Identify the name of the criteria that are used to diagnose serotonin syndrome. 9. List three clinical conditions that may be mistaken for malignant hyperthermia. 10. Identify the usual time of onset of the signs and symptoms of serotonin syndrome. 11. Identify three serious complications of serotonin syndrome. 12. Identify the best therapy, three specific treatments, and three drugs that may help in serotonin syndrome. 13. Identify three drugs that may be helpful in treating serotonin syndrome. 14. List drugs that should not be used to treat serotonin syndrome. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 3

4 Target Audience Advanced Practice Registered Nurses, Registered Nurses, Licensed Practical Nurses, and Associates Course Author & Director Disclosures Dana Bartlett, RN, BSN, MSN, MA, William S. Cook, PhD, Douglas Lawrence, MS, Susan DePasquale, CGRN, 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, CGRN, MSN, FPMHNP-BC. Release Date: 3/3/2014 Termination Date: 3/3/2017 Please take time to complete the self-assessment Knowledge Questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4

5 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5

6 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 b. Metabolic, neuromuscular, cognitive c. Cognitive, neuromuscular, autonomic d. 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6

7 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 7

8 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 8

9 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. It inhibits gastric secretion, acts as a smooth muscle stimulant, promotes platelet aggregation, affects vascular tone, and is a central and peripheral neurotransmitter. In the brain, serotonin is involved in mood, personality, affect, appetite, motor function, temperature regulation, sexual activity, pain perception, and sleep induction. 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 Ca 2+ 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9

10 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 (e.g., decreased peristalsis) and the physiological action produced by inhibition may be an increase in a particular function (e.g., 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 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 10

11 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: 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11

12 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 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 12

13 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 Most cases resolve within 24 hours, but there have been reports of the serotonin syndrome lasting for several days. 26 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13

14 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: Sympathomimetics: Fenfluramine, phentermine, phenylpropanolamine 5-HT1 agonists: Almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan Monoamine oxidase inhibitors: Isocarboxazid, moclobemide, phenelzine, selegiline, and tranylcypromine nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 14

15 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 15

16 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; 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 Further, 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 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 16

17 medical literature about drug combinations that can cause serotonin syndrome. MAOIs and amphetamines, dexttromethorphan, 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 serotoninreuptake inhibitors, ecstasy, dextromethorphan, or meperidine. 42 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 17

18 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 misdiagnosed 43, 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 18

19 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 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 19

20 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 (e.g., 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 20

21 Dunkley, et al., (2003) insert study year here) make the point that the term serotonin syndrome may contribute to the confusion surrounding this syndrome and the under-diagnosis of serotonin syndrome. 51 They feel 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 mentioned above by Dunkley, et al., also suggest that serotonin toxicity may 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 21

22 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, e.g., the pupils are not mydriatic, the patient will have normal bowel sounds, and bradyreflexia and a rigid leadpipe 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: nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 22

23 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, nonconvulsive seizures, sympathomimetic syndrome caused by a large dose or an overdose of sympathomimetic drugs), sepsis, serotonin discontinuation syndrome, thyroid storm, and tetanus 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 23

24 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 24

25 TREATMENT Most cases of serotonin syndrome will improve dramatically or resolve with 24 hours 61 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 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 25

26 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 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 26

27 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 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 27

28 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 28

29 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 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, 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 EW (2005) and Cooper BE (2013) note there are no controlled studies that have evaluated the use of cyproheptadine nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 29

30 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 30

31 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 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 31

32 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 32

33 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 the NURSECE4LESS.COM course planners evaluate nursing knowledge needs met following completion of this course by completing the self-assessment Knowledge Questions after reading the article. Correct Answers, page 37. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 33

34 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 34

35 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 b. Metabolic, neuromuscular, cognitive c. Cognitive, neuromuscular, autonomic d. 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 35

36 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 36

37 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 37