Serotonin Syndrome

Written by: Jason Chodakowski, MD (NUEM PGY-3) Edited by: Evan Davis, MD (NUEM Alum ‘18) Expert commentary by: Benjamin Schnapp, MD (NUEM Alum ‘16)

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Background

Serotonin syndrome is a condition characterized by increased serotonergic activity in the central nervous system. This can result from therapeutic use, inadvertent interactions, or intentional self-poisoning of any combination of drugs that have the net effect of increasing serotonergic neurotransmission. Serotonin syndrome most often causes mental status changes, autonomic and neuromuscular hyperactivity while severe cases may result in DIC, rhabdomyolysis, metabolic acidosis, renal failure, ARDS, and death.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly implicated group of medications, with other culprits including serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and recreational drugs like cocaine, ecstacy, and amphetamines. The syndrome classically occurs after the initiation of a single drug, after increasing the dose of an existing medication, or simultaneous administration of two serotonergic agents. Serotonin syndrome involving a monoamine oxidase inhibitor may be especially severe and more likely to result in death. It’s important to keep in mind that antidepressants aren’t the only serotonergic agents, and that many commonly administered medications such as tramadol, meperidine, fentanyl, dextromethorphan, and linezolid among others have serotonergic activity.

Clinical Features

The majority of cases present within 24 hours, and most within 6 hours of a change or initiation of drug. The syndrome is characterized by the triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities. The diagnosis, however, can be quite challenging as these three non-specific domains of symptomatology can present with very wide spectrum of severity.

Diagnosis

There is no confirmatory test for serotonin syndrome, the diagnosis is entirely clinical. The best validated diagnostic criteria for serotonin syndrome is the Hunter Toxicity Criteria. To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet one of the following conditions:

• Spontaneous clonus

• Inducible clonus plus agitation or diaphoresis

• Ocular clonus plus agitation or diaphoresis

• Tremor plus hyperreflexia

• Hypertonia plus temperature above 38ºC plus ocular clonus or inducible clonus

Differential Diagnosis:

Multiple other entities can present with a general sympathomimetic picture and should be considered in the differential diagnosis. These include:

• Neuroleptic malignant syndrome (NMS)

• Anticholinergic toxicity

• Malignant hyperthermia

• Intoxication from other sympathomimetic agents

• Opioid withdrawal

• Sepsis

• Meningitis/encephalitis

• Heat stroke

• Delirium tremens

• Thyroid storm

Neuromuscular findings, particularly myoclonus is an important distinguishing feature of serotonin syndrome from the above etiologies.  

Serotonin syndrome can typically be differentiated from other similar conditions by its characteristic neuromuscular findings of hyperreflexia and clonus. For example, conditions such as NMS, malignant hyperthermia, and sympathomimetic toxicity all typically lack these features.

Labs/Imaging

While serotonin syndrome is a clinical diagnosis labs and imaging can be useful for monitoring complications in severe cases and to help differentiate from other diagnoses in the differential above. The most severe complications of serotonin syndrome include DIC, rhabdomyolysis, metabolic acidosis, renal failure, and ARDS. Thus, you should consider checking the following to evaluate for these:

• CBC

• BMP

• CK

• LFTs

• Lactic acid

• DIC panel

• UA

• CXR

If the diagnosis is uncertain, you might also consider blood cultures, CT brain, lumbar puncture, urine toxicology screen and/or TSH to evaluate for other things on the differential.

Management

The mainstay of therapy for serotonin syndrome is supportive care. The main hallmarks of management include:

• Discontinue the offending agent.

• IV fluids to correct hypovolemia

• Sedation with benzodiazepines. Options include Lorazepam 2-4mg and Diazepam 5-10mg, which can be repeated every 10 minutes.

• Aggressive control of hyperthermia with standard cooling techniques. Since hyperthermia is often due to increased muscle activity in serotonin syndrome, consider early intubation and paralysis in severe hyperthermia.

• Management of autonomic instability. Consider esmolol and nitroprusside for hypertension and tachycardia, while avoiding long-acting agent like propranolol. MAOIs can sometimes cause hypotension, treat this with pressors such as phenylephrine, epinephrine, and norepinephrine as necessary.

If benzodiazepines and supportive care fail to improve agitation and correct vital signs, you can consider cyproheptadine, an antidote of sorts with anti-histaminergic and anti-serotonergic activity. Cyproheptadine is only dosed orally, with a recommended initial dose of 12mg, followed by 2 mg every two hours until clinical response is seen. Symptoms from serotonin syndrome typically resolve within 24 hours.

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Expert Commentary

Gathering an accurate medication history is the key to making this diagnosis.  As mentioned above, this is a clinical entity that generally manifests quite quickly after medication initiation.  Checking the medication list in the computer isn’t going to help you here - ask the patient what kinds of new medication they might have been prescribed or they might be taking.  Remember - selective serotonin reuptake inhibitors (SSRIs) are not the only class of medications that can affect serotonin and it may be the interacting agent that you’re looking for.  Besides the above, other common medications that can be problematic include triptans, ondansetron, valproic acid, carbamazepine, lithium, cyclobenzaprine, and even herbal supplements like St. John’s wort (patients may not think supplements are worth mentioning!). 

One underappreciated aspect of serotonin syndrome is the extent to which it occurs on a spectrum.  Studying for the boards and looking at the Hunter Criteria can leave one with the impression that clonus is necessary to make the diagnosis of serotonin syndrome.  This is not the case, and it has been suggested that many milder cases, presenting with only symptoms such as tachycardia, diarrhea, and restlessness, may be going missed.  Again, medication history is essential here.

Benjamin Schnapp, MD

Assistant Residency Program Director, University of Wisconsin-Madison Emergency Medicine

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How To Cite This Post

[Peer-Reviewed, Web Publication]  Chodakowski J, Davis E (2018, November 19). Serotonin Syndrome  [NUEM Blog. Expert Commentary by Schnapp B]. Retrieved from http://www.nuemblog.com/blog/serotonin-syndrome

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Other Posts You May Enjoy

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 References

1. Boyer, Edward W., and Michael Shannon. "The serotonin syndrome." New England Journal of Medicine 352.11 (2005): 1112-1120.

2. LoVecchio, Frank, and Erik Mattison.. "Atypical and Serotonergic Antidepressants." Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e Eds. Judith E. Tintinalli, et al. New York, NY: McGraw-Hill, 2016,

3. Mason, Peter J., Victor A. Morris, and Thomas J. Balcezak. "Serotonin Syndrome Presentation of 2 Cases and Review of the Literature." Medicine 79.4 (2000): 201-209.

Serotonin Syndrome

Written by: Jacob Stelter, MD (NUEM PGY-3) Edited by: Elizabeth Byrne, MD,  (NUEM Graduate 2017) Expert Commentary by: Patrick Lank, MD

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The Case

A 21-yearold male with history of PTSD and depression presented to the ED complaining of “feeling anxious.” When evaluated, the patient was found to be anxious, continuously pacing around the room. His speech was pressured as he tangentially answered questions.  During the interview he stated that he was discharged a few days ago from a psychiatric hospital after he had intentionally overdosed on clonazepam. He then admited that two hours prior to arrival in your ED he took 30 pills of his prescribed sertraline 100mg tabs to “calm his nerves.” He denied any concurrent substance abuse. Despite the stated overdose, he denied any suicidal intent with his ingestion.

Physical Exam:

Vital Signs: T 98.9F oral   HR 137   BP  152/89   RR 20    Sat 99% on room air

General: Awake, alert, anxious-appearing, pacing around the room, mildly diaphoretic

Head: normocephalic, atraumatic

HEENT: PERRL,  EOMI, anicteric sclera, mydriatic pupils b/l, 8mm

Cardiac: tachycardic,  regular rhythm, no MRG

Resp: clear to auscultation, nonlabored, no crackles appreciated

Abd: Soft, not distended, not-tender to palpation, +bowel sounds

Extremities: well perfused, 2+ radial and DP pulses b/l, mildly diaphoretic

Neuro: AAOx3, 5/5 strength in all 4 extremities, +ankle clonus, hyperreflexia on patellar reflexes.

Psych: Cooperative but anxious with pressured and tangential speech., no HI , SI, hallucinations/delusions

Pertinent Labs:

WBC 12.5, Hgb 15.8, electrolytes within normal limits,  LA of 1.7.

Urine drug screen was positive for amphetamines and benzodiazepines. Acetaminophen, salicylate, and ethanol concentrations were below detection limits.

ECG:

Sinus tachycardia, QTc 457, no abnormal morphology of the QRS complexes

Diagnosis?

Serotonin Syndrome due to SSRI overdose.

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Serotonin Syndrome

Overview

Serotonin syndrome is a disorder that is precipitated by excess serotonin. It is classically described as having a combination of hyperautonomic hemodynamic changes, neuromuscular derangements, and a change in the patient’s mental status. [1]  Serotonin syndrome is a medical condition seen only in patients with exposure to serotonergic medications and has been more recently appreciated since the advent of serotonergic drugs used to treat depression and anxiety. However, in addition to pharmaceuticals, botanicals and recreational drugs of abuse can also be serotonergic.  Causative substances increase the amount of circulating serotonin in the bloodstream, which leads to an increased propensity to develop serotonin syndrome [2].  This is not a rare diagnosis; there are approximately 7,300 cases per year results in about 100 deaths [1].

Clinical Presentation

View fullsize

Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20.

The diagnosis of serotonin syndrome will often manifest around the time of a dose increase, addition of another serotonergic agent or an overdose on a serotonergic agent [3]. Serotonin syndrome will typically manifest within 24 hours of exposure to the serotonergic agent [4]. Symptom presentation  can be separated into three main categories: cognitive, autonomic and neuromuscular. Cognitive symptoms range from restlessness and anxiety to agitation and altered mental status [2].  Autonomic signs and symptoms include tachycardia, mydriasis, hyper- or hypotension, hyperthermia and diaphoresis [2]. Neuromuscular symptoms are also usually observed, ranging from akathisia to muscle rigidity, hyperreflexia and myoclonus [2].  Serotonin syndrome can be a life-threatening condition if not promptly recognized and treated as it can progress to seizures or shock [1]. 

View fullsize

Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20.

Treatment

The most important initial step to the treatment of serotonin syndrome is to remove exposure to the offending agent. Use of activated charcoal to assist with gastrointestinal decontamination can be considered in the setting of a recent ingestion [1].  Following this, the cornerstone of therapy of serotonin syndrome is symptom based supportive care, with benzodiazepines being one of the most important components of treatment [1, 2]:

• Obtain an ECG to evaluate the QTc and QRS durations.
• Begin IV fluid rehydration and resuscitation.
•  If the patient is hyperthermic, especially greater than 40 ºC, begin active external cooling.
• Antipyretics are not useful for the treatment of hyperthermia secondary to serotonin syndrome. This is because the hyperthermia is due to increased muscle activity and not secondary to change in the hypothalamic temperature set point.
• Benzodiazepines improve numerous symptoms of serotonin syndrome, especially agitation and are one of the most important elements of treatment.
• Use easily titrated medications like nitroprusside or esmolol for severe hypertension.
• If needed, vasopressors should be used for refractory hypotension.
• A recent study has suggested the potential utility of dexmedetomidine to treat serotonin syndrome (5).
• Cyproheptadine, a serotonin antagonist, has long been proposed anecdotally for the treatment of serotonin syndrome.  However, multiple studies suggest that it does not change outcomes and may only help temporarily control symptoms (6).

Unless the clinical features are very mild, these patients will likely need monitoring in an ICU setting for at least 24 hours after being initially managed in the Emergency Department (ED).  As always, especially in the case of an intentional overdose, contacting the local Poison Control Center is a valuable resource in helping to treat these patients.

What about Neuroleptic Malignant Syndrome?

One of the disorders that can present similarly to serotonin syndrome is neuroleptic malignant syndrome (NMS).  Pathophysiologically, NMS is related to an inherited genetic mutation in skeletal muscle and is provoked in the presence of certain neuroleptics [7]. Neuroleptic malignant syndrome often occurs after exposure to drugs that affect the central dopaminergic system, such as haloperidol. There are inherent differences between NMS and serotonin syndrome. Serotonin syndrome tends to present within 24 hours of exposure to the offending agent, whereas NMS will often be more delayed, presenting after 7 days of starting the neuroleptic [4]. Patients with serotonin syndrome will often be agitated and delirious while NMS patients will often have dysphagia, incontinence and increased secretions [4]. NMS will often have extrapyramidal side effects, muscle rigidity and rhabdomyolysis compared to the mydriasis, clonus and hyperreflexia of serotonin syndrome [4].

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Return to the Case

As noted above, the patient in this case exhibited all the hallmark signs of serotonin syndrome, including agitation, restlessness, diaphoresis, mydriasis, hyperreflexia and clonus.  In the emergency department, this patient was treated with multiple rounds of lorazepam and boluses of saline which helped to control his symptoms.  This patient was admitted to the medical ICU and monitored for an additional 24 hours.  After his symptoms and vital signs normalized, he was transferred to the floor and received the psychiatric evaluation and treatment that he needed.  His hospital course was uncomplicated and he was transferred to an inpatient psychiatric treatment facility for further care.

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Take Home Points

1. Serotonin syndrome can be a life-threatening condition. Keep a high suspicion for this in patients on serotonergic agents.
2. The hallmark signs and symptoms of serotonin syndrome are anxiety and restlessness, diaphoresis, mydriasis, clonus, hyperrflexia, tachycardia and hypertension.
3. Treatment is mainly supportive care and includes intravenous fluids, benzodiazepines titrated to symptom control and blood pressure control as needed.
4.  Serotonin syndrome is often confused with NMS.  Remember, NMS is in the setting of exposure to neuroleptics and tends to present later on with symptoms of extrapyramidal side effects, muscle rigidity and increased secretions.
5. Local poison control centers are a great resource in helping manage the treatment of patients with serotonin syndrome and most will require at least 24 hours in an ICU setting after ED diagnosis and management.

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Expert Commentary

Dear Dr. Stelter,

Thank you again for yet another exciting tox blog post! This case has a tremendous amount to dissect, but I want to focus on a few things.  For this case, let’s talk about the tox history, the tox physical exam, and the “supportive care” recommendation. Really, this is the definition of bread and butter medical toxicology.

The patient history described above is incredibly common, and that makes sense! Patients with a known history of psychiatric disease have higher risk of having psychiatric emergencies and have access to psychiatric medications. So whether by misunderstanding the purpose of their medication or by intentionally trying to harm oneself, it is common that we as medical toxicologists have to consider the effect a patient’s psychiatric medications have had (or will have) on their current clinical state. So what I want to know out of this patient is what all he could have been exposed to and when. Here are examples of questions I ask:

•  “When did you take this medication?” (Looking at the clock) “Ok. It’s 3pm. You took it 2 hours ago, so at 1pm you sat down and swallowed 30 pills?” In essence, I want the patient to describe exactly how he was exposed – this can also clue me into his intent.
• “Did you take anything else?” (Answer is commonly “no” – always dig deeper) “Are you on any other medication? When is the last time you took that medication? When you started to feel sick before you came into the emergency department, did you take anything else to help with your symptoms?”
•  “This may sound silly to you, but I also care about anything else you are taking. Are you on any vitamins or diet pills or herbals or cleanses? Is there anything you have purchased and taken in the last week which was not food or a prescription medication we have already talked about?”
• “Do you do any drugs?” I purposely leave the word “illicit” out. I don’t really care about legality. I just want to make them better. “I have seen many patients use all sorts of things that make them feel as sick as you feel now. Is there anything you can think of that you’ve taken which could make you this sick?”

This physical examination gave you your diagnosis! Usually we are clued into these diagnoses based on hyperthermia, which this patient frustratingly did not have. But that “hot tox” differential is something all emergency physicians should be aware of and facile in differentiating between. It includes serotonin syndrome, NMS, sympathomimetic toxicity (including cocaine, amphetamines, MDMA, cathinone derivatives, etc.), anticholinergic toxicity, and severe salicylate toxicity just to name a few.  Although this patient did not have hyperthermia, he did have almost every other finding associated with serotonin syndrome with the most specifically-associated being clonus. Once I see clonus, I take a step back and see if serotonin syndrome fits into the clinical picture.

Finally, I greatly appreciate your description of symptom-focused supportive care in this clinical scenario. As you have displayed, “supportive care” is not super simple. It is nuanced and multifaceted and very frequently life-saving. Before fellowship I was frustrated that there wasn’t necessarily a specific antidote or procedure we could do to reverse toxicity in all poisoned patients. With time, however, I have gained great respect for “supportive care” – regretting when it is not performed adequately and truly appreciating when it is life-saving.

So in this single case you have touched on the key major aspects of the specialty of medical toxicology. I hope some of my points were helpful to you in further appreciating the stellar medical care you provided this sample patient.

Sincerely,

Patrick Lank, MD

Associate Program Director Northwestern Emergency Medicine 

Assistant Professor of Emergency Medicine

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How to cite this post

[Peer-Reviewed, Web Publication] Stelter J,  Byrne E (2017, Nov 13). Serotonin Syndrome [NUEM Blog. Expert Commentary By Lank P]. Retrieved from http://www.nuemblog.com/blog/serotonin-syndrome

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References

1. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med 2005;352:1112-20.
2.  LoVecchio F, Mattison E. Atypical and serotonergic antidepressants. In Tintinalli’s emergency medicine: A comprehensive study guide. J Tintinalli (Ed.) (pp. 1219-24). 2016. New York, NY: McGraw-Hill.
3. Pedavally S, Fugate JE, Rabinstein AA. Serotonin syndrome in the intensive care unit: Clinical presentations and precipitating medications. Neurocrit Care 2014;21:108-13.
4. Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: A brief review. Can Med Assc J 2003;168:1439-42.
5.  Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Ann Pharmacotherapy 2014;14:1651-4.
6.  McDaniel WW. Serotonin syndrome: Early management with cyproheptadine. Ann Pharmacother 2001;35:870-3.
7.  Keck PE, Caroff SN, McElroy SL. Neuroleptic malignant syndrome and malignant hyperthermia: End of a controversy? J Neuropsychiatry Clin NeuroSci 1995;7:135-44.

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