1. Sarah Laubach, BSN, SRNA Thomas Jefferson University Class of 2016
Serotonin Syndrome
Sarah Laubach, BSN, SRNA
Thomas Jefferson University
Class of 2016

2. Objectives Identify symptoms of serotonin syndrome
Identify medications at risk to cause syndrome development
Identify possible differential diagnoses
Discuss appropriate syndrome treatment
Review case study

3. Serotonin in the Body 5-hydroxytryptamine (5-HT)
Monoamine neurotransmitter
90% of total serotonin in the GI tract
Regulates enteric neurons and GI motility
10% synthesized in serotonergic CNS neurons
Regulates attention, behavior, thermoregulation

4. Serotonin Syndrome: What is it?
A rare, but potentially fatal adverse drug reaction
Caused by increased serotonergic activity in the CNS
Characterized by a symptom triad:
Altered mental status
Neuromuscular hyperactivity
Autonomic instability or hyperactivity
Potential for rapid onset and progression
Early recognition is key!

5. Serotonin Syndrome: What is it?
Can be caused by certain drugs, interactions between drugs, or intentional overdose
Symptoms range from mild to severe
Can be fatal if left untreated
Terms used interchangeably
Toxicity: more accurate term, as it “reflects the broad spectrum of serotonin-related side effects progressing to toxicity.”
Syndrome: used more commonly in the literature

6. Incidence
2012 Annual Report of the American Association of Poison Control Centers’ National Poison Data
47,115 people reported toxicity related to SSRIs
1723 moderate adverse events
152 major adverse events
7 deaths
Affects all age groups from newborns to older adults

7. Incidence Numbers most likely underestimated
May be confused with other medical conditions, especially if symptoms are mild
Incidence likely to increase in the future
Increasing prescriptions for SSRIs for treatment of depression and other conditions

8. Serotonin Syndrome: Cause
Drugs with serotonergic activity
SSRIs are most commonly implicated
Increased extracellular serotonin levels by limiting reabsorption into the presynaptic cell
Increased serotonin in the synaptic cleft, available to bind to the postsynaptic receptor

9. Signs & Symptoms Manifests many different ways
Mental status changes
autonomic hyperactivity
neuromuscular abnormalities
may be accompanied by rigidity, especially in the lower extremities
Mild symptom presentations can rapidly progress to more severe symptoms
Important to pay close attention to warning signs of suspected serotonin syndrome

10. Mild Symptoms Akathisia Anxiety Diaphoresis Hyperreflexia
Mild hypertension
Tachycardia
Mydriasis
Myoclonus
Shivering
Tremor

11. Moderate Symptoms Agitation Hypervigilance Increased Confusion
Myoclonus
Ocular clonus
Pressured Speech
Temperature of at least 40 degrees Celsius

12. What is Problematic?
Mild and some moderate symptoms are often masked by anesthesia, preventing the clinician from early identification of serotonin syndrome development!

13. Severe Symptoms Dramatic swings in pulse rate and blood pressure
Seizures
Metabolic Acidosis
Muscle rigidity
Rhabdomyolysis
ARDS
Renal failure
Respiratory failure
Coma
Disseminated Intravascular Coagulation
Shock

14. Symptom ID Made Easy

15. Symptom Onset Can be rapid
Symptoms can occur within minutes of drug administration, a dosage change or overdose
Approximately 60% of reported cases present within six hours of drug therapy

16. Treatment Cease administration of serotonergic medication
After cessation of the serotonergic drugs, symptoms usually end within 24 hours
Severe cases can take several days for recovery
Should the case be cancelled? Can it end quickly?
Primarily supportive treatment based on symptoms
Identify extent of symptom development through diagnostic testing such as labs and physical assessment

17. Associated Drugs SSRIs Opioid analgesics Herbal products
Serotonin-releasing agents

18. SSRIs Selective serotonin reuptake inhibitors Fluoxetine Fluvoxamine
Paroxetine
Citalopram
Sertraline
Escitalopram

19. Other antidepressants
Selective Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine
Tricyclic Antidepressants (TCAs)
Clomipramine
Imipramine
Monoamine Oxidase Inhibitors
Phenelzine
Tranylcypromine

20. Serotonin-releasing Agents
Fenfluramine
Amphetamines
Methylenedioxymethamphetamine
MDMA
Ecstasy

21. Miscellaneous
Lithium
Tryptophan
Linezolid
St. John’s Wort

22. Opioid analgesics
Fentanyl
Tramadol
Pethidine
Dextreomethorphan

23. Fentanyl & SSRI Interaction
Barash, 2011, states serotonin syndrome may be caused by an interaction between fentanyl and SSRIs
Exact mechanisms through which this reaction occurs are not fully understood
Fentanyl is commonly used analgesic in many anesthetic techniques
Barash’s Clinical Anesthesia

24. Fentanyl & SSRI Interaction
Phenylpiperidine opioids seem to be weak SSRIs
May also enhance serotonin release
Types include:
Fentanyl
Remifentanil
Sufentanil
Alfentanil
Tramadol
Meperidine

25. Symptom Diagnosis No laboratory tests available for diagnosis
Lab and diagnostic testing used to rule out other alternative explanations for the observed signs and symptoms
May initially resemble other conditions
Examination of specific neurological symptoms and ruling out other conditions will aid in making the differential diagnosis

26. Differential Diagnosis
What conditions can you think of that may resemble the symptoms of Serotonin Syndrome?

27. Differential Diagnosis
Malignant Hyperthermia
Neuroleptic Malignant Syndrome
Severe sepsis
Meningoencephalitis
Delirium tremens
Heat stroke
Anticholinergic toxicity

28. Differential Diagnosis: Neuroleptic Malignant Syndrome
Bradykinesia results in a state of immobilization, akinesia, stupor, fever and autonomic instability
Serotonin toxicity caused by serotonergic drugs frequently and predictably, also is dose related
NMS occurs with neuroleptics, but rarely and idiosyncratically, and is NOT dose related
SS rapid onset and progression over hours
NMS has slow onset and progression over days
SS: hyperkinesia, hyperreflexia/clonus, pyramidal rigidity
NMS: bradykinesia and extrapyramidal rigidity

29. Differential Diagnosis: Anticholinergic Delirium
Both AD and SS manifest with impaired consciousness, tachycardia and pyrexia
SS: Diaphoresis, clonus and hyperreflexia present
AD: Dry skin and mucous membranes without increased tone or hyperreflexia

30. Diagnosis Criteria Sternbach’s Criteria
Two main diagnostic criteria to establish serotonin syndrome
Sternbach’s Criteria
Hunter Serotonin Toxicity Criteria

31. Diagnosis: Hunter Serotonin Toxicity Criteria
Developed more recently
Consists of simple but accurate decision rules
Emphasis on clonus as the most important feature
Statistically more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach’s criteria
Considered to be the preferred diagnostic tool

33. Current Research
October 2014 AANA practice update states research primarily based on case studies
Can be prone to research bias and limited generalizability
Case studies described suggests that pts taking SSRIs are at an increased risk for serotonin syndrome following fentanyl administration
Most of the patients reviewed developed severe symptoms and required emergency care

34. The Case of Libby Zion 18yoF college student, 1984
Prescribed Phenelzine (MAOI) for depression
Experienced worsening “flu-like” symptoms, febrile
Presented to ED at 1130 pm

35. The Case of Libby Zion
Initial Assessment: writhing and agitated, but able to convey history
Febrile to 103.5o F
Normal chest xray
Elevated WBC 18,000/mm3
Admitted to hospital’s medical service
Evaluation by intern and resident, with diagnosis of “viral syndrome with hysterial symptoms”
Additional cultures ordered, prescribed IM meperidine for agitation and shivering

36. The Case of Libby Zion Over next hour, agitation increased
Became “confused”, began thrashing around in bed
Physical restraints and haloperidol 1mg ordered
Pt calmed briefly, agitation returned shortly thereafter
Temperature increased to 107o F
Cooling measures initiated
0630am Respiratory/Cardiac arrest
Cooling measures included a cooling blanket and cold compresses. Despite all efforts, Libby was unable to be resuscitated, and she died less than 12 hours after coming into the hospital.

37. Libby Zion Law
ED physicians did not properly diagnose serotonin syndrome
Led to discussions on physician supervision and long work hours for residents
Libby Zion Law, 1989
NY State Department of Health Code, Section 405
Regulation limits amount of resident physicians’ work in NY state hospitals to 80 hours/week
July 2003, the Accreditation Council for Graduate Medical Education adopted similar regulations for all accredited medical training institutions in the US
The ED physicians may not have even been aware of serotonin syndrome at this time.

38. Moving Forward
Fentanyl will continue to be a staple of anesthetic management
Goal is to keep serotonin syndrome in mind as a possible differential diagnosis during intraoperative events
Remember Symptom Triad:
Neuromuscular hyperactivity
Autonomic hyperactivity
Altered mental status
Early identification is key!

39. Thank you for your time and attention!

40. References
Barash, P. G. (2013). Clinical anesthesia. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins. Davis, J., Buck, N., Swenson, J., Johnson, K., & Greis, P. (2013). Serotonin syndrome manifesting as patient movement during total intravenous anesthesia with propofol and remifentanil. Journal of Clinical Anesthesia, 25, Gillman, P. K. (2005). Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anesthesia, 95(4), doi: /bja/aei210 Greenier, E., MPH, MBA, Lukyanova, V., PhD, & Reede, L., CRNA, DNP, MBA. (2014). Serotonin syndrome: Fentanyl and selective serotonin reuptake inhibitor interactions AANA Journal, 82(5), Stanford, S., Stanford, B., & Gillman, P. (2009). Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: An update on a case report of post-operative delirium. Journal of Psychopharmacology, , 1-6. doi: / Swadron, S. (2011). Serotonin syndrome and the libby zion affair. Retrieved from syndrome-and-the-libby-zion-affair/