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54. Serotonin Syndrome: When the Happy Hormone Gets Angry
Keywords
Serotonin syndromeFentanylOpioidsToxicologyDrug reactionsCritical careCase
Unexplained fever, tachycardia, and hypertension in the ICU.
Pertinent History
A 42-year-old male with a history of subglottic stenosis presented to the emergency department with dyspnea and stridor. He was evaluated by otolaryngology and taken to the operating room urgently for tracheal dilation. After intubation with a 4.0 endotracheal tube in the operating room, he was unable to be oxygenated or ventilated so emergent tracheotomy was performed. However, due to significant subglottic narrowing, a tracheostomy tube could not be placed. Instead, a 6.0 endotracheal tube was placed through the tracheotomy incision and left sutured in place with a plan for sedation and chemical paralysis to prevent dislodgement until revision could be performed in a few days. On arrival to the intensive care unit, the patient was agitated, tachycardic, and hypertensive with high requirements for sedation. Shortly later he developed fevers.
PMH
Depression, PTSD, subglottic stenosis, factor V Leiden, obesity
Home Meds
Oxycodone, clonazepam, paroxetine
Current Meds
Midazolam 4 mg/hour, fentanyl 100 mcg/hour, propofol 50 mcg/kg/min, cisatracurium 2.5 mcg/kg/min
SH
5 pack-year smoking history, no EtOH or illicit drugs
Pertinent Physical Exam
BP 179/73, Pulse 105, Temp 99.5 °F/37.5 °C, RR 26, SpO2 93% (on ventilator)
General: Intubated, restless, and agitated
HEENT: Bilateral mydriasis, metal-lined endotracheal tube with sutures intact per tracheotomy incision
CV: Regular, tachycardic without murmurs
Pulm: Clear mechanical breath sounds bilaterally
Abd: Soft without obvious tenderness
Neuro: Agitated, no facial asymmetry, moving all extremities equally with full strength
Ext: Warm, well-perfused, no edema
Plan (2200)
Maintain deep sedation and chemical paralysis to avoid dislodgement of the endotracheal tube
Update 1 (0900)
Patient with ongoing agitation, hypertension, and tachycardia despite heavy sedation regimen. Concern for anxiety due to inadequate sedation during neuromuscular blockade. Midazolam titrated up to 10 mg/hour and fentanyl to 300 mcg/hour. Cisatracurium rebolused. Dexmetetomidine added at 0.6 mcg/kg/hour.
Update 2 (1200)
Called to bedside for BP 231/85, HR 133, and temperature 102.2. Septic workup initiated but concern raised for serotonin syndrome after paroxetine was noted on medication review. Repeat exam notable for ongoing agitation, bilateral mydriasis, ocular clonus, increased muscle tone, and sustained ankle clonus. Fentanyl infusion stopped and cyproheptadine initiated at 4 mg per NG tube every 4 hours.
Update 3 (1600)
Significant improvement in agitation. BP now 124/60, HR 60, Temp 99.7.
Learning Points
Priming Questions
- 1.
What is the serotonin syndrome (SS)?
- 2.
What are some of the most common and most overlooked medications that can precipitate SS?
- 3.
How is SS diagnosed?
- 4.
What are the most important features of the management of SS?
Introduction/Background
- 1.
SS is a potentially life-threatening toxidrome caused by pharmacologic overactivation of 5-hydroxytryptamine (5HT) 1a and 2a receptors. It is characterized by the triad of altered mental status, neuromuscular abnormalities, and autonomic hyperactivity [1].
- 2.
Incidence of SS has been increasing over the past several decades, partially owing to increased use of SSRIs in clinical practice [2], as well as likely increased symptom recognition by physicians.
- 3.
Extrapolating from national poison center data [3], more than half of the cases are attributed to intentional ingestion, likely reflecting the frequent use of SSRIs in patients prone to suicidal and parasuicidal behaviors. The majority of other cases are likely due to drug-drug interactions and polypharmacy.
- 4.
Though data on mortality rates are difficult to come by, death and major adverse outcomes are likely uncommon, though acute illness can be severe with multiorgan system failure.
- 5.
Remember the Libby Zion case? Well you should! The headline-topping 1984 death of this young female patient due to the missed diagnosis of SS by allegedly overworked and under-supervised residents led to the Bell Commission that ultimately resulted in the ACGME duty hour regulations that we all know and love [4].
Libby Zion
Libby Zion, a college freshman, died on March 5, 1984. She was admitted to the hospital for rehydration and observation with “flu-like” symptoms. She was taking the antidepressant phenelzine daily. She was seen inpatient by an intern and a second-year resident. She was noted to have unusual jerking movements and was given meperidine (Demerol®) to help control the symptoms. After becoming progressively more agitated, a phone order was given for haloperidol. The patient fell asleep, but early the next morning she was found to have a temperature of 107 °F (41.7 °C). When this was recognized, the team mobilized to begin cooling but before they were able to start the process, she suffered a fatal cardiac arrest. The cause of death was determined to be serotonin syndrome resulting from the combination of medications, all of which have effects on serotonin levels.
Physiology/Pathophysiology
- 1.
5HT is synthesized endogenously from the amino acid L-tryptophan and metabolized primarily in the liver by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid (5-HIAA) which is then excreted by the kidneys [5].
- 2.
Approximately 90% of the body’s 5HT is synthesized in the enterochromaffin cells of the gut with the remainder coming from serotonergic neurons in the CNS, particularly the brain’s raphe nuclei, and in platelets [5].
- 3.
The physiologic effects of 5HT are diverse and include systemic vasoconstriction, vasodilation in skeletal and cardiac muscle, bronchoconstriction, platelet aggregation, activation of gut peristalsis, modulation of mood, sleep, temperature, attention, and appetite, and stimulation of the vomiting reflex as well as both pain and itch sensation [5].
5HT is involved in the pathophysiology of migraine, mood disorders, and carcinoid syndrome.
- 4.
The list medications that have been described as precipitants of SS is long and spans multiple therapeutic classes including antidepressants, analgesics, antiemetics, muscle relaxers, antibiotics, anti-Parkinsonian drugs, cough suppressants, and herbal supplements (see Table 54.1).
Drugs implicated in the development of serotonin syndrome by mechanism and class
Psychiatric medications | Non-psychiatric medications |
|---|---|
Inhibitors of serotonin reuptake | |
Selective serotonin reuptake inhibitors (e.g., sertraline, fluoxetine, citalopram) | Tricyclic skeletal muscle relaxants (e.g., cyclobenzaprine) |
Serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) | Phenylpiperidine opioids (e.g., fentanyl, dextromethorphan) |
Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, clomipramine) | 5HT3 receptor antagonists (e.g., ondansetron) |
Dopamine-norephinephrine reuptake inhibitors (e.g., buproprion) | Local anesthetics (e.g., cocaine) |
Serotonin modulators (e.g., trazodone) | Herbal supplements (e.g., St. John’s Wort) |
Tetracyclic antidepressants (e.g., mirtazapine) | Tramadol |
Meperidine | |
Methadone | |
MDMA | |
Inhibitors of serotonin metabolism | |
Monoamine oxidase inhibitors (e.g., phenelzine, selegiline) | Other drugs which inhibit MAO (e.g., linezolid, methylene blue) |
Drugs which increase serotonin synthesis or release | |
Lithium | L-tryptophan |
Amphetamines | |
Dopamine agonists (e.g., L-dopa, bromocriptine) | |
MDMA | |
Ethanol | |
Lorcaserin | |
Valerian root | |
Cocaine | |
Serotonin receptor agonists | |
Buspirone | Triptans |
Vortioxetine | Anticonvulsants (e.g., valproate, carbamazepine) |
Vilazodone | Ergot alkaloids |
Atypical antipsychotics (e.g., quetiapine, aripiprazole, clozapine) | Fentanyl |
Metoclopramide | |
LSD | |
Postsynaptic receptor sensitizers | |
Lithium | |
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