A Case of Serotonin Syndrome
Taylor Lansing, PharmD Candidate 2018, Virginia Commonwealth University School of Pharmacy
Angela Holian, PharmD, BCPS, University of Virginia Health-System
A 75-year-old female presented to the Emergency Department (ED) after intentional paroxetine overdose (~42 tablets). The patient initially presented as alert and oriented but soon became altered, hypertensive, restless, and hyperreflexic. Upon physical exam she was mildly diaphoretic, had increased tone bilaterally in upper and lower extremities with ankle clonus and mild horizontal and vertical nystagmus. Toxicology and pharmacy were quickly consulted for possible serotonin syndrome.
Serotonin syndrome is a clinical triad of mental-status changes, autonomic hyperactivity, and neuromuscular abnormalities resulting from excess serotonin in the central nervous system.1-3 Most of the endogenous serotonin in the body is found in the periphery and is involved in the regulation of vascular tone and gastrointestinal motility.2 Serotonin in the central nervous system is primarily responsible for wakefulness, mood, emotional and food behaviors, and thermoregulation.2 In serotonin syndrome, the overall amount of serotonin in the body is less a concern compared to the amount trapped in the neuronal synapses, which becomes dangerous leading to over stimulation of receptors and imbalance in normal functions.2 Excess serotonin can be a consequence of an increase in serotonin release, direct serotonin receptor agonism, decreased reuptake into the presynaptic neuron, or decreased metabolism of serotonin via monoamine oxidase depending on the offending agent.4 There are 14 distinct serotonin receptor subtypes found throughout the body; the two involved in the mechanism of serotonin syndrome are 5-HT2A and 5-HT1A.2,4,5 The 5-HT2A receptors are perhaps the most important since they cause the main symptoms of serotonin syndrome including tachycardia, hypertension, and hyperthermia, while 5-HT1A receptors are responsible for myoclonus.5 These physiologic abnormalities are what lead to the triad associated with serotonin syndrome.
Toxicity usually presents about 6 hours after ingestion, and duration depends on the mechanism of the offending agent, absorption, half-life, and amount ingested.3 Common signs and symptoms include tremor, diarrhea, delirium, neuromuscular rigidity, and hyperthermia. 1,2 Not every patient will present the same, however most will exhibit myoclonus, helping to distinguish serotonin syndrome from other toxidromes.3 Many causes are a result of medication overdose, especially from over-the-counter (OTC) cold preparations with dextromethorphan and prescription selective serotonin reuptake inhibitors (SSRIs) and tramadol. Other causes can include a single dose of medication, recent increase in dose, or drug-drug interaction between two serotonergic medications.3 Figure 1 shows the most common medication classes found to cause serotonin syndrome.3 Diagnosis can be made based on the Hunter Criteria looking at patient specific symptoms in the presence of one or more serotonergic medications (Table 1).2,5 The Hunter criteria helps to distinguish serotonin syndrome from other syndromes such as neuroleptic malignant syndrome, malignant hyperthermia, and intoxication from other sympathomimetic medications, which may appear similar and complicate care.2,3
The initial step to any medication related reaction is to immediately stop the offending agent and begin supportive care.1,2 Supportive care includes fluid resuscitation and stabilization of vital signs such as blood pressure and pulse. For the treatment of agitation, tachycardia, and hypertension, the use of benzodiazepines such as midazolam and lorazepam are indicated. 1,2 Other agents that may be considered are 5-HT2A antagonists such as cyproheptadine, a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties.1,2 Research points to 5-HT2A as the main receptor involved in the symptoms of serotonin syndrome, therefore the thought behind these agents is to inhibit the binding of serotonin to receptors and reduce effects.1 These medications are usually only used in severe cases when blockade of receptors may be crucial to long-term survival outcomes or when symptoms are severe, such as respiratory abnormalities and fever.2 Cyproheptadine dosing to treat serotonin syndrome is 12 mg orally followed by 2 mg every 2 hours as needed for symptoms.1,2 It is important to constantly monitor and provide care to stabilize vitals when treating patients.1 In severe cases hyperthermia may persist, complicating care and delaying patient recovery.1 Hyperthermia is not a result of alterations in hypothalamic temperature set-point therefore, antipyretic medications such as acetaminophen are not indicated.1 Instead, it is important to prevent excessive muscle activity and consider intubation and medication-induced paralysis using neuromuscular blocking agents. Intubation and airway support are important along with medication-induced paralysis to decrease muscle activity, decrease hyperthermia, and prevent rhabdomyolysis.1 While these therapies are currently the standard care plan for patients with serotonin syndrome, new therapies are emerging that may be considered for certain patients.
New studies and case reports have discussed the use of dexmedetomidine in the treatment of serotonin syndrome.6,7 Dexmedetomidine has been compared to traditional treatment with benzodiazepines, showing some superiority in animal studies.6 Kawano et al. conducted a study in rats and found that treatment with dexmedetomidine resolved all symptoms from serotonin syndrome while midazolam resolved hyperlocomotive response but not specific serotonin syndrome behaviors, such as forepaw treading, flat body posture, and hyperthermia.6 Dexmedetomidine is a centrally acting alpha-2 agonist that produces sedation and analgesia.6 Some advantages to its use are minimal suppression of respiratory function and a short-half life, making it easy to titrate.6 The proposed mechanism for the use of dexmedetomidine in serotonin syndrome is a reduction in central noradrenergic stimulation of serotonin neurons, causing stabilization of the autonomic nervous system.7 Some of the disadvantages to use include hypotension, bradycardia, and nausea. However, as patients with serotonin syndrome normally present with tachycardia and hypertension these effects of dexmedetomidine may be desirable when monitored appropriately.6 Several case reports using dexmedetomidine have shown effectiveness in patients diagnosed with serotonin syndrome, especially when refractory to benzodiazepine therapy.7 One case report used dexmedetomidine in a 15-year-old male who presented after an overdose of an OTC cold medication containing dextromethorphan.7 Dexemedetomidine was used as monotherapy after the patient remained symptomatic with adequate benzodiazepine administration. The patient's symptoms resolved within 48 hours after starting dexmedetomidine, and he was able to be extubated and discharged with a full recovery.7
In revisiting the 75-year-old female who presented to the ED, the patient continued to worsen and an EKG showed prolonged QTc 546. One liter of NaCl 0.9% was started, one dose of magnesium sulfate 2 g IVPB was given for QTc prolongation, and a single dose of lorazepam 1 mg IV was given for agitation. Upon continued agitation, a second dose of lorazepam 1 mg was administered with minimal effect on patient symptoms. The team discussed the need for intubation but decided to closely monitor for now given that the patient was maintaining O2 saturation on room air. The Toxicology Team confirmed serotonin syndrome, and with the help of pharmacy a long-term treatment plan was developed. Given the patient's age and concerns for delirium and respiratory depression with long-term benzodiazepine use, the patient was started on dexmedetomidine 0.1 mcg/kg/hr IV infusion, titrated to a RASS of 1. The infusion was titrated up to 0.3 mcg/kg/hr and the patient was admitted to the Medical ICU in stable condition and not requiring intubation. Over the next 24 hours, the patient improved and the dexmedetomidine infusion was discontinued. Full clinical improvement was seen in 48 hours and the patient was transferred to the psychiatric floor for further monitoring and care. She was discharged home in a week after a full recovery.
While no randomized clinical trials have been done to show the effectiveness of dexmedetomidine in treating serotonin syndrome, case reports such as this have shown success in treating agitation, tachycardia, hyperthermia, and hypertension. As a provider, recognizing the signs and symptoms of serotonin syndrome quickly and beginning treatment are imperative to preventing further complications. The key to distinguishing the syndrome from other toxidromes is the presence of clonus. Recognizing key symptoms can help quickly guide treatment especially in cases when the substance ingested is unknown. More studies are needed to see the effectiveness of dexmedetomidine, though it has shown benefit anecdotally and may be considered when treating overdose victims. As with all treatment plans, patient specific factors must be accounted for and considered to develop the best plan for optimal patient outcomes.
Figure 1.
Common medication classes associated with Serotonin Syndrome
|
Medication Class
|
Examples
|
|
MAOI
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isocarboxazid, phenelzine, selegiline
|
|
SSRI
|
paroxetine, fluoxetine, sertraline, citalopram
|
|
SNRI
|
venlafaxine, duloxetine
|
|
Other Antidepressants
|
buspirone, mirtazapine, trazodone
|
|
Opiates
|
tramadol, fentanyl, meperidine, methadone
|
|
OTC
|
dextromethorphan
|
|
Atypical Antipsychotics
|
olanzapine, risperidone
|
|
Antibiotics
|
ciprofloxacin, linezolid
|
MAOI=monoamine oxidase inhibitor, SSRI=selective serotonin reuptake inhibitor, SNRI=serotonin/norepinephrine inhibitor, OTC=over-the-counter
Table 1.
Hunter Criteria for Diagnosis of Serotonin Syndrome
|
Presence of serotonergic agent and one of the following:
|
- Spontaneous clonus
- Inducible clonus with agitation or diaphoresis
- Ocular clonus with agitation or diaphoresis
- Tremor and hyperreflexia, OR
- Hypertonia, temperature >38°C, and ocular or inducible clonus
|
References
1. Boyer EW, Shannon M. Serotonin Syndrome. The New England Journal of Medicine. 2005;352:1112-1120.
2. Sun-Edelstein C, Tepper SJ, Shapiro RE. Drug-induced serotonin syndrome: A review. Expert Opinion on Drug Safety. 2008; 7(5):587-596.
3. Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin Syndrome. The Ochsner Journal. 2013; 13(4):533-540.
4. Birmes P, Coppin D, Schmitt L, Lauque D. Serotonin syndrome: A brief review. CMAJ. 2003; 168(11):1439-1442.
5. Frank C. Recognition and treatment of serotonin syndrome. Canadian Family Physician. 2008; 54:988-992.
6. Kawano T et al. A comparison of midazolam and dexmedetomidine for the recovery of serotonin syndrome in rats. J Anesth. 2015; 29:631-634.
7. Rushton WF, Charlton NP. Dexmedetomidine in the treatment of serotonin syndrome. Annals of Pharmacotherapy. 2014; 48(12):1651-1654.
