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Identifying Serotonin Syndrome in the ICU: Case Report

Caralyn Bencsik, MN, ACNP

Abstract

An 18-year-old female who presented with altered level of consciousness, myoclonus, and hemodynamic instability was admitted to the intensive care unit with suspected serotonin syndrome. Serotonin syndrome is an under-recognized disorder that can cause altered levels of consciousness, neuromuscular and autonomic dysfunction, and even death. Increasing critical care nurses’ and multidisciplinary team members’ awareness of serotonin syndrome will lead to more timely identification, avoidance of the use of synergistic medications, intervention, and outcomes for critically ill patients.

Implications for Critical Care Nurses

  • Serotonin syndrome is under recognized by critical care providers. Educating the critical care team is the first step to identifying, preventing, and early intervention for serotonin syndrome.
  • Left untreated, serotonin syndrome is associated with significant morbidity and mortality. Patients can experience encephalopathy, rhabdomyolysis, and cardiac arrest.
  • Serotonin syndrome can occur acutely from an adverse drug reaction, accidental iatrogenic use of synergistic medications, and from overdose of serotonergic agents.
  • Serotonin syndrome mimics include neuroleptic malignant syndrome, anticholinergic syndrome, and malignant hyperthermia.

Preface

This case report describes acute presentation of serotonin syndrome in an eighteen-year-old female survivor of a suspected attempted suicide admitted to the intensive care unit. This syndrome is unknown to many critical care nurses and providers. Early recognition of serotonin syndrome will lead to avoidance of administration of medications with synergistic effects and more timely intervention, which improves outcomes for critically ill patients.

Background

Serotonin syndrome is a clinical diagnosis and typically presents acutely as an adverse drug reaction, accidental iatrogenic use of synergistic medications or co-ingestion, or following intentional high dose ingestion of serotonergic agents.

Serotonin syndromes result in altered levels of consciousness, neuromuscular, and autonomic dysfunction (Ables & Nagubill, 2010; Botros et al., 2016). The objective of this case report is to illustrate the risk factors, pathophysiology, diagnostic criteria, management, and prevention of serotonin syndrome to increase providers’ awareness and increase early identification of this syndrome.

Case Report

An 18-year-old female with a past medical history of primary generalized epilepsy, depression, and a prior suicide attempt as a juvenile in the context of a trial of Levetiracetam for her seizure disorder presented to the emergency department after being found in an altered state by her father at home. EMS reported empty prescription bottles on her desk. The patient was unresponsive (Glasgow Coma Scale 3/15) and was transported to the emergency department. She was endotracheally intubated for airway protection and admitted to the intensive care unit. She was noted to have shaking episodes that were initially described by emergency room staff as generalized tonic-clonic seizures, but later were deemed to be myoclonus by the critical care team. On physical exam she had increased tone throughout, myoclonus, sinus tachycardia (130 bpm), hypotension requiring norepinephrine for vasopressor support, and altered level of consciousness. The patient was not hyperthermic but was diaphoretic. Her cough, gag, and oculocephalic reflexes were intact. She had mydriasis (dilated pupils) that were equal and reactive, but sluggish. Her neurological exam was non-localizing. She had a CT head that revealed no acute intracranial pathology and an EEG that ruled out seizures, epileptiforms, and non-convulsive status epilepticus. She had no nuchal rigidity, history of infection, or symptoms to elicit concern for meningitis or encephalitis.

Upon review of her prescription medications, it was suspected she may have intentionally ingested Duloxetine and/or Lamotrigine. Based on her history, medications (Duloxetine), and physical exam findings (flushing, increased tone, myoclonus, tachycardia, and altered level of consciousness) there was high clinical suspicion of serotonin syndrome. The Poison and Drug Information Service (PADIS) (Alberta Health Services, 2022) was formally consulted and recommended gastrointestinal binding with activated charcoal. It is important to note that procedures for poison and drug control consultation varies per institution. It was advised that she remain sedated with benzodiazepines as needed to relax muscles, reduce spontaneous clonus, and provide anxiolytic effects.

There was also a concern for this patient developing rhabdomyolysis from elevated creatinine kinase (CK), which could be produced from persistent myoclonus. She was fluid resuscitated to reduce the risk of hypotension, renal hypoperfusion, and vasoconstriction, with the goal of increasing renal blood flow, glomerular filtration, and urination. If patients develop acute tubular necrosis (ATN) and renal failure in the context of rhabdomyolysis, they may demonstrate some sequalae of acute renal failure such as metabolic acidosis, volume overload, and electrolyte disturbances such as severe hyperkalemia. In some circumstances, alkaline diuresis with IV sodium bicarbonate may be beneficial for treating severe metabolic acidosis. For patients with florid renal failure with acid base disturbances, volume overload, and dangerous electrolyte disturbances, critical care providers should consider a form of renal support such as continuous renal replacement therapy (CRRT) (Chatzizisis et al, 2008; Hui, Leung, & Padwal, 2016; Vanholder, Sever, Erek, & Lameire, 2000).

The patient did not develop high fevers, so at the direction of the poison and drug team she was not treated with Cyproheptadine. Cyproheptadine affects 5HT-2A receptors and acts as an antihistamine, but also has serotonin receptor blocking properties. PADIS consultants indicated that Cyproheptadine was not indicated in this case because the patient was not febrile and was improving clinically with benzodiazepines as sedation and a myoclonus suppressant agent (Volpie-Abadie et al., 2013).

Within 24 hours, the patient no longer had myoclonus and our team was able to wean benzodiazepines. She was awake and hemodynamically stable after 48 hours and was liberated from endotracheal tube intubation. She did not develop rhabdomyolysis or end organ damage. She returned to her prior neurological baseline within 72 hours and was discharged from the intensive care unit with the psychiatry consult liaison team following.

Discussion

What is serotonin?

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter located in the raphe nuclei located near the midline of the brainstem, and is important in regulating behavioral processes such as mood (including anger and aggression), perception, appetite, memory, addiction, stress response, temperature control, and sexuality. Aside from behavioral effects in the central nervous system, serotonin has influence on vascular resistance and pulmonary vasculature, blood pressure and heart function, homeostasis and platelet function, respiratory vasculature and control centers, metabolism, the endocrine system, both gastrointestinal and genitourinary function, and reproductive health (Berger et al., 2009).

Pathophysiology of serotonin syndrome

Serotonin syndrome was first identified in the literature by Oates and Sjoerdsma (1960). Since then, it has been described in hundreds of case reports. Serotonin syndrome is a clinical diagnosis and can present as an adverse reaction to a medication, accidental use of iatrogenic medications with synergistic effects, or following intentional ingestion or co-ingestion of serotonergic medications (Table 1: Drugs associated with serotonin syndrome). The pathophysiology of serotonin syndrome is complex; however, it is thought to occur as a result of excess stimulation of the 5-HT receptors as the primary mechanism. There are several pathways in which these receptors can be excessively stimulated, including with excess amounts of serotonin antagonist and reuptake (i.e., Trazodone), decreased serotonin reuptake (i.e., SSRIs), increased release of serotonin (i.e., cocaine or methamphetamine), decreased metabolism of serotonin (i.e., MAOIs), and administration of synergistic drug combinations that can cause serotonin syndrome (i.e., Linezolid in combination with SSRIs) (Ables & Nagubill, 2010; Bartlett, 2017; Berger et al., 2009; Birmes et al., 2003; Bodner, Lynch, Lewis, Kahn, 1995; Botros et al., 2016; Boyer & Shannon, 2005; Lane, & Baldwin, 1997; LoCurto, 1997; Mason et al., 2000; Martin, 1996; Scotton et al., 2019; Sporer, 1995; Sternbach, 1991).

How does serotonin syndrome present?

Since serotonin syndrome is a clinical diagnosis, patients presenting with concerning symptoms require a detailed history as well as physical and neurological exam. Symptoms can range from mild to severe but include a triad of alterations in neuromuscular (muscle rigidity, myoclonus, hyper-reflexia), autonomic (hyperthermia, tachycardia, diaphoresis, and hypertension), and mental status (confusion, agitation, and anxiety) (Mason et al., 2000; Scotton et al., 2019; Volpie-Abadie et al., 2013). In a review of the literature, Mason et al. (2000) found that most patients (74.3%) present within 24 hours of medication overdose, change in dose, or initiation of offending medications. Most commonly, patients presented with confusion, agitation, tachycardia, myoclonus, diaphoresis, and hyperreflexia. 48% of patients included in the review required supportive therapy alone, and 57.5% of patients had complete resolution of symptoms within 24 hours of presentation.

How is serotonin syndrome diagnosed?

There are multiple accepted diagnostic criteria for serotonin syndrome including the Sternbach and Hunter Serotonin Toxicity Criteria (Ables & Nagubill, 2010). The Hunter criteria are the most commonly used and require a minimum of one of the following clinical features or group of clinical features: spontaneous clonus (typically characterized by large and rhythmic muscle contractions); inducible clonus with agitation or diaphoresis; ocular clonus (abnormal and involuntary oscillatory eye movements which occur either spontaneously or triggered by eye movements) with diaphoresis or agitation; tremor with hyperreflexia; or increased tone with fever > 38C (Ables & Nagubill, 2010; Buckley et al., 2014; Dunkley et al., 2003; Scotton, 2019).

Differential diagnosis for serotonin syndrome

Differential diagnosis for serotonin syndrome includes neuroleptic malignant syndrome (NMS), anticholinergic syndrome, malignant hyperthermia, meningitis, encephalitis, and hyperthermia. Therefore a thorough history, exam, and medication profile including non-prescription medications are important in making an accurate and timely diagnosis (Scotton et al., 2019). NMS is often confused with serotonin syndrome but is generally characterized by decreased neuromuscular activity and extrapyramidal symptoms such as lead pipe rigidity (hypertonicity felt throughout the range of movement of a joint). In NMS, clonus and hyperreflexia are rare, which is an important distinction from serotonin syndrome (Mills, 1997; Scotton et al., 2019). The features of anticholinergic syndrome include mydriasis, dry mucous membranes, altered mental state, flushed skin, hypoactive bowel sounds, and normal tone and reflexes (Isbister & Buckley, 2005; Scotton et al., 2019). Malignant hyperthermia occurs as a result of inhaled anesthetic agents or administration of depolarizing muscle paralytics such as succinylcholine. Clinical manifestations include muscle rigidity, metabolic acidosis, hyperthermia, and tachycardia (Ali et al., 2003; Scotton et al., 2019). Patients who have meningitis, encephalitis, and hyperthermia can be distinguished from serotonin syndrome based on the low likelihood of increased neuromuscular activity with these syndromes. Lumbar punctures are also helpful in diagnosing meningitis and encephalitis in comatose or altered patients (Boyer et al., 2022; Scotton et al., 2019).

Management of serotonin syndrome

Once a diagnosis is made, it is crucial to support the patient physiologically. This may include identifying and holding all serotonergic agents, effectively communicating the diagnosis with the patient and family as appropriate and amongst the multidisciplinary team, involving poison and drug control teams as per local protocols, and treating accordingly. Treatment may include physiological support with IV fluids, sedation, endotracheal tube intubation if required for airway protection, and possible admission to the intensive care unit. Pharmacological management of serotonin syndrome can include use of medication such as Cyproheptadine, a 5-HT2A serotonin antagonist, and Chlorpromazine, a 5-HT1A and 5-HT2A serotonin antagonist. Chlorpromazine can cause hypotension and NMS, so providers should administer it cautiously and with the involvement of poison control consultants. Benzodiazepines are useful for symptomatic relief because they have muscle relaxing and anxiolytic effects. For severe cases, practitioners can use neuromuscular blocking agents such as Rocuronium. Succinylcholine should be avoided if possible because it can exacerbate hyperkalemia and rhabdomyolysis and can cause NMS. If fever develops, providers should also consider other causes for fever such as infection. Fevers may be treated with antipyretics such as acetaminophen unless there are concerns for co-ingestion. For fevers that are refractory to conventional therapy, use of cooling blankets and ice packs or intravenous cooling catheters may also be effective in maintaining normothermia.

For patients who have mild to moderate serotonin syndrome, it is important to monitor closely and avoid progression of symptoms if possible. If left unidentified and untreated, serotonin syndrome is associated with significant morbidity and mortality. Patients can experience encephalopathy, severe hyperthermia, disseminated intravascular coagulation, acute respiratory distress syndrome (ARDS), rhabdomyolysis with subsequent renal failure, and cardiac arrest or death (Ables & Nagubill, 2010; Berger et al., 2009; Birmes et al., 2003; Botros et al., 2016; Boyer & Shannon, 2005; Boyer et al., 2022; Buckley et al., 2014; Fong et al., 2018; Gillman, 1999; Gillman, 1996; Sternbach, 1991; Velamoor et al., 1994; Wang et al., 2016).

Prevention of serotonin syndrome

Prevention of serotonin syndrome begins with awareness on the part of all medical care team members including Physicians, Nurse Practitioners, Registered Nurses, and Pharmacists. Most cases are avoidable, and prevention requires the vigilance of all caregivers. Many patients who are admitted to the ICU with serotonin syndrome already carry the diagnosis. However it is possible that patients may develop the syndrome from accidental use of synergistic medications while in the ICU, such as the administration of the antibiotic Linezolid concomitantly with an SSRI, or long-term use of an SSRI with antiemetics such as Ondansetron. When patients are admitted to hospital and the intensive care unit, providers should ensure to identify all prescription, herbal, and non-prescription drugs that patients may be taking as well as consider any possible co-ingestions. Identifying serotonergic agents on medication reconciliation and avoiding high dose or long-term administration of synergistic agents can aid in avoiding accidental iatrogenic harm and development of serotonin syndrome (Boyer & Shannon, 2005; Foong, 2018; Scotton et al., 2019; Volpie-Abadi et al., 2013).

Conclusion

The diagnosis of serotonin syndrome was clear for this young female patient who presented with decreased level of consciousness, persistent and spontaneous myoclonus, and autonomic symptoms following a suspected suicide attempt. Serotonin syndrome can present as an adverse reaction to a medication, accidental use of iatrogenic medications, co-ingestion of medications with synergistic effects, or following intentional ingestion of serotonergic medications. The Hunter criteria provide a highly sensitive and specific set of diagnostic characteristics. Educating the critical care team is the first step in preventing, identifying, and managing serotonin syndrome. Early identification prevents mortality and morbidity in critically ill patients with serotonin syndrome.

Author Notes

Caralyn Bencsik, MN ACNP, Department of Critical Care Medicine Calgary

Corresponding Author 

Caralyn Bencsik, Nurse Practitioner, Department of Critical Care Medicine, Rockyview General Hospital, Room 4574, 7007 14 St SW Calgary, AB T2V 1P9

Email: Caralyn.Bencsik@ahs.ca

Funding and Conflict of Interest Statement

The author has no funding and no conflict of interest to declare.

References

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Appendices

Table 1

Drugs Associated with Serotonin Syndrome

Drug TypeDrug Name(s)    
AntiemeticsOndansetronMetoclopramide   
Analgesics/OpioidsFentanylCyclobenzaprineTramadolMethadoneMeperidine
Tricyclic antidepressantsAmitriptyline    
Serotonin norepinephrine reuptake inhibitors (SNRI)  Duloxetine    
Selective serotonin reuptake inhibitors (SSRI)  FluoxetineSertraline   
Serotonin antagonist and reuptake inhibitor (SARI)  Trazodone    
Monoamine oxidase Inhibitor / MAOi effect  Methylene Blue (Antidote)Linezolid (Oxazolidinone; Mild MAOi effect)Procarbazine (Anti-cancer Agent)Safinamide 
Antimigraine and antiseizure medications  CarbamazepineValproic acid   
Illicit drugsCocaineAmphetaminesLSDMDMA 
Dopamine agonistsLevodopaBupropion   
Dopamine serotonin receptor agonists  LithiumSumatriptan   
AntibioticsErythromycin (Macrolide)Ciprofloxacin (Fluoroquinolone)Linezolid (Oxazolidinone; Mild MAOi effect)  
Antifungal agentsFluconazole (CYP2C19 Inhibitor)    
Antiretroviral agentsRitonavir (CYP2D6 Inhibitor)    
Herbal supplementsSt. John’s Wart    
Dietary supplementsTryptophan    
Cold remediesDextromorphan    

(Adapted from: Ables & Nagubill, 2010; Berger et al., 2009; Birmes et al., 2003; Botros et al., 2016; Boyer & Shannon, 2005; Mason et al., 2000; Scotton et al., 2019; Wang et al., 2016)

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