When more is not always better

When More Is Not Always Better

Author: Caitlin Boyle, DO; Emergency Medicine Resident PGY1
Fellow: Alexis Cates, DO; Medical Toxicology Fellow PGY6
Faculty: David Goldberger, MD; Medical Toxicology / Emergency Medicine Attending

The case:

You are working on a Friday afternoon in a busy Philadelphia emergency department when a 36 year old female is brought in by EMS from home due to altered mental status and confusion. The patient’s husband is at bedside and states that he called EMS because he found his wife at home tremulous and confused and he states that she was answering questions inappropriately. He states that his wife is very healthy and only has a history of depression for which she has been taking sertraline for many years. He states that she had her wisdom teeth removed 2 days prior. He states that she has been healing well from it and besides from some mild swelling, her pain has been well controlled with the tramadol she was prescribed. The patient has no allergies to any medications and does not drink alcohol, use tobacco products or use recreational drugs.

At your initial evaluation, the patient is unable to provide any more history and appears confused and agitated. She is awake but is oriented to self only. She is immediately placed on the cardiac monitor and vitals are significant for BP 156/90, HR 118, and RR 28. At this time the patient is protecting her airway and she is saturating 96% on room air. Her rectal temperature is 39.1°C. Her point-of-care blood glucose is 98.

On your physical exam, the patient appears diaphoretic and tremulous. Her skin is flushed. Her pupils are 6mm bilaterally, equal, round and reactive. Her mouth and cheeks have mild swelling from her recent teeth extractions but there is no bleeding or signs of infection. Her lungs are clear.  She is tachycardic, but without notable murmurs, rubs or gallops. She has hyperactive bowel sounds and her reflexes are 3+ throughout. She has inducible clonus in her lower extremities.

You recognized that the presence of clonus is a peculiar finding and may be related to serotonin toxicity from the interaction between her sertraline and tramadol. You consult toxicology over your concern.  

Learning point 1: Serotonin and the pathogenesis of serotonin syndrome

  • Serotonin, also known as 5-hydroxytryptamine (5-HT), is a neurotransmitter that plays a role in many bodily functions. When there is too much serotonergic activity in the central nervous system (CNS), usually as a result of drug-drug interaction, this may cause a potentially life-threatening condition called serotonin syndrome.
  • While serotonin is most often known for its effects of mood regulation in the brain, it also influences many things such as memory, sexuality, circadian rhythm, respiratory drive, motor control, and cellular excitation. Outside of the CNS, serotonin has an effect on nearly every organ system including cardiovascular function, bowel motility, platelet aggregation, and vascular tone.
  • There are 15 different types of serotonin receptors that are located throughout the body. The effects of serotonin specifically on the 5-HT1A and 5-HT2A receptors are thought to cause the classic symptoms associated with serotonin syndrome.
    • Activation of 5-HT1A is associated with myoclonus, hyperreflexia, and altered mental status
    • Activation of 5-HT2A is considered the most important receptor in serotonin syndrome. It is responsible for cellular excitation, muscle contraction, as well as stimulation of the adrenals and hypothalamus that results in hyperthermia, hypertension, and tachycardia.
  • Serotonin syndrome is most often caused by drug-drug interactions that increase serotonergic activity through a variety of mechanisms that lead to increased serotonin, but can occur with monotherapy in the overdose setting.
  • Some of the different mechanisms of medications that are responsible for inducing serotonin syndrome include inhibiting serotonin reuptake, inhibiting serotonin metabolism, increasing serotonin synthesis and release, acting as a direct serotonin receptor agonist or increasing the sensitivity of serotonin postsynaptic receptor
  • Common medications associated with serotonin syndrome are listed below:

Table 1: Medication Associated with Serotonin Syndrome. From Zick et. al. (2019)

The case continued:

Toxicology was consulted and agreed that this patient’s presentation is suggestive of serotonin syndrome. They stated that serotonin syndrome is classically characterized by altered mental status, autonomic hyperactivity, and neuromuscular excitation. They recommended obtaining lab work including CBC, CMP, lactate, CPK, VBG, coagulation panel, UA and urine pregnancy, blood and urine cultures, toxicology screen including UDS, salicylate, acetaminophen, and alcohol levels, an ECG and a chest x-ray. These studies not only help rule other causes of this patient’s presentation but can monitor for any potential complications of serotonin syndrome. The patient’s ECG showed sinus tachycardia at a rate of 120 and she was started on IV fluids.  

Learning point 2: Clinical features of serotonin syndrome and making a diagnosis

  • Serotonin syndrome is a clinical diagnosis with a wide range of symptoms and may be more appropriately referred to as “serotonin toxicity” as it exists on a spectrum

Diagnosis is made when: 

  • Involvement of serotonergic agent(s) PLUS
  • Classic triad:
    • Altered mental status
      • Anxiety, confusion, agitation, delirium, seizures, coma
    • Autonomic instability/ Sympathetic hyperactivity
      • Hyperthermia, tachycardia, hypertension, diaphoresis, flushing, mydriasis, nausea, vomiting, diarrhea
    • Neuromuscular excitation
      • Hyperreflexia, clonus, tremor, rigidity 

Figure 1: Shows range of symptoms from mild to severe

  • Complications from serotonin syndrome include: rhabdomyolysis, metabolic acidosis, DIC, renal failure, respiratory failure, death.
  • It is important to rule out other conditions that may present in a similar way such as sympathomimetic or anticholinergic toxidrome, alcohol or benzodiazepine withdrawal, sepsis, thyrotoxicosis, heat stroke, meningitis, encephalitis, or neuroleptic malignant syndrome.
  • Hunter’s Criteria can be used to help diagnose serotonin syndrome. It was found to be 84% sensitive and 97% specific, although it faces criticism that mild cases may not meet criteria. Some studies have also reported that 57% of patients with serotonin syndrome do not have clonus.

The case continued:

The patient’s lab work was notable for mildly elevated CK and creatinine levels and mild leukocytosis. Her UA, UDS and chest x-ray were unremarkable. Salicylate, acetaminophen, and alcohol levels were all undetectable. After checking on the patient you noticed that her mental status was still the same and she appeared agitated. The patient fulfilled Hunter’s Criteria and from the work-up already completed, there was no other obvious cause for her symptoms. The patient was given medications for her symptoms as recommended by toxicology and the Step Down Unit was paged for admission for continuous cardiac monitoring.

Learning point 3: Treatment and Disposition

  • Discontinue the offending serotonergic agents
  • Activated charcoal can be considered in the right context without contraindications, particularly if an acute intentional ingestion is suspected
  • Supportive care
    • Cardiac monitoring
    • Oxygen
    • Intravenous fluids as needed
  • For hyperthermia, treat with cooling measures such as applying ice packs, cooling blanket, evaporative techniques, and cooled IV fluids. Antipyretics are not helpful in this situation.   
    • Sedation, paralysis, intubation is necessary for severe hyperthermia (>41.1 °C)
  • For paralysis, use a non-depolarizing agent such as rocuronium
  • For sedation, consider propofol since it can be titrated easier than benzodiazepine infusion
  • Benzodiazepines should be titrated to agitation while monitoring vital signs and can be given as needed. Agitation will increase hyperthermia, risk for rhabdomyolysis and lactic acidosis.
    • Lorazepam 2-4mg IV or Diazepam 5-10mg IV; may be dosed every 8-10 minutes or as needed.  Monitor for stacking effects, if patient is not intubated, as this may result in significant sedation. 
  • Short acting beta-blockers or nitroprusside can be used for severe hypertension or tachycardia
    • Avoid long acting beta-blockers such as propranolol as these can mask tachycardia and cause prolonged hypotension
  • Consider dexmedetomidine (Precedex) infusion
    • Stimulates alpha-2C receptors in striatum which may inhibit serotonin release
    •  Has benefit of not suppressing respiratory drive and its use may help prevent intubation
  • Cyproheptadine can be considered in moderate to severe cases of serotonin syndrome
    •  It is an H1 antagonist, 5-HT1A and 5-HT2A antagonistic, and a weak anticholinergic agent
    • Only available in oral formulation
    • Contraindicated in angle closure glaucoma, symptomatic BPH, and bladder obstruction
    • Side effects include sedation, hypotension, and anticholinergic toxidrome
    • Off- label use for serotonin syndrome
    • Dose:
      • 12 mg oral followed by 2 mg every 2 hours or 4 to 8 mg every 6 hours
      • Peds: 0.25 mg/kg/day divided every six hours
    • There is a lack of definitive evidence for its use and symptoms usually resolve before it is considered
  • 5-HT2A antagonists such as olanzapine and chlorpromazine have not been proven to be effective  
  • Avoid Bromocriptine as it has serotonergic effects and can worsen symptoms
  • Dantrolene should also be avoided as it has not been shown to be effective
  •  For mild cases of serotonin syndrome, patient should be observed for 4-6 hours and if vitals remain normal with no increase in clonus, patient may be discharged with close follow-up
  •  For moderate symptoms where the patient has abnormal vitals signs, continued altered mental status or lab abnormalities, the patient should be admitted and have continuous cardiac monitoring
  •  If symptoms are severe and/or the patient requires intubation, the patient should be admitted to the ICU. The mortality rate of severe serotonin syndrome has been reported to be 2-12%
  • Symptoms typically resolve in 24-72 hours of discontinuation of inciting xenobiotics

Case Conclusion:

The patient was given more IV fluids and 4mg IV lorazepam while in the Emergency Department which improved her agitation, heart rate, and blood pressure. The use of cyproheptadine was considered, but because the patient was responding well to the benzodiazepines the decision was made to hold off on administering it.  She was admitted to the Step Down Unit where she received continuous monitoring, supportive care, and benzodiazepines as needed. After 24 hours, her mental status had returned to baseline and the patient was no longer exhibiting clonus. The patient was downgraded to the general medicine floor and was discharged the next day. The patient was counseled extensively on avoiding other medications that have serotonergic properties while taking her SSRI, as well as clinical signs to look out for that may indicate serotonin toxicity. With close follow-up from her primary care provider, she was re-initiated on sertraline at a lower dose.

After discussing this case with a medical student, the student asks you how serotonin syndrome is different from neuroleptic malignant syndrome since she recently learned about these conditions and is confused about how to differentiate them in the clinical setting.

Learning point 4: Neuroleptic Malignant Syndrome vs. Serotonin Syndrome

  • Neuroleptic malignant syndrome (NMS) is a neurological emergency caused by a reaction to antipsychotic (anti-dopaminergic) medications that block the D2 receptor or withdrawal of dopaminergic agents
  • It is thought to occur secondary to decreased dopamine in the CNS, although exact pathophysiology is unclear. It likely involves a lack of dopamine in mainly the nigrostriatal, hypothalamic, and mesocortical pathways in the brain. It is also thought that dopamine helps regulate efferent sympathetic nervous activity, so lack of dopamine leaves the sympathetic nervous system unopposed leading to increased muscle tone, metabolism, vasomotor activity, along with hyperthermia, labile blood pressure and heart rate.
  • NMS is characterized by hyperthermia, altered mental status, muscle rigidity, and autonomic dysfunction
    • Typically this temperature elevation is more severe than what is seen in serotonin syndrome
    • Muscle rigidity is described as “lead pipe”
    • Other symptoms include hypertension, tachycardia, tachypnea, diaphoresis
  • It is considered an idiosyncratic reaction and may occur at any point while taking anti-dopaminergic medications, even at therapeutic doses, but symptoms are more likely to occur within first 2 weeks of initiation or increase in dose of medication (66% in first week)
  • NMS is most often caused by 1st generation (typical) antipsychotics such as haloperidol and prochlorperazine, although it may also occur from 2nd generation antipsychotics, antiemetics such as metoclopramide, or from withdrawal of dopaminergic medications such as levodopa or bromocriptine
  • Treatment involves first stopping the offending medication or re-initiating the dopaminergic agent if recently stopped. Otherwise treatment is similar to serotonin syndrome in that it involves supportive care, treatment of hypertension and hyperthermia if severe, and benzodiazepines. There should be a low threshold for intubation, especially in the setting of severe hyperthermia.
    • Other medications such as dantrolene (a muscle relaxant) and dopamine agonists such as bromocriptine or levodopa have been used in case reports, but there have not been randomized controlled studies to prove their efficacy.
  • Symptoms of NMS typically resolve in 2 weeks (as compared to 2-3 days for serotonin syndrome). These patients typically require ICU level as they require a high level of monitoring and can have many secondary complications such as arrhythmias, cardiovascular, respiratory, or renal failure, and death occurs in 5-20% of patients.
  • Upon resolution of symptoms it is important to wait at least 2 weeks before beginning another antipsychotic and it should be switched to a different agent.
Serotonin SyndromeNeuroleptic Malignant Syndrome
CauseSerotonergic agentsDopamine antagonists or withdrawal of dopamine agonists
Classic FindingsAMS, autonomic hyperactivity, neuromuscular excitation, GI symptoms, mydriasisAMS, autonomic dysfunction, fever, muscular rigidity
Shared FindingsHypertension, tachycardia, tachypnea, hyperthermia, diaphoresis
OnsetWithin hoursWith days-weeks or longer
Neuromuscular FindingsClonus, hyperreflexia, hyperreflexiaLead-pipe rigidity, bradyreflexia
Duration1-3 days2 weeks
Treatment optionsSupportive, benzodiazepines, consider cyproheptadineSupportive, benzodiazepines, dantrolene, dopamine agonist (Bromocriptine or Levodopa)

References

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  8. Nummenmaa, Lauri & Seppälä, Kerttu & Vesa, Putkinen. (2020). Molecular imaging of the human emotion circuit. 10.31234/osf.io/5w63q.
  9. Ozdemir, Ercan. (2017). The pathophysiological role of serotonin receptor systems in opioid analgesia and tolerance. International Journal of Basic & Clinical Pharmacology. 6. 217. 10.18203/2319-2003.ijbcp20170312.
  10. Perry, P. J., & Wilborn, C. A. (2012). Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists, 24(2), 155–162.
  11. Simon LV, Keenaghan M. Serotonin Syndrome. [Updated 2021 Jan 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482377/
  12. Scotton, W. J., Hill, L. J., Williams, A. C., & Barnes, N. M. (2019). Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions. International Journal of Tryptophan Research. https://doi.org/10.1177/1178646919873925.
  13. Zick, J. E., Rettey, S. S., Cunningham, E. A., & Thomas, C. J. (2019). Serotonin syndrome: How to keep your patients safe. Current Psychiatry, 18(7), 38-42.

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