Approach

The treatment of serotonin toxicity consists of ceasing the serotonergic medication, assessing the severity of toxicity, providing supportive care, and, in moderate and severe cases, the use of specific antiserotonergic agents.[1][2] Severe serotonin toxicity is a medical emergency that often requires emergency treatment.[1][2][3]

A poison centre should be contacted as soon as toxic ingestion is suspected to ensure optimal management. Availability and contact with poison centres may differ between countries and regions, healthcare providers should keep a record of their local contact number. In the UK, information on management of poisoning can be found at TOXBASE. TOXBASE® The primary clinical toxicology database of the National Poisons Information Service. Opens in new windowIn the US, information on management of poisoning can be found at the American Association of Poison Control Centers. American Association of Poison Control Centers Opens in new window

Assessment of severity

The spectrum of serotonin toxicity can be divided into 3 groups of severity based on the requirement for medical intervention.[2][4] The severity should be assessed early so appropriate treatment can be started immediately.

Mild toxicity

  • Serotonergic features that may or may not concern the patient. Such features include hyper-reflexia (almost always universally present in patients prescribed selective serotonin-reuptake inhibitors), inducible clonus, tremor, myoclonic jerks, and diaphoresis, or sometimes more non-specific symptoms such as headache or sweating.

  • These patients do not meet the Hunter Serotonin Toxicity Criteria (HSTC).[4]

Moderate toxicity

  • Causes significant distress and requires treatment but is not life-threatening.

  • Characterised by anxiety and agitation. Tachycardia is also common.

  • Patients meet the HSTC, but hyperthermia (temperature >38.5°C [>101.3°F] or rapidly rising) and hypertonia are absent.[4]

Severe toxicity

  • Considered a medical emergency, as it progresses to multi-organ failure if not treated. Almost always associated with exposure to a combination of serotonergic drugs that act by different pharmacological mechanisms.

  • Patients meet the HSTC and have hyperthermia and hypertonia.[4]

Severe serotonin toxicity

This is a medical emergency and the patient needs to be treated in a critical care area. Initial assessment of airway, breathing, and circulation should be undertaken. Hyperthermia should be treated with rapid cooling.[2][3] In the majority of patients it is best to sedate, intubate, and ventilate early, including induction of muscle paralysis to treat spontaneous clonus and hyperthermia. Sedation can be achieved either with morphine and midazolam or with propofol, avoiding fentanyl. Propofol allows for a more rapid wake-up afterwards compared with morphine and midazolam. The aim is to prevent major complications, including rhabdomyolysis, multi-organ failure, and death.[24] Early treatment may prevent the development of these complications. In patients with rhabdomyolysis, muscle paralysis and cooling are indicated.[24][25][26] See Rhabdomyolysis.

If severe serotonin toxicity is a result of an overdose, then decontamination with a single dose of activated charcoal may be considered if the overdose occurred within the last 2 hours, and advice from a Poison Centre is essential.

Although there is limited evidence for the use of specific 5-HT antagonists, intravenous chlorpromazine has been anecdotally successful.[25][27] Repeat doses can be used, and often a dose can be used to sedate the patient rather than using a benzodiazepine. Hypotension due to peripheral alpha-antagonism must be avoided by pre-administration of intravenous fluids. For patients with neuromuscular excitation and agitation a single high dose of cyproheptadine (a non-specific 5-HT2 antagonist and antihistamine) may be used.[27][28][29][30] For longer-acting serotonergic agents (e.g., fluoxetine), regular lower doses should be used. It also has sedative effects that may be useful. Once the patient has been stabilised, consideration should be given to stopping all serotonergic medications.

Moderate serotonin toxicity

All serotonergic drugs must be ceased. Patients should be observed in hospital for at least a 6-hour period, although they are unlikely to develop severe or life-threatening toxicity. Occasionally, severe serotonin toxicity may present early as moderate toxicity, such as with extended-release venlafaxine.[8] If toxicity becomes life-threatening, patients should be treated as per guidelines for severe toxicity.

Treatment focuses on symptomatic relief of anxiety and agitation and the distressing effects of neuromuscular excitation. There is no evidence to support best treatment, except the existence of case reports.[1][2][3] Benzodiazepines may be used to treat anxiety and also sedate the patient. For patients with neuromuscular excitation and agitation that is distressing or unpleasant, cyproheptadine (a non-specific 5-HT2 antagonist and antihistamine) may be used.[27][28][29][30] It also has sedative effects that are useful.

Mild serotonin toxicity

No treatment is required in these patients, except possibly ceasing the offending medication(s) or reducing the dose of the medication, if appropriate.[4] Often, simple identification of the serotonergic symptoms may be sufficient, and continuation of the medication can then be decided on based upon the patient's tolerance of these effects and benefits of the treatment.

Restarting treatment

Depending on the situation that has led to the serotonin toxicity (e.g., increased dose, overdose, drug-drug interaction), a single serotonergic medication may be re-started at a lower dose after the condition has resolved, while the patient is monitored closely. If the serotonin syndrome resulted from a drug-drug interaction, specifically use/overdose of an illicit substance, you can restart their prescribed medication at their normal dose.

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