FRCA Notes

Serotonin syndrome

Resources

  • Serotonin syndrome is a:

    • 'potentially life-threatening drug interaction caused by excessive serotonergic activity in the CNS'

  • It is classically described as a triad of:
    1. Change in mental status
    2. Neuromuscular excitability
    3. Autonomic dysfunction/hyper-activity
  • It can cause death by hyperpyrexia-induced multi-organ failure

Production

  • Serotonin (5-hydroxytryptamine) is a derivative of the essential amino acid tryptophan
  • It is produced by a combination of tryptophan hydroxylation and decarboxylation

Elimination

  • Re-uptake via SERT transporters
  • Inactivation by MAO to 5-hydroxyindoleacetic acid
  • Renally excreted

Receptors

  • There are seven classes of serotonin receptor (5-HT1-7) but each class has subtypes (e.g. 5-HT1A - 1F), leading to many subtypes
  • The majority are G-protein coupled receptors, although the renowned 5-HT3 receptor which is ionotropic
Receptor(s) Effects of agonism
5-HT1A & 5-HT2 Mediation of serotonin syndrome
5-HT2 Mediate platelet aggregation
Involved in smooth muscle contraction
5-HT3 Concentrated in the GI tract and area postrema
Mediate nausea and vomiting
5-HT6-7 Involved in limbic function


  • The true incidence is difficult to ascertain, but may be increasing due to:
    • Greater number of patients taking anti-depressant drugs (14% receive an SSRI in the peri-operative period)
    • Overdoses of SSRI's or other antidepressants (9% of total adult exposures)

  • There are a smorgasbord of 'serotonergic' agents, which can precipitate the syndrome through their interactions
  • They either inhibit re-uptake, up-regulate the receptors or otherwise modulate receptor sensitivity
  • The (non-exhaustive) table below should certainly satisfy any FRCA exam(iner)
Psychiatric drugs Drugs of abuse Opioids Others
SSRIs MDMA Tramadol Tryptophan
SNRIs Amphetamines Fentanyl St. John's Wort
TCAs Cocaine Oxycodone Triptans
MAO-Is Methylene blue
Lithium Linezolid


  • Clinical diagnosis is based on the classical triad of altered mental status (40% of patients), autonomic dysfunction (50%) and neuromuscular excitability (50%) + some exposure to a serotonergic agent

  • Symptoms are typically:
    • Rapid onset
    • Within 12 - 48hrs of exposure to the triggering agent
    • Rapidly resolved, although may be prolonged depending on half-life of agent (e.g. fluoxetine is 7 days)

  • Diagnostic criteria include the (older) Sternbach criteria and the (younger and more popular) Hunter criteria

Sternbach criteria

  • Require 1 of the major criteria:
    • Recent addition or increase of serotonergic agent
    • No recent addition or increase of neuroleptic agent
    • Absence of other possible aetiologies

  • Require 3 of the minor criteria:
    • Psychiatric: Mental status changes | agitation | hypervigilance
    • Neurological: Myoclonus | hyper-reflexia | tremor | incoordination | mydriasis | tachycardia & hypertension
    • Constitutional: Diaphoresis | shivering | fever | diarrhoea | sialorrhoea

Hunter criteria

  • Are more sensitive (84%) and specific (97%) than Sternbach criteria
  • Require the patient to be on a serotonergic agent and:
    • Have spontaneous clonus, OR
    • Have inducible/ocular clonus + 1 of agitation, sweating or hyperthermia with hypertonia, OR
    • Tremor and hyper-reflexia

Other findings

  • Metabolic acidosis
  • Raised liver enzymes
  • Raised creatinine
  • Raised CK ± rhabdomyolysis
  • Leukocytosis
  • (NB no correlation between serum serotonin levels and severity of serotonin syndrome)

  • Management is largely supportive, with monitoring in L2 or L3 areas for those with moderate or severe symptoms
  • Naturally the offending agent(s) should be witheld

Anxiety and agitation

  • Benzodiazepines e.g. diazepam 10-20mg IV, lorazepam 1-2mg IV or IM, midazolam 5-10mg IM
  • Dexmedetomidine

Autonomic dysfunction

  • IV fluid for hypotension
  • Directly acting sympathomimetic agents for hypotension e.g. noradrenaline
    • Avoid ephedrine and dopamine
  • Short-acting anti-hypertensives for hypertension (e.g. GTN, esmolol) as BP/HR may swing precipitously

Hyperthermia

  • Paracetamol largely ineffective as the hyperthermia is mediated by muscle hyperactivity
  • Benzodiazepine sedation may help
  • Topical cooling e.g. fans, ice packs
  • External cooling e.g. arcticsun
  • May require aggressive treatment with sedation, paralysis (no sux.!) and ventilation
  • Invasive cooling methods e.g. cold fluid lavage, intravascular cooling devices
  • NB dantrolene not proven to be effective although TOXBASE does suggest trying it in refractory/severe cases

Specific treatment

  • Specific serotonin receptor antagonists may be used if supportive care has failed

  • Cyproheptadine is an H1, 5-HT1A and 5-HT2A receptor antagonist
  • Initial dose 12mg PO/NG, then 4-8 mg every 6 hours until clinical improvement

  • A number of other drugs have anti-serotonergic activity and could be used whilst someone tracks down the cyproheptadine:
    • Propanolol
    • Chlorpromazine - 12.5-25 mg IV (fluid load first to avoid hypotension) followed by 25 mg orally every 6 hours.
    • Olanzapine
    • Haloperidol