Serotonin toxicity

• Serotonin toxicity, aka serotonin syndrome

Serotonin syndrome typical resolves within 12 -24 hours. Exceptions may occur following massive overdoses, in the presence of multiple serotonergic agents (especially MAOIs) and in the context of intercurrent illness.

Serotonin syndrome has 3 types of clinical manifestations (‘CAN’):

• central nervous system
  • altered mental state (agitation, anxiety, confusion or stupor), seizures
• autonomic dysfunction
  • hypertension or hypotension, tachycardia or bradycardia, hyperthermia, dysrhythmias, flushing, sweating, mydriasis
• neuromuscular dysfunction
  • rigidity (lower limbs more so than upper limbs), hyper-reflexia, clonus (including ocular), tremor, myoclonus

Serotonin toxicity can be diagnosed using the Hunter Serotonin Toxicity Criteria.

• use of a serotonergic agent in the past 5 weeks,
• AND
• no other cause present,

• AND
• spontaneous clonus,

• OR
• tremor and hyperthermia,

• OR
• inducible OR ocular clonus, AND either of:

• diaphoresis OR agitation,
• OR
• rigidity AND hyperthermia.

The Hunter Serotonin Toxicity Criteria – believe it or not – are simpler than the original Sternbach criteria for diagnosing serotonin syndrome and are more sensitive (84%) and more specific (97%).

In practice, the diagnosis is often more of a gestalt impression based of the history, absence of other causes and the findings on physical examination.

The differential diagnosis of serotonin syndrome is extensive.

Drugs, poisons and toxins

• anticholinergic syndrome
• neuroleptic malignant syndrome
• sympathomimetic syndromes
• salicylism
• theophyline toxicity
• nicotinic toxicity

Encephalopathies

• metabolic
• infective
• organic brain disorders

Psychiatric disorders

• including lethal catatonia

Malignant hyperthermia

Serotonergic agents are the cause – funnily enough – either in overdose or a combination of therapeutic agents. Here are the main groups with common examples:

• Selective-serotonin reuptake inhibitors (SSRIs)
  • [fluoxetine, paroxetine, citalopram.]
• Selective noradrenergic reuptake inhibitors (SNRIs)
  • [duloxetine, reboxetine (not so selective in overdose or in combination with others!)]
• Opioids and related drugs
  • [pethidine, fentanyl, tramadol, dextromethorphan.]
• Tricyclic antidepressants (TCAs)
  • [amitryptyline, nortriptyline, dothiepin.]
• monamine oxidase inhibitors (MAOIs)
  • [moclobemide, tranylcypramine.]
• Antibiotics
  • [linezolid]
• Antiemetics
  • [metoclopramide, ondansetron.]
• Mood stabilisers
  • [lithium, sodium valproate.]
• Recreational drugs
  • [amphetamines, ecstasy, lysergic acid (LSD)]
• Herbal agents
  • [St. John’s Wort, Ginseng.]

Usually of greater importance than investigations is obtaining a reliable history of exposure to serotonergic agents. This should be vigorously pursued:

• call GP and/or pharmacist
• check scripts
• ask paramedics if they searched the scene – consider arranging a ‘House, MD’ style investigation of the scene…
• talk to family and friends regarding access to, and use of, pharmaceuticals, recreational drugs or herbal remedies

Investigations:

• screening tests – ethanol level, APAP level, ECG, BSL.
• check for complications and rule out other differential diagnoses – CK, urinalysis (including myoglobin), UEC, ABG as required.

Intubation may be indicated for airway protection:

• decreased GCS is associated with increased aspiration risk
  — GCS<12 is a somewhat arbitrary threshold; GCS 8 has not been validated in toxicological settings
• prolonged or recurrent seizures

Intubation, ventilation and paralysis may be indicated for severe serotonin syndrome independent of the need for airway protection:

• truncal rigidity impeding ventilation
• hyperthermia (T39.5C+)
• rising PaCO2
• rising CK

As always, using the ‘Resus-RSI-DEAD’ approach:

Resuscitation —

• Assess the patient in a setting suitably staffed and equiped for resuscitation and monitoring.
• Identify immediate life threats:
  — decreased level of consciousness
  — rigidity, hyperthermia and hypercapnea: requires intubation, ventilation and neuromuscular blockade
  — seizures
• Airway, Breathing, Circulation:
  — administer oxygen
  — check cardiac rhythm and output
  — establish IV access
• Check for and correct hypoglycaemia:
  — if glucose <4mM then administer 50mL of 50% dextrose IV (5ml/kg of 10% dextrose in children)
• Control ongoing seizures (see Toxicology Conundrum #023):
  • benzodiazepines are first line:
    e.g. diazepam 5-10mg IV over 3-5 min (0.1-0.3 mg/kg in children) repeated as necessary.
  • barbiturates are second line:
    e.g. phenobarbitone 100-300mg slow IV (10-20 mg/kg in children) or thiopentone IV 3-5 mg/kg (if intubated and ventilated)
  • refractory seizures require intubation and ventilation with continuous sedation.
• Correct hyperthermia:
  — continuously monitor if T>38.5 C
  — consider intubation and ventilation with neuromuscular blockade if T >39.5 C
• Discontinue any sertonergic agents and avoid administration of further serotonergic agents.

Risk assessment —

• this patient has serotonin syndrome probably due to a combination of antidepressants and recreational drugs. It is likely to resolve over 1-2 days. More history is needed regarding drugs ingested, doses, times of ingestion and comorbidities.

Supportive care and monitoring —

• reassurance and careful observation
• fluid management
• agitation, hypertension and tachycardia – usually responds to benzodiazepines
• consider the potential for rhabdomyolysis – see Laboratory Tester #002 for management.

Investigations — see Q6 above.

Decontamination —

• activated charcoal (50g PO/NG) should only be administered if the airway is secure and will remain so (e.g. post intubation).

Enhanced Elimination — nil.

Antidotes —

• Benzodiazepines are the mainstay of treatment as noted above.
• Serotonin antagonists are of unproven efficacy and may have side-effects
  • cyproheptadine
    — consider if prolonged or benzodiazepine-resistant
    — 12mg NG, if clinical response noted administer 8mg q8h for 24h
  • olanzapine — 10mg SL
  • chlorpromazine — 25-100mg in 100 mL normal saline over 30-60 minutes

Disposition —

• very mild cases may be discharged with symptomatic treatment, reassurance and appropriate follow up (e.g. GP or mental health team).
• patients with abnormal mental state or vital signs require admission (usually for about 24h) for observation, supportive care and pharmacotherapy until symptoms resolve.
• severe cases require ICU level care (e.g. intubation and ventilation).
• patients at risk of serotonin syndrome due to a deliberate self-poisoning should be observed for at least 8 hours and not discharged at night. This may vary depending on the risk assessment of the specific agent ingested.

Serotonin toxicity typically occurs in one of these settings:

• overdose of a serotonergic agent
• initation or increase in dose of a serotonergic agent
• replacement of one serotonergic agent with another, without an adequate washout period
• interaction of 2 or more therapeutic agents
• interaction of a therapeutic agent with a recreational drug or an alternative medicine.

• Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991 Jun;148(6):705-13.
• Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM. 2003 Sep;96(9):635-42
• Boyer EW, Shannon M. The serotonin syndrome. The New England journal of medicine, 2005;352 (11), 1112-20
• Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust. 2007 Sep 17;187(6):361-5.
• Torre LE, Menon R, Power BM. Prolonged serotonin toxicity with proserotonergic drugs in the intensive care unit. Crit Care Resusc. 2009 Dec;11(4):272-5