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HYPERTHERMIA SYNDROMES- 4: DRUG INDUCED HYPERTHERMIA

"The fact that patient gets well, does not prove that diagnosis was correct"
                                                                 - Samuel J. Meltzer

SEROTONIN SYNDROME (SS):
SS is characterized by hyperthermia, altered mentation, mydriasis, increased muscle tone, hyperreflexia, clonus, diarrhea and autonomic instability, developing 6-12 hours after exposure to serotonin agonist agents.

There is prominent diaphoresis and sialorrhea.

Clonus is the most specific sign of SS.

Drugs associated with SS are:
  • Selective serotonin reuptake inhibitors (SSRI)- fluoxetine, sertraline, citalopram, escitalopram,
  • Serotonin norepinephrine reuptake inhibitors (SNRI)- venlafaxine, duloxetine, 
  •  TCA- clomiperamine, imipramine, trazodone,
  • MAO inhibitors- selegiline, procarbazine, linezolid, furazolidone,
  • Opiates- meperidine, tramadol, fentanyl, dextromethorphan, pentazocine, dextropropxyphene,
  •  Antiemetics- ondansetron, granisetron, metocloperamide,
  •  Antihistamines- chlorpheniramine,
  •  Antimigraine drugs- triptans,
  • Supplemental /Herbal dietary products- St. John’s wort, tryptophan, 5 hydroxytryptophan, ginseng,
  • Stimulants- amphetamine, 3,4-methylenedioxymetamphetamine (ecstasy),
  • Psychedelics- lysergic acid diethylamide (LSD).

Of these fentanyl, tramadol, linezolid, ondansetron, granisetron, metocloperamide and chlorpheniramine are commonly used drugs in ICU.

PATHOPHYSIOLOGY: Excessive stimulation of postsynaptic 5HT1A and 5HT2A receptors by serotonergic agents has been implicated in SS.

SS is classically associated with simultaneous administration of two serotonergic agents, but can occur with single serotonergic agent or with dose escalation.

True incidence of SS is not known probably because of underdiagnosis, but has been reported in around 14% cases of SSRI overdose.

DIAGNOSIS: Diagnosis is established using Hunter Serotonin toxicity criteria.  Presence of any of the following, with history of exposure to serotonergic drug, establishes diagnosis of SS:

1.      Spontaneous clonus; or
2. Inducible clonus or ocular clonus and agitation or diaphoresis; or
3. Inducible clonus or ocular clonus and increased muscle tone and temperature more than 38˚C; or
4.     Tremors and hyperreflexia.

Symptoms usually evolve over 6-12 hours of exposure to serotonergic drugs and resolve within 24 hours of discontinuation of offending agent.

But fluoxetine and other long acting drugs may produce prolong course.

TREATMENT:
Discontinuation of all serotonergic medication is the mainstay of therapy.

External cooling should be established as early as possible.

ABC (Airway, breathing and circulation) should be assessed and managed accordingly, including endotracheal intubation if needed. Intravascular volume should be optimized to ensure organ perfusion and prevent complications of rhabdomyolysis.

Benzodiazepines may reduce agitation and hypertonicity. Intubated patients should be optimally sedated with midazolam.

Definitive therapy involves serotonin antagonist, cyproheptadine (antihistamine with 5HT1A, 5HT2A receptor antagonist activity). It is administered as 12 mg stat dose, followed by 2 mg every 2 hourly until symptoms resolve, then 8 mg every 6 hourly.

Cyproheptadine may cause sedation, which helps in reducing agitation. It may also precipitate hypotension, which may respond to fluid boluses.

Chlorpromazine, antipsychotic with 5HT2A receptor antagonist activity, may be used as alternative to cyproheptadine. It is given as 50-100 mg intramuscular injection, and repeated every 6 hourly if needed.

Propranolol should not be used, to control adrenergic symptoms and hypertension, as it also has 5HT1A receptor antagonist activity, and can precipitate hypotension. Other long acting beta blocker should also be avoided. Short acting agents like esmolol may be used to control blood pressure.

In case of exposure to MAO inhibitors and hypotension, dopamine should be avoided, because of the risk of exaggerated hemodynamic response. Noradrenaline or phenylephrine may be used.

NMS and SS must not be confused with other, as definitive treatment is entirely different. Bromocriptine (dopamine agonist) administered for mistaken diagnosis of NMS, may worsen SS. Similarly chlorpromazine (dopamine antagonist) given for erroneous diagnosis of SS, may worsen NMS.

Neuroleptic malignant syndrome
Serotonin syndrome
Onset
Variable, 1-3 days
Variable, < 12 hours
Overlapping
Features
Diaphoresis
Pallor
Diaphoresis
Variable, stupor, coma, alert
Variable, agitation, coma
'Lead-pipe' rigidity in all muscle groups
Increased tone,
especially in lower extremities
Distinct Features
Hyporeflexia
Hyperreflexia
Clonus  
Normal pupils
Dilated pupils
Normal or decreased bowel sound
Hyperactive bowel sounds

                

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