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TABLE 7

Differentiation of the Drug Toxicity Syndromes

Serotonin SyndromeNMSMalignant HyperthermiaAnticholinergic Poisoning
Etiology Excessive serotonin Decreased dopamine Calcium release from sarcoplasmic reticulum Inhibit acetylcholine binding to muscarinic receptors 
Precipitant Proserotonergic drugs Dopamine antagonist or withdrawal of dopaminergic drug Inhalational anesthetic with or without succinylcholine Anticholinergic drugs or antimuscarinic drugs 
History Nonidiosyncratic, add new drug, ↑ dosage of drug, or add second drug Idiosyncratic, exposure to dopamine antagonist drug or withdrawal from dopaminergic drug Inherited (+ family history) or new genetic mutation Anticholinergic drug exposure antihistamines, tricyclic antidepressants, sleep aids, cold preparations, diphenhydramine, atropine 
Onset Minutes to hours Days Hours Minutes to hours 
Usual: 6–24 h Usual: 1–7 d Usual: <12 h Usual: 0.5–24 h 
Vital signs     
 Temperature Elevated (≤41.1°C) Elevated (≤41.1°C) Elevated (≤46°C) Mild elevation (<38.8°C) 
 Heart rate Tachycardia Tachycardia Tachycardia Tachycardia 
 Respirations Tachypnea Tachypnea Tachypnea Tachypnea 
 Blood pressure Hypertension (may deteriorate to hypotension) Hypertension Hypertension Hypertension (mild) 
Mental status Agitated delirium Variable: alert, mutism, stupor, coma Agitation Agitated delirium 
Neuromuscular abnormalities     
 Muscle tone Increased, lower extremities greater than upper extremities “Lead pipe” rigidity Rigor mortis–like rigidity (masseters or generalized) Normal 
 Muscle reflexes Hyperreflexic, clonus; may be masked by hypertonicity Slowed, bradyreflexic Hyporeflexic Normal 
Physical examination     
 Skin Diaphoretic Diaphoretic Diaphoretic, mottled Hot, dry, erythemaa 
 Pupils Mydriasis Normal Normal Mydriasis 
 Mucous membranes Sialorrhea Sialorrhea Normal Drya 
 Gastrointestinal motility Hyperactive bowel sounds, may have diarrhea Normal or hypoactive bowel sounds Hypoactive bowel sounds Hypoactive or absent bowel sounds 
Treatment considerations  
 General Discontinue precipitant drug, supportive care, benzodiazepine for agitation 
 Specific If severe: serotonin2A antagonists (eg, cyproheptadine) If severe: smooth muscle relaxant (eg, dantrolene), dopamine agonists (eg, bromocriptine, amantadine) If severe: dantrolene Sodium bicarbonate for prolonged QRS or dysrhythmias, treat hyperthermia, physostigmine 
Serotonin SyndromeNMSMalignant HyperthermiaAnticholinergic Poisoning
Etiology Excessive serotonin Decreased dopamine Calcium release from sarcoplasmic reticulum Inhibit acetylcholine binding to muscarinic receptors 
Precipitant Proserotonergic drugs Dopamine antagonist or withdrawal of dopaminergic drug Inhalational anesthetic with or without succinylcholine Anticholinergic drugs or antimuscarinic drugs 
History Nonidiosyncratic, add new drug, ↑ dosage of drug, or add second drug Idiosyncratic, exposure to dopamine antagonist drug or withdrawal from dopaminergic drug Inherited (+ family history) or new genetic mutation Anticholinergic drug exposure antihistamines, tricyclic antidepressants, sleep aids, cold preparations, diphenhydramine, atropine 
Onset Minutes to hours Days Hours Minutes to hours 
Usual: 6–24 h Usual: 1–7 d Usual: <12 h Usual: 0.5–24 h 
Vital signs     
 Temperature Elevated (≤41.1°C) Elevated (≤41.1°C) Elevated (≤46°C) Mild elevation (<38.8°C) 
 Heart rate Tachycardia Tachycardia Tachycardia Tachycardia 
 Respirations Tachypnea Tachypnea Tachypnea Tachypnea 
 Blood pressure Hypertension (may deteriorate to hypotension) Hypertension Hypertension Hypertension (mild) 
Mental status Agitated delirium Variable: alert, mutism, stupor, coma Agitation Agitated delirium 
Neuromuscular abnormalities     
 Muscle tone Increased, lower extremities greater than upper extremities “Lead pipe” rigidity Rigor mortis–like rigidity (masseters or generalized) Normal 
 Muscle reflexes Hyperreflexic, clonus; may be masked by hypertonicity Slowed, bradyreflexic Hyporeflexic Normal 
Physical examination     
 Skin Diaphoretic Diaphoretic Diaphoretic, mottled Hot, dry, erythemaa 
 Pupils Mydriasis Normal Normal Mydriasis 
 Mucous membranes Sialorrhea Sialorrhea Normal Drya 
 Gastrointestinal motility Hyperactive bowel sounds, may have diarrhea Normal or hypoactive bowel sounds Hypoactive bowel sounds Hypoactive or absent bowel sounds 
Treatment considerations  
 General Discontinue precipitant drug, supportive care, benzodiazepine for agitation 
 Specific If severe: serotonin2A antagonists (eg, cyproheptadine) If severe: smooth muscle relaxant (eg, dantrolene), dopamine agonists (eg, bromocriptine, amantadine) If severe: dantrolene Sodium bicarbonate for prolonged QRS or dysrhythmias, treat hyperthermia, physostigmine 

All of these drug toxicity syndromes can present with altered mental status, autonomic dysfunction, and neuromuscular abnormalities as manifested by abnormal vital signs including fever, hypertension, and tachycardia. Treatment in all 4 syndromes may include removing the precipitating agent and providing supportive care. Other specific therapy may differ depending on the disorder. Not all patients will have all the classic signs and symptoms. For example, a patient with mild serotonin syndrome may be afebrile but have tachycardia and hypertension. Typical findings are listed in this table.

a

Anticholinergic syndrome described as “Red as a beet, dry as a bone, hot as a hare, blind as a bat, mad as a hatter, full as a flask.”

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