Cholinergic poisoning

Cholinergic poisoning is most commonly caused by exposure to substances that decrease acetylcholinesterase activity, increasing the concentration of acetylcholine at muscarinic and nicotinic receptors. Organophosphorus compounds such as insecticides and nerve agents are the most likely substances to cause life-threatening poisoning. Classic symptoms include miosis, bronchospasm, bronchorrhea, diarrhea, diaphoresis, and increased lacrimation and salivation. Severe poisoning results in profound muscle weakness and respiratory failure, usually within minutes to hours after exposure. Diagnosis of cholinergic poisoning is typically based on history and physical exam. Decreased levels of acetylcholinesterase and/or butyrylcholinesterase are surrogate markers for cholinergic poisoning, but these tests are not often readily available and reporting of results may be delayed. Treatment of cholinergic poisoning includes respiratory support, high doses of atropine, oxime therapy, and extensive body surface decontamination. Providers caring for these patients must wear personal protective equipment at all times to prevent personal contamination and secondary poisoning.

Insecticides ^[1][2]

Individuals may be exposed to these agents unintentionally, e.g., while working in a field treated with the chemical, or intentionally for self-harm. ^[3]

• Organophosphorus compounds: irreversibly inhibit acetylcholinesterase
  • Parathion (E605)
    • Broad spectrum insecticide used primarily in agriculture
    • Persists in the environment for days to weeks
    • Garlic-like or petrol-like odor
  • Malathion
    • Broad-spectrum insecticide currently used in agriculture, gardening, and for mosquito abatement
    • Used topically for the treatment of head lice
  • Tetrachlorvinphos: found in flea and tick treatments and collars
• Carbamates: reversibly inhibits acetylcholinesterase

Nerve agents ^[3][4]

These potent organophosphorus compounds were developed for use in chemical warfare, large-scale terror attacks, and, more recently, targeted assassinations. They irreversibly inhibit acetylcholinesterase.

• Sarin
  • Volatile liquid organophosphate that is odorless, tasteless, and easily vaporized
  • Much higher potency than organophosphate insecticides
• VX ^[3][5]
  • Amber-colored oily liquid with low volatility
  • Usually absorbed through the skin but droplets can also be inhaled
  • Persists in the environment after deployment
• Novichok agents ^[6]
  • A new class of weaponized organophosphorus compounds that are more potent than VX
  • Have been used to intentionally poison individual people

Parasympathomimetic drug overdose

Parasympathomimetic drugs are commonly prescribed for a variety of diseases, e.g., myasthenia gravis, glaucoma, Alzheimer disease, Sjogren syndrome, postoperative ileus, and neurogenic bladder.

• Direct parasympathomimetics: e.g., pilocarpine, methacholine
• Indirect parasympathomimetics (usually reversible acetylcholinesterase inhibitors): e.g., physostigmine, neostigmine, pyridostigmine, edrophonium, rivastigmine, donepezil, galantamine

Other

• Cholinergic mushroom poisoning ^[7]
  • An uncommon type of mushroom poisoning
  • Most commonly caused by Clitiocybe and Inocybe species
• Nicotine poisoning ^[8]

• Absorption of the causative agent through the skin, respiratory system, or gastrointestinal tract → inhibition of acetylcholinesterase → ↑ acetylcholine levels → hyperstimulation of muscarinic and nicotinic acetylcholine receptors ; → life-threatening overactivation of the parasympathetic nervous system → bronchospasm, bradycardia, weakness, and miosis ^[3]
• Many agents also cause a non-cholinergic-mediated neural inflammatory response, which leads to early depression of the central respiratory drive and/or chronic neurocognitive deficits; see “Gulf War illness.” ^[9][10]

Cholinergic toxidrome is an acute manifestation of cholinergic poisoning that occurs minutes to hours after exposure. Manifestations of both muscarinic and nicotinic receptor hyperactivation are present with the clinical presentation varies based on the agent, route of absorption, total dose, and time since exposure. ^[3][4][11]

Muscarinic hyperstimulation

• Diarrhea, vomiting, abdominal pain
• Urinary incontinence
• Miosis, blurred vision
• Bronchospasm, bronchorrhea
• Bradycardia, hypotension
• Increased lacrimation and salivation
• Diaphoresis

Miosis is the most common feature of cholinergic poisoning. ^[3]

Though the clinical features of muscarinic hyperstimulation usually predominate in cholinergic poisoning, nicotinic hyperstimulation can cause contrasting symptoms of mydriasis, tachycardia, and hypertension. ^[3]

Nicotinic hyperstimulation

• Fasciculations
• Muscle weakness
• Respiratory failure secondary to paralysis

CNS effects

• Confusion, agitation, tremors, seizures, lethargy, coma
• Decreased respiratory drive

“DUMBBBELLSS” is an acronym for the clinical features of cholinergic toxidrome: Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Bronchorrhea, Emesis, Lacrimation, Lethargy, Sweating, Salivation.

“SLUDGE-M” is another acronym for the clinical features of the cholinergic toxidrome: Salivation, Lacrimation, Urination, Defecation, GI upset, Emesis, Miosis.

Cholinergic poisoning is a clinical diagnosis based on the presence of cholinergic toxidrome and potential exposure to a poison; confirmatory studies may be obtained but empiric treatment should not be delayed. ^[3]

Supportive studies ^[3]

Atropine challenge test ^[12]

• Improvement in cholinergic symptoms after atropine administration suggests cholinergic poisoning.
• Expert opinion differs on the diagnostic utility of the test; criticisms include: ^[3]
  • Patients with severe poisoning may not experience improvement in cholinergic symptoms.
  • Atropine can cause antimuscarinic symptoms in patients without cholinergic poisoning.

Laboratory studies ^[3][11]

Laboratory studies are used to assess for secondary complications and guide subsequent management.

• CBC
• BMP
• ECG
• Chest x-ray

Confirmatory studies ^[3][13]

Confirmatory studies must be performed at regional reference laboratories, and the results are unlikely to be available in time to guide initial management. Trends in enzyme activity may help guide ongoing therapy. ^[13]

• Cholinesterase activity assays: Decreased enzyme activity is an indirect marker of cholinergic poisoning.
  • Red blood cell acetylcholinesterase activity assay
  • Butyrylcholinesterase activity assay
• Serum or urine assays for specific cholinergic compounds or their metabolites

• Myasthenic crisis (See “Myasthenic crisis vs. cholinergic crisis.”)
• Opioid overdose ^[4]

The differential diagnoses listed here are not exhaustive.

Approach ^[3][11]

• Don level C personal protective equipment.
• Follow the ABCDE approach in poisoning, especially:
  • Monitor closely for signs of impending respiratory failure.
  • Consider early intubation in patients with muscle weakness to reduce the risk of aspiration. ^[14]
  • Avoid succinylcholine for rapid sequence intubation.
• Initiate atropine therapy as quickly as possible.
• Initiate oxime therapy (e.g., pralidoxime) with, or shortly after, atropine.
• Manage agitation and toxic seizures with benzodiazepines.
• Begin thorough decontamination of the patient.
  • Follow protocols for body surface decontamination (if not already performed in the field).
  • Consider single-dose activated charcoal in intubated patients if the poison was ingested. ^[3]
  • Dispose of contaminated clothes and shoes following local hazardous material protocols.
• Call poison control: In the US, the national Poison Help line is 1-800-222-1222.

Always wear personal protective equipment when caring for patients with potential exposure to organophosphorus compounds or other nerve agents. ^[11]

Respiratory failure is the leading cause of death in cholinergic poisoning; initial treatment should focus on airway management and respiratory support. ^[9][11]

Atropine therapy ^[3][13]

• Mechanism
  • Acts as a competitive inhibitor of muscarinic receptors to reverse hyperstimulation
  • No effect on nicotinic receptor hyperstimulation
• Dosing and administration
  • Loading dose(s): atropine (off-label) ^[3][13]
    • Adults: atropine 1–3 mg IV
    • Children: atropine 0.05 mg/kg IV (max. initial dose 3 mg)
    • Double and repeat the previous dose every 5 minutes until heart rate is > 80 bpm, systolic blood pressure is > 80 mm Hg, and chest sounds are clear.
  • Maintenance dose: atropine (off-label) ^[3][13]
    • Atropine 10–20% of the total loading dose of atropine per hour as a continuous IV infusion (max. 2 mg/hour)
  • Autoinjectors containing fixed amounts of atropine and/or pralidoxime are commercially available; follow local protocols for use.

Extremely high doses of atropine are often required; notify the pharmacy early if therapy is initiated. ^[11]

Continue to monitor patients for muscle weakness and impending respiratory failure after atropine administration; atropine does not reverse nicotinic effects.

Oxime therapy ^[3][13]

The effectiveness of oxime therapy (e.g., pralidoxime, obidoxime) in cholinergic poisoning is not well-established but it is still recommended as an adjunct to atropine by most experts. ^[3][15]

• Mechanism
  • Dephosphorylates acetylcholinesterase, resulting in enzyme reactivation ^[3]
  • Reverses both nicotinic and muscarinic effects of poisoning
• Timing
  • Administered with atropine or shortly after initiation of atropine, as oximes may transiently increase acetylcholinesterase inhibition
  • Most effective if given early ^[3]
• Dosing and administration
  • Loading dose: pralidoxime (2-PAM) ^[13]
  • Some experts recommend higher loading doses and continuous infusions; consult poison control for further guidance. ^[3][13]

Disposition ^[3][13]

• Admit patients with severe symptoms (e.g., seizures, respiratory failure) to the intensive care unit.
• Most patients require hospitalization to monitor for worsening neurological function and muscle weakness.
• Consider discharging patients who are asymptomatic or have mild symptoms after 6 hours of observation in consultation with poison control.

Nicotine poisoning ^[3][16]

• Etiology
  • Ingestion of cigarettes ^[3]
  • Ingestion of e-cigarette fluid
  • Dermal exposure to wet tobacco plants (see “Green tobacco sickness”)
• Pathophysiology ^[3]
  • Mild poisoning: direct stimulation of nicotinic acetylcholine receptors in the CNS, autonomic ganglia, and neuromuscular junctions → sympathetic stimulation
  • Severe poisoning: persistent activation of nicotinic acetylcholine receptors → receptor desensitization and depolarization blockade → parasympathetic stimulation and neuromuscular blockade
• Clinical features
  • Mild poisoning or early phase of severe poisoning
    • Vomiting (most common) ^[3]
    • Headache, agitation, restlessness, tremors
    • Tachycardia, hypertension, vasoconstriction
  • Late phase of severe poisoning
    • Lethargy, seizures, coma
    • Bradycardia, hypotension
    • Muscle weakness
    • Respiratory failure
• Management ^[3][16]
  • Initiate mechanical ventilation for respiratory failure.
  • Administer atropine for bradycardia and/or other symptoms of cholinergic toxidrome (see “Atropine therapy” in “Treatment”).
  • Manage agitation and toxic seizures with benzodiazepines.
  • Perform body surface decontamination (e.g., remove dermal patches).
  • Administer single-dose activated charcoal to intubated or alert patients with an ingestion < 1 hour ago.
• Disposition ^[16]
  • Admit patients with severe symptoms (e.g., respiratory failure, hypotension) to the intensive care unit.
  • Consider discharging asymptomatic patients with small ingestions after 4–6 hours of observation.

Intermediate syndrome ^[9][17]

• Onset: 1–4 days after cholinergic poisoning from organophosphate exposure
• Clinical features
  • Proximal muscle weakness (especially in the neck flexors)
  • Cranial nerve palsies
  • Respiratory failure
  • Decreased or absent deep tendon reflexes
• Management: See “Respiratory failure management.”

Organophosphate-induced delayed polyneuropathy ^[11][18]

• Onset: weeks to months after exposure to organophosphorus compounds
• Clinical features
  • Peripheral neuropathy (motor symptoms predominate)
  • Extrapyramidal symptoms
• Management ^[3]
  • Administration of atropine or pralidoxime does not improve the clinical course.
  • Recovery occurs over months to years, but residual deficits are common.

Chronic organophosphate-induced neuropsychiatric disorder ^[19]

• Mechanism: chronic low-dose exposure to organophosphorus compounds
• Clinical features
  • Fatigue
  • Depression
  • Cognitive impairment
  • Extrapyramidal symptoms
  • Peripheral neuropathy
  • Autonomic dysfunction
• Management: Refer to psychiatry for comprehensive care.

• Pulmonary edema
• Aspiration pneumonitis
• Organophosphate-induced delayed polyneuropathy
• Chronic organophosphate-induced neuropsychiatric disorder

We list the most important complications. The selection is not exhaustive.