Organophosphate toxicity

Background
  • Organophosphates found in:
  • Highly lipid soluble: absorbed via dermal, gastrointestinal or respiratory routes
  • Colorless, odorless, low volatility, and high lipophilicity
  • These compounds act as Acetylcholinesterase inhibitors
    • Block acetylcholinesterase, resulting in excess accumulation of acetylcholine at the neuromuscular junction and cholinergic toxicity
  • LD50 of 0.04mg/kg (10 mg). Death can occur within 15 minutes after absorption

Autonomic Nervous System Receptors and Their Effects
  • Parasympathetic - ACh is transm
    • Muscarinic
      • receptors in heart, eye, lung, GI, skin and sweat glands
      • Bradycardia
      • Miosis
      • Bronchorrhea / Bronchospasm
      • Hyperperistalsis (SLUDGE)
      • Sweating
      • Vasodilation
    • Nicotinic
      • receptors in both sympathetic and parasympathetic nervous systems
      • fasciculations, flaccid paralysis
      • ?Mild bradycardia, hypotension
  • Sympathetic
    • Alpha effects (vessels, eye, skin)
    • Beta effects (heart, lungs)

Clinical Features
  • Symptoms caused by acetylcholine buildup in CNS and PNS.
  • CNS symptoms = headache, confusion, vertigo, seizures, coma
  • Muscarinic Receptors
    • SLUDGE(M) = Salivation, Lacrimation, Urination, Diarrhea, GI pain, Emesis, Miosis
    • DUMBELLS = Diarrhea, diaphoresis, Urination, Miosis, Bradycardia, Bronchorrea, Emesis, Lacrimation, Lethargic, Salivation
  • Nicotinic Receptors (NMJ)
    • MTWThF (days of week) = Mydriasis/Muscle cramps, Tachycardia, Weakness, Twitching, Hypertension/Hyperglycemia, Fasciculations, Seizures, Somnolent
  • Common causes of death in organophosphate toxicity
    • Killers B's = Bradycardia, Bronchorrhea, Bronchospasm

Intermediate Syndrome

Differential Diagnosis

SLUDGE Syndrome

Weakness

Chemical weapons

Symptomatic bradycardia

Evaluation

Work-up

Diagnosis
  • Clinical diagnosis
  • Blood tests such as RBC and plasma pseudocholinesterase levels are available, but little clinical utility

Management

Decontamination
  • Providers should wear appropriate PPE during decontamination.
    • Neoprene or nitrile gloves and gown (latex and vinyl are ineffective)
  • Dispose of all clothes in biohazard container
  • Wash patient with soap and water

Supportive Care
  • IVF, O2, Monitor
  • Aggressive airway management is of utmost importance.
    • Intubation often needed due to significant respiratory secretions / bronchospasm.
    • Use nondepolarizing agent (Rocuronium or Vecuronium)
    • Succinylcholine is absolutely contraindicated

Antidotes
  • Dosing with atropine and pralidoxime are time dependent and provides ability to reverse symptoms while awaiting agent metabolism
  • For exposure to nerve agents, manufactured IM autoinjectors are available for rapid administration:
    • Mark 1
      • Contains 2 separate cartridges: atropine 2 mg + 2-PAM 600 mg
      • Being phased out with newer kits
    • DuoDote
      • Single autoinjector containing both medications
      • Same doses as Mark 1: atropine 2 mg + 2-PAM 600 mg

Antidotes

Atropine
  • Competitively blocks muscarinic sites (does nothing for nicotinic-related muscle paralysis)
  • May require massive dosage (hundreds of milligrams)
  • Dosing[1]
  • Adult: Initial bolus of 2-6mg IV; titrate by doubling dose q5-30m until tracheobronchial secretions controlled
    • Once secretions controlled → start IV gtt 0.02-0.08 mg/kg/hr
    • Child: 0.05-0.1mg/kg (at least 0.1mg) IV; repeat bolus q2-30m until tracheobronchial secretions controlled
    • Once secretions controlled → start IV gtt 0.025 mg/kg/hr

Pralidoxime
  • AKA 2-PAM
  • For Organophosphate poisoning only - reactivates AChE by removing phosphate group → oxime-OP complex then excreted by kidneys.
    • This must be done before "aging" occurs - conformational change that makes OP bond to AChE irreversible[2]
    • Pralidoxime can actually bind and inhibit AChE once all AChE enzymes have aged, and can make the toxicity worse
    • Window to aging depends on the agent, and is a matter of debate, but pralidoxime within 1-2 hours of exposure is the goal
  • Dosing[1]
    • Adult: 1-2gm IV over 15-30min; repeat in 1 hour if needed or 50 mg/hr infusion.
    • Child: 20-40mg/kg IV over 20min; repeat in 1 hour if needed or 10-20 mg/kg/hr infusion.

Disposition
  • Minimal exposure + asymptomatic at least 12 hours after exposure can likely be discharged.
  • Admit all symptomatic patients!
  • If evidence of deliberate self harm, place on hold and consult psychiatry

See Also

References
  1. Agency for Toxic Substances and Disease Registry, Case Studies in Environmental Medicine, Cholinesterase Inhibitors: Including Pesticides and Chemical Warfare Nerve Agents. Centers for Disease Control (CDC). PDF Accessed 06/21/15
  2. Eddleston M, Szinicz L, Eyer P, Buckley, N (2002) Oximes in Acute Organophosphate Pesticide Poisoning: a Systematic Review of Clinical Trials. QJM. 95(5): 275–283.
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