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Organophosphorus agents

Organophosphate and carbamate insecticides are responsible for 100,000+ deaths worldwide, particularly in developing countries due to its availability. Organophosphorus agents can be broken down into three groups:

  • Organophosphates: Chlorpyrifos, Coumaphos, Diazinon, Dichlorvos, Dimethoate, Ethion, Fenthion, Malathion, Parathion and Trichlorfon.
  • Carbamates: Aidicarb, Carbendazim, Carbendazole, Carbazine, Carbaryl, Carbofuran, Ethienocarb, Fenobucarb, Oxamyl, Methomyl and Propoxur
  • Chemical nerve agents: Sarin, Soman, Tabun and VX.

Toxic Mechanism:

Organophosphosphorus agents inhibit acetylcholinesterase (AChE) enzymes and increase acetylcholine (Each) concentration at both muscarinic and nicotinic cholinergic receptors.

Organophosphates tend to be more toxic due to the “ageing” process. Ageing is the irreversible loss of an alkyl side chain which results in irreversible permanent binding to AChE. Once “ageing” has occurred AChE can not be reactivated by the antidote pralidoxime. Time for ageing occurs is variable between agents.

Pearl: Donepezil and tacrine are central-acting AChEIs that cause procholinergic side effects in overdose. Organophosphates and carbamates often have a hydrocarbon solvent that causes a headache and dizziness, this in and of itself does not indicate organophosphate poisoning.

Toxicokinetics: 

  • Rapidly absorbed following ingestion.
  • Most are well absorbed across the skin and via inhalation
  • Highly lipid soluble and distribute to fat stores hence repeated occupational exposures is an important source.
  • Carbamates have less CNS distribution
  • Undergo hepatic metabolism prior to urinary excretion
  • Elimination of some organochlorines may take weeks to months

Resuscitation:

  • Potential life threats include:
    • Coma – intubate and ventilate
    • Hypotension
    • Seizures – IV benzodiazepines incrementally dosed every 5 minutes to effect.
      • Check the patient is not in a dysrhythmia
      • Can be managed with benzodiazepines (varying doses in the textbooks, easy method is 0.1mg/kg IV for lorazepam (max 4mg) / midazolam (max 10mg) / diazepam (max 10mg). Or…
      • Lorazepam 0.1mg/kg max 4mg
      • Diazepam 0.15mg/kg max 10mg
      • Midazolam 0.2mg/kg max 10mg
    • Respiratory failure
    • The presence of miosis, sweating, reduced air entry, wheeze, cough, signs of pulmonary oedema, bradycardia or hypotension require escalating doses of atropine.
    • There have been no reports of nosocomial poisoning, and therefore resuscitation should not be interrupted by decontamination or excessive staff PPE.

Risk Assessment

  • Deliberate self-poisoning always produces a life-threatening toxicity. Carbamates produces a similar toxicity but is generally shorter duration and likely to be less life-threatening.
  • Clinical features may be delayed for up to 12 hours with some agents.
  • Inadvertent or accidental occupation exposure can cause toxicity but is rarely life threatening.
  • In children any ingestion is potentially life-threatening.
  • Clinical features:
    • Muscarinic: DUMBBELS – Diarrhoea, urination, miosis, bronchorrhoea, bronchospasm, emesis, lacrimation, salivation. Plus bradycardia and hypotension.
    • Nicotinic: Fasiculations, tremor, weakness, respiratory muscle paralysis, tachycardia (can also be secondary to hypoxia and hypotension) and hypertension.
    • CNS: Agitation, coma and seizures
    • Respiratory: Chemical pneumonitis if the hydrocarbon solvent is aspirated.
  • Intermediate Syndrome: Seen with Fenthion, Diazinon and Malathion whereby individuals develop paralysis 2 – 4 days after initial recovery. The pathophysiology is not well understood and theories range from inadequate pralidoxime dosing or redistribution from lipid stores.
  • Delayed Neurotoxicity: Organophosphate-induced delayed neuropathy (OPIDN) is rare and occurs 1 – 5 weeks post exposure with Fenthiom, Chlorpyrifos and Parathion. Patients develop an ascending sensorimotor polyneuropathy secondary to ageing of axonal neuropathy target esterase (NTE).
  • Chronic Organophosphate-induced Neuropsychiatric Disorder: Can occur with either acute or a chronic occupational exposure.

Supportive Care

  • Agitation: titrated doses of benzodiazepines are effective e.g. diazepam 2.5 – 5 mg every 5 minutes IV until gentle sedation is achieved
  • If intubated consider FASTHUGSINBED Please

Investigations

  • Screening: 12 lead ECG, BSL, Paracetamol level
  • Specific:
    • Red cell and plasma cholinesterase activities can be used to make a definitive diagnosis (despite this usually being clinical) and to monitor therapy. Access to these tests in a timely manner is a major limiting factor.
    • Significant clinical features occur with levels <25% of normal activity
    • Plasma cholinesterase activity is sensitive for anticholinesterase exposure. It falls more rapidly and recovers faster than red cell cholinesterase activity (4 – 6 weeks). Once it starts to increase it suggests the plasma concentration of the anticholinesterase compounds is negligible.
    • Red cell cholinesterase activity correlates with severity but takes longer to recover (120 days). It returns to normal following successful oxime therapy and is used to monitor progress when oxides are withdrawn.
    • Mixed Cholinesterase test: Currently not validated but involves mixing patient serum and a control serum in a 50:50 ratio. The mean levels of the patient and control serum cholinesterase activity are recorded, if the mixed test has a lower level this would imply that the patient’s plasma contains unbound organophosphate and increased oxime administration is required.

Decontamination:

  • Remove clothes and wash skin with soap and water.

Enhanced Elimination

  • Not clinically useful.

Antidotes

  • Atropine in escalating doses until the cholinergic symptoms are controlled (sweating, reduced breath sounds, wheeze, cough, bradycardia and hypotension).
  • Pralidoxime  is required to prevent ‘ageing’ and also to reverse neuromuscular blockade with organophosphates only (not carbamates). It’s use is disputed because of mixed clinical outcomes in trials and this probably relates to the different pharmacokinetics of the various organophosphates and variable doses used.

Disposition

  • Any adult with a deliberate self-poisoning requires 12 hours of observation. Discharge should not occur overnight.
  • Children with potential ingestions should be observed for 12 hours, if asymptomatic they may be safely discharged (but not overnight).
  • Patients with objective findings of poisoning require antidote administration and to be observed in an area capable of detecting respiratory and neuromuscular complications. Once they are clinically improving they will require a further 24 hours of monitoring after cessation of any oxime therapy given.
  • Follow up needs to be arranged to detect any intermediate or delayed syndromes.
  • Occupational exposure does not require hospitalisation unless significant symptoms develop.

References and Additional Resources:

Additional Resources:

Video: Dr Eddleston Pesticide Deaths in Asia: Looking for the Clues in Prevention

References:

toxicology library antidote 700 1

Toxicology Library

DRUGS and TOXICANTS

Tox Library

Dr Neil Long BMBS FACEM FRCEM FRCPC. Emergency Physician at Kelowna hospital, British Columbia. Loves the misery of alpine climbing and working in austere environments (namely tertiary trauma centres). Supporter of FOAMed, lifelong education and trying to find that elusive peak performance.

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