Organophosphate toxicity

Background

• Organophosphates (OPs) found in:
  • Pesticides (e.g. malathion, parathion, chlorpyrifos, diazinon)
  • Chemical weapons / nerve agents (e.g. sarin, soman, tabun, VX, novichok)
  • Medications (e.g. echothiophate, neostigmine, edrophonium)
• Highly lipid soluble; absorbed via dermal, gastrointestinal, or respiratory routes
• Generally colorless, odorless, low volatility, and high lipophilicity
  • Some formulations have a garlic or petroleum-like odor (important clinical clue)
• These compounds act as Acetylcholinesterase inhibitors
  • Irreversibly bind and inhibit acetylcholinesterase (AChE), resulting in excess accumulation of acetylcholine at muscarinic receptors, nicotinic receptors (including the NMJ), and in the CNS → cholinergic toxicity
  • This binding undergoes aging (dealkylation), which makes the enzyme permanently inactivated and resistant to reactivation by oximes (see below)

Organophosphates vs Carbamates

• Carbamate poisoning (e.g. aldicarb, carbaryl, physostigmine) produces an identical cholinergic toxidrome
• Key difference: carbamates reversibly inhibit AChE → shorter duration, spontaneous recovery
• Carbamates do not undergo aging → pralidoxime is generally not needed (and its role is controversial)
• Carbamate toxicity is typically less severe and shorter-lasting

Aging and Oxime Window

• After OPs bind AChE, a secondary aging reaction (dealkylation) occurs, making the bond permanent and unresponsive to oxime therapy
• Aging half-life varies dramatically by compound:

Compound	Type	Aging Half-Life
Soman	Nerve agent	~2-6 minutes
Sarin	Nerve agent	~3 hours
Malathion	Dimethyl pesticide	~3.7 hours
Tabun	Nerve agent	~19 hours
Parathion	Diethyl pesticide	~33 hours
VR	Nerve agent	~139 hours

• Clinical pearl: Dimethyl OPs (e.g. malathion) age rapidly → oximes must be given early. Diethyl OPs (e.g. parathion) age slowly → oxime therapy may be effective for longer
• If pralidoxime is given after aging is complete, it may paradoxically worsen toxicity (pralidoxime itself competitively inhibits AChE)

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)
    • Mydriasis, hypertension, sweating
  • Beta effects (heart, lungs)
    • Tachycardia, bronchodilation

Clinical Features

• Onset of symptoms varies from minutes (inhalation/nerve agents) to hours (dermal/ingestion) depending on route and agent
• Symptoms caused by acetylcholine buildup at muscarinic receptors, nicotinic receptors, and in the CNS

CNS Effects

• Headache, confusion, agitation, vertigo, seizures, coma
• Respiratory depression (central drive suppression — a major cause of death)

Muscarinic Effects

• SLUDGE(M) = Salivation, Lacrimation, Urination, Diarrhea, GI pain, Emesis, Miosis
• DUMBELLS = Diarrhea/Diaphoresis, Urination, Miosis, Bradycardia/Bronchorrhea, Emesis, Lacrimation, Lethargic, Salivation

Nicotinic Effects (NMJ)

• MTWThF (days of week) = Mydriasis/Muscle cramps, Tachycardia, Weakness, Twitching, Hypertension/Hyperglycemia, Fasciculations
• Note: Nicotinic stimulation can cause mydriasis and tachycardia, which may mask the classic muscarinic findings of miosis and bradycardia — do not use these alone to rule out OP poisoning

Common Causes of Death

• Killer B's = Bradycardia, Bronchorrhea, Bronchospasm
• Respiratory failure is the primary cause of death: combination of bronchospasm, bronchorrhea, central respiratory depression, and diaphragmatic weakness

Intermediate Syndrome

• Occurs 24-96 hours after acute cholinergic crisis, typically after resolution of the acute cholinergic phase
• Characterized by weakness of proximal limb muscles, neck flexors, and cranial nerve palsies
  • Clinical pearl: Earliest sign is often inability to lift the head from the pillow (neck flexor weakness) — a useful bedside test to detect impending respiratory failure
• Respiratory muscles may be affected → respiratory failure requiring mechanical ventilation
• Can last for days to weeks
• Thought to result from prolonged NMJ dysfunction due to sustained cholinergic overstimulation
• Pralidoxime and atropine do NOT prevent or treat the intermediate syndrome

Organophosphate-Induced Delayed Neuropathy (OPIDN)

• Also called Type III syndrome or organophosphate-induced delayed polyneuropathy (OPIDP)
• Rare; onset 1-5 weeks after acute exposure
• Distal sensorimotor axonopathy: paresthesias in stocking-glove distribution → ascending symmetric motor weakness → foot drop, wrist drop
• Not related to AChE inhibition; thought to involve inhibition of neuropathy target esterase (NTE)
• No specific treatment; pralidoxime and atropine do not prevent OPIDN
• Recovery is often incomplete — sensory symptoms may improve but motor deficits can be permanent
• Historical example: "Ginger Jake paralysis" in 1930s Prohibition-era USA (tri-ortho-cresyl phosphate contamination)
• Key differential: Guillain-Barré syndrome (can mimic OPIDN; check history of OP exposure)

Differential Diagnosis

SLUDGE Syndrome

• Carbamate toxicity
• Mushroom toxicity, especially:
  • Amanita muscaria
  • Inocybe
  • Clitocybe
• Organophosphate toxicity
• Nerve agent
  • Sarin
  • VX
  • Novichok agent
• Nicotine toxicity (look alike)
• Acetylcholinesterase inhibitor overdose (e.g in myasthenia gravis or post anesthesia reversal)

Weakness

• Neuromuscular weakness
  • Upper motor neuron:
    • CVA
    • Hemorrhagic stroke
    • Multiple sclerosis
    • Amyotrophic Lateral Sclerosis (ALS) (upper and lower motor neuron)
  • Lower motor neuron:
    • Spinal and bulbar muscular atrophy (Kennedy's syndrome)
  • Spinal cord disease:
    • Infection (Epidural abscess)
    • Infarction/ischemia
    • Trauma (Spinal Cord Syndromes)
    • Inflammation (Transverse Myelitis)
      • Acute flaccid myelitis
    • Degenerative (Spinal muscular atrophy)
    • Tumor
  • Peripheral nerve disease:
    • Guillain-Barre syndrome
    • Toxins (Ciguatera)
    • Tick paralysis
    • Diabetic peripheral neuropathy
  • Neuromuscular junction disease:
    • Myasthenia gravis crisis
    • Botulism
    • Organophosphate toxicity
    • Lambert-Eaton myasthenic syndrome
  • Muscle disease:
    • Rhabdomyolysis
    • Dermatomyositis
    • Polymyositis
    • Alcoholic myopathy
• Non-neuromuscular weakness
  • Can't miss diagnoses:
    • ACS
    • Arrhythmia/Syncope
    • Severe infection/Sepsis
    • Hypoglycemia
    • Periodic paralysis (electrolyte disturbance, K, Mg, Ca)
      • Hypokalemic periodic paralysis
      • Thyrotoxic periodic paralysis
    • Respiratory failure
  • Emergent Diagnoses:
    • Symptomatic Anemia
    • Severe dehydration
    • Hypothyroidism
    • Polypharmacy
    • Malignancy
    • Aortic disease - occlusion, stenosis, dissection
  • Other causes of weakness and paralysis
    • Acute intermittent porphyria (ascending weakness)

Chemical weapons

• Blister chemical agents (Vesicants)
  • Lewisite (L)
  • Sulfur mustard (H)
  • Phosgene oxime (CX)
• Pulmonary chemical agents (Choking agents)
  • Ammonia toxicity
  • Methyl isocyanate
  • Methyl bromide
  • Hydrochloric acid
  • Chlorine gas
  • Phosgene
• Incendiary agents
  • Agent orange
  • White phosphorus
• Cyanide chemical weapon agents (Blood agents)
  • Prussic acid (AKA hydrogen cyanide, hydrocyanic acid, or formonitrile)
• Nerve Agents (organophosphates)
  • Acetylcholinesterase inhibitors
  • Household and commercial pesticides (diazinon and parathion)
  • G-series (sarin, tabun, soman)
  • V-series (VX)
• Lacrimating or riot-control agents
  • Pepper spray
  • Chloroacetophenone
  • CS

Symptomatic bradycardia

• Cardiac
  • Inferior MI (involving RCA)
  • Sick sinus syndrome
• Neurocardiogenic/reflex-mediated
  • Increased ICP
  • Vasovagal reflex
  • Hypersensitive carotid sinus syndrome
  • Intra-abdominal hemorrhage (i.e. ruptured ectopic)
• Metabolic/endocrine/environmental
  • Hyperkalemia
  • Hypothermia (Osborn waves on ECG)
  • Hypothyroidism
    • Myxedema coma
  • Hypoglycemia (neonates)
• Toxicologic
  • B-blocker
  • Ca-channel blocker
  • Clonidine
  • Digoxin toxicity
  • Ethanol
  • Opioids
  • Organophosphates
  • Xylazine toxicity
• Infectious/Postinfectious
  • Chagas disease
  • Lyme disease
  • Syphilis
• Other
  • Brash syndrome

Evaluation

Work-up

• Point-of-care glucose — hyperglycemia may be present (nicotinic effect); hypoglycemia must be excluded in altered patients
• CBC
  • May show leukocytosis
• Comprehensive Metabolic Panel
• Lipase — pancreatitis has been reported as a complication
• VBG/ABG — assess for respiratory failure and acidosis
• CXR
  • Pulmonary edema in severe cases
• ECG
  • Ventricular dysrhythmias, torsades, QT prolongation, AV block, sinus bradycardia or tachycardia
  • QTc prolongation has prognostic value — correlates with severity

Diagnosis

• Clinical diagnosis based on history and cholinergic toxidrome
• Garlic or petroleum-like odor on patient's breath or clothing may be a clue
• RBC acetylcholinesterase and plasma butyrylcholinesterase (pseudocholinesterase) levels:
  • Can confirm exposure but results are rarely available in time to guide acute management
  • RBC AChE is more specific for OP poisoning; plasma cholinesterase is more sensitive but less specific
  • Useful for confirmation, medicolegal documentation, and monitoring recovery
• Peradeniya Organophosphorus Poisoning (POP) scale can be used to grade severity

Management

Decontamination

• Staff safety first: Don PPE before patient contact — nitrile or neoprene gloves (latex is insufficient), gown, eye protection
• Remove ALL clothing and bag separately; clothing can harbor residual OP
• Wash skin thoroughly with soap and water
• GI decontamination: Limited role
  • Activated charcoal: May be considered if within 1 hour of ingestion and airway is protected; limited evidence of benefit
  • Gastric lavage: Only if very early presentation (<1 hour) with large ingestion and protected airway
  • Neither is routinely recommended due to rapid absorption and risk of aspiration

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
• Benzodiazepines for seizures

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

• First-line antidote — muscarinic antagonist; treats bronchorrhea, bronchospasm, bradycardia, and secretions
• Does NOT reverse nicotinic symptoms (weakness, fasciculations, paralysis)
• Starting dose: Atropine 1-2 mg IV (double q5min until atropinization) IV — May need 100+ mg in first 24h; endpoint is drying of secretions
• Pediatric: Atropine 0.02-0.05 mg/kg IV (min 0.1 mg), double q5min IV
• Doubling protocol: If inadequate response after 5 minutes, double the dose (1 → 2 → 4 → 8 → 16 mg...) until atropinization is achieved
• Massive doses may be required — total doses of 100+ mg in the first 24 hours have been reported
• Endpoints of adequate atropinization (goal of therapy):
  • Drying of bronchial secretions (most important endpoint)
  • Heart rate >80 bpm
  • Systolic BP >80 mmHg
• Do NOT target: Fully dilated pupils, absent bowel sounds, or HR >150 — these indicate atropine toxicity
• After initial atropinization: Consider atropine infusion (10-20% of loading dose per hour) to maintain effect
• Optimize oxygenation before giving atropine to reduce risk of dysrhythmias (though in resource-limited settings, do not withhold atropine waiting for oxygen)

Pralidoxime

• AKA 2-PAM
• Oxime that reactivates phosphorylated AChE → primarily reverses nicotinic symptoms (weakness, fasciculations, respiratory muscle paralysis)
• Must give atropine BEFORE pralidoxime to prevent worsening of muscarinic symptoms
• Must be given before aging occurs (see aging table above)
• Pralidoxime 1-2 g IV over 15-30 min, then 8-10 mg/kg/hr infusion (or repeat bolus in 1 hr) IV
• Pediatric: Pralidoxime 20-50 mg/kg IV, then 5-10 mg/kg/hr infusion IV
• Continue until clinical improvement or patient is off ventilator
• Controversies:
  • Evidence for benefit of pralidoxime is inconsistent; several meta-analyses have not shown clear mortality benefit when added to atropine
  • However, per AHA 2023 guidelines and expert consensus, oximes should still be given for significant OP poisoning, particularly when fasciculations, weakness, or paralysis are present
  • Efficacy depends on timing (before aging), dose, and the specific OP compound involved
• Caution: Administer slowly — rapid IV push can cause hypertensive crisis, cardiac arrest

Benzodiazepines

• Diazepam or midazolam for seizures
• Diazepam 5-10 mg IV (pediatric: 0.2-0.5 mg/kg); repeat as needed
• Prophylactic benzodiazepines may be considered in severe poisoning (especially nerve agent exposure)
• Do NOT use phenytoin — ineffective for OP-induced seizures and may worsen toxicity
• Animal studies suggest benzodiazepines may also reduce OP-related brain injury

Supportive Care

• Airway management: Early intubation for copious secretions, respiratory failure, or altered mental status
  • Avoid succinylcholine — metabolized by plasma cholinesterase (inhibited by OPs) → prolonged paralysis
  • Use non-depolarizing agents (e.g. rocuronium) if RSI is needed; may require higher doses
• IV fluid resuscitation for hypotension
• Vasopressors if hypotension refractory to fluids
• Continuous cardiac monitoring and pulse oximetry
• Avoid: morphine, theophylline, aminophylline, phenothiazines, and reserpine (all potentiated by OPs or may worsen toxicity)

Adjunctive Therapies (Emerging/Limited Evidence)

• Magnesium sulfate: Some studies suggest benefit in reducing ICU stay, need for ventilation, and cardiac toxicity; insufficient evidence for routine use
• Sodium bicarbonate: Has been explored as adjunct; not yet standard of care
• Lipid emulsion therapy: Case reports only; not established
• Fresh frozen plasma: Theoretical benefit (provides butyrylcholinesterase); limited evidence

Disposition

• Minimal exposure + completely asymptomatic for at least 6-12 hours after exposure → may be considered for discharge
  • Longer observation (up to 24 hours) for fat-soluble agents or large dermal exposures due to risk of delayed onset
• Admit all symptomatic patients — most will require ICU-level care
• ICU admission criteria:
  • Need for atropine infusion
  • Respiratory distress or intubation
  • Hemodynamic instability
  • Seizures
  • Altered mental status
• Monitor admitted patients for 48-96 hours for intermediate syndrome onset (watch for proximal weakness and neck flexor weakness)
• If evidence of deliberate self-harm → place on psychiatric hold and consult psychiatry
• Poison control/toxicology consult for all significant exposures
• If mass casualty or suspected nerve agent → activate HAZMAT response and notify public health authorities

Consultant Pearls

• Toxicology: Call early for guidance on pralidoxime duration, atropine infusion management, and identification of the specific OP (dimethyl vs diethyl affects aging time)
• ICU/Critical Care: Discuss need for mechanical ventilation and anticipate intermediate syndrome
• Psychiatry: Mandatory for intentional ingestions
• If EMS can identify the specific product/label: Bring it in — different OPs have different aging times, which directly impacts whether pralidoxime will be effective

Medication Dosing

Antidotes

Adults

• Atropine 1-2 mg IV, then double q5min as needed IV — Titrate to drying of secretions; massive doses may be required
• Pralidoxime 1-2 g over 15-30 min, then 500 mg/hr infusion IV — Must give before aging occurs; continue until off ventilator

Pediatrics

• Atropine 0.02-0.05 mg/kg (min 0.1 mg) IV — Double dose q5min until secretions dry
• Pralidoxime 20-50 mg/kg, then 5-10 mg/kg/hr infusion IV

Seizures

• Diazepam 5-10 mg IV
• Diazepam 0.2-0.5 mg/kg IV

See Also

• Toxidromes
• Cholinergic crisis
• Carbamate poisoning
• Nerve agent
• Pralidoxime
• Atropine
• Acetylcholinesterase inhibitors