Nerve Agent Exposure

Aka: Nerve Agent Exposure, Nerve Toxin, Nerve Agent, Organophosphate Poisoning Management, Tabun, Sarin, Soman, Novichok

1. See Also
   1. Cholinergic Toxicity
   2. Organophosphate
   3. Biological Weapon
   4. Neurotoxin
   5. Pesticide
   6. Poisoning
2. Types: G Agents
   1. Characteristics
      1. Clear, colorless, tasteless liquids that dissolve in water and solvents
      2. Volatile at Ambient Temperature
      3. Aeroselize easily
      4. Degrade quickly
   2. Agents
      1. Tabun (GA)
      2. Sarin (GB)
      3. Soman (GD)
      4. GF Nerve Agent
3. Types: V Agents
   1. Characteristics
      1. Long-lasting liquids which are easily absorbed via skin
      2. Rapidly fatal within minutes of inhalation, ingestion or skin exposure
   2. Agents
      1. VX Nerve Agent
4. Types: Pesticides and Insecticides
   1. See Organophosphate
   2. See Cholinergic Toxicity
5. Types: Fourth Generation
   1. Novichok Agents (Russian for "Newcomer")
      1. Organophosphate agents with 5-8 fold toxicity of VX agents
      2. Low volatility, but highly persistent as liquid on surfaces
         1. Dermal exposure is most common and effects may be delayed by days
         2. Inhalation or ingestion may also occur
      3. Developed in Soviet Union in 1970's and used in politically motivated assassinations
         1. https://en.wikipedia.org/wiki/Novichok_agent
   2. Carbamates (EA-3990, EA-4056)
      1. Non-Organophosphate agents with toxicity 3 fold higher than VX Nerve Agents
6. History
   1. Developed in Germany before World War II
   2. U.S. stockpiles included GB, VX
   3. Iraq has used Nerve Agents frequently
      1. Iran-Iraq war
      2. Kurdish Refugees
   4. Tokyo subway 1995
      1. Aum Shinrikyo cult used dilute sarin (GB)
7. Pathophysiology
   1. Penetrates skin, eyes, and lungs
   2. Toxic effects manifest as Cholinergic Toxicity (with acetylcholine accumulation)
   3. Organophosphate esters (Acetylcholinesterase Inhibitors)
      1. Most toxic of chemical agents
      2. Similar to Insecticide Organophosphates (e.g. Malathion), but far more potent
      3. Even single drops of some Nerve Agents are lethal within 15 minutes of exposure
8. Adverse Effects: Lethal doses
   1. Skin LD50 (from least to most toxic)
      1. GA, GB: 1000, 1700 mg
      2. GD, GF: 50, 30 mg
      3. VX: 10 mg
   2. Vapor LCt50 (from least to most toxic)
      1. GA: 400 mg-min/m3
      2. GB: 100 mg-min/m3
      3. GD: 70 mg-min/m3
      4. GF: Unknown
      5. VX: 50 mg-min/m3
9. Signs: General
   1. See Cholinergic Toxicity
   2. Children - common presentation (initially misdiagnosed in 80% of cases)
      1. Cholinergic Muscarinic affects
         1. Miosis
         2. Excessive Salivation
      2. Cholinergic Nicotinic affects
         1. Muscle Weakness and hypotonia
         2. Lethargy
         3. Tachycardia (contrast with Bradycardia in adults)
         4. Apnea
         5. Seizure
   3. Adults - common presentations
      1. Cholinergic Muscarinic affects are prominent
         1. Excessive Salivation and Lacrimation
         2. Urination and Defecation
      2. Cholinergic Nicotinic affects are also present
         1. Muscle Fasciculations and weakness
         2. Paralysis
         3. Respiratory arrest
         4. Altered Mental Status
         5. Autonomic instability
10. Signs: Muscarinic receptor (Smooth Muscle, glands)
    1. Increased Glandular secretion ("All faucets on")
       1. Salivation
       2. Lacrimation
       3. Rhinorrhea
       4. Airway secretions
       5. Sweating
    2. Ocular
       1. Miosis
       2. Eye Pain
       3. Dim or Blurred Vision
       4. Conjunctival injection
    3. Respiratory
       1. Bronchoconstriction
       2. Central Apnea within minutes of severe exposure
    4. Gastrointestinal
       1. Nausea and Vomiting (early signs of liquid on skin)
       2. Diarrhea with severe exposure
11. Signs: Nicotinic Receptors (Skeletal Muscle, Ganglia)
    1. Skeletal Muscle changes
       1. Initial
          1. Fasciculations
          2. Muscle Twitching
       2. Later
          1. Weakness
          2. Flaccid Paralysis
    2. Ganglionic effects
       1. Tachycardia
       2. Hypertension
    3. Cardiovascular Effects
       1. Heart Block
       2. Ventricular Arrhythmia
    4. Neurologic Effects
       1. Onset
          1. Vapor: 1 minute of large exposure
          2. Skin contact: 1-30 minutes
       2. Acute
          1. Loss of consciousness
          2. Seizures
          3. Apnea
       3. Prolonged (4-6 weeks)
          1. Forgetfulness
          2. Inability to concentrate fully
          3. Insomnia
          4. Bad dreams
          5. Irritability
          6. Impaired judgment
          7. Depression
          8. No frank confusion or Hallucination
12. Grading: Severity of exposure (used to dose antidote)
    1. Vapor Exposure (Effect in seconds, Peaks in minutes)
       1. Low Exposure
          1. Miosis
          2. Rhinorrhea
          3. Dyspnea
       2. High Exposure
          1. Altered Level of Consciousness
          2. Seizures
          3. Apnea
          4. Flaccid Paralysis
          5. Death
    2. Liquid Exposure
       1. Small amount (delayed effects up to 18 hours)
          1. Localized sweating
          2. Fasciculations
       2. Moderate amount (delayed effects up to 18 hours)
          1. Gastrointestinal effects
       3. Large amount (Effects within 30 minutes)
          1. Altered Level of Consciousness
          2. Seizures
          3. Apnea
          4. Flaccid Paralysis
          5. Death
13. Differential Diagnosis
    1. See Cholinergic Toxicity
    2. Children (misdiagnosed initially in 80% of cases)
       1. Head Trauma
       2. Cerebral Aneurysm
       3. Heat Stroke
       4. Diabetic Ketoacidosis
    3. Adults
       1. Syncope
       2. Heat Stroke
       3. Drug Overdose
       4. Alcohol Intoxication
       5. Cyanide
          1. No increased secretions
          2. No Miosis
          3. Cyanosis uncommon
14. Labs: General
    1. See Poisoning
    2. Troponin
       1. Reflects myocardial injury
    3. Lactic Acid
       1. Decreased
15. Labs: Detection
    1. Odor
       1. Fish or fruit
    2. Detection kits
       1. M256A1: GB, VX (unknown threshold for GF, GA, GD)
       2. M272: GA, GB, GD, VX
       3. MINICAMS: GB, GD, VX
       4. ICAD: GA, GB, GD
       5. M18A2: GB, VX
       6. M21: GA, GB, GD
       7. M90: GA, GB, GD, GF, VX
       8. M93A1 Fox: GB, GD, VX
       9. ACAMS: GB, VX
       10. Bubbler: GB, VX
       11. CAM: GA, GB, GD, GF, VX
       12. DAAMS: GB, VX
16. Labs: Diagnosis (Obtain prior to therapy if possible)
    1. Plasma Pseudocholinesterase Level (easiest to measure)
       1. Decreased after exposure
    2. Erythrocyte cholinesterase activity (best reflects clinical activity)
       1. Severe Nerve Agent Exposure results in <30% baseline
       2. Return to exposure risk when level >75% baseline
17. Management: General
    1. Medical providers wear full protective gear and mask
       1. Level C Personal Protection Equipment
       2. Risk of patient off-gassing
    2. Decontamination
       1. Vapor
          1. Remove all clothing (risk of trapped vapor)
       2. Liquid
          1. Hypochlorite
          2. M291
          3. M258A1
          4. Blot skin with cloth to remove any visible product
          5. Wash with soap and copious water irrigation of all contacted areas
18. Management: Antidotes for Military in field (MARK I Kits)
    1. Preparations: Kit contents
       1. Kits contain and autoinjector with both Atropine and 2-PAM (and separate Diazepam)
          1. Three kits are given to each of U.S. military
       2. Atropine
          1. Effects muscarinic receptors more than nicotinic
             1. Decreases secretions and improves respiratory status
          2. MARK I Auto-injectors contain 2 mg Atropine per injector
       3. Pralidoxime chloride (Protopam chloride, 2-PAMCl)
          1. MARK I Auto-injectors contain 600 mg of 2-PAM per injector
       4. Diazepam (also contained in kit, but is not in autoinjector)
          1. Raises Seizure threshold
          2. Useful if Status Epilepticus ensues
          3. Administer if 3 MARK I Kits are given at same time
    2. Protocol (based on severity rated above)
       1. Mark I auto-injectors may be used in children >2 years old and >12 kg
       2. Mild to moderate vapor or liquid Nerve Agent Exposure
          1. Mark I kit (Atropine and 2-PAMCl): 1-2 doses
       3. Severe vapor or liquid Nerve Agent Exposure
          1. Mark I kit: 3 doses
          2. Diazepam (Valium)
19. Management: Triage (Field)
    1. See Personal Protection Equipment
    2. See Contaminated Casualty Management
    3. See Decontamination
    4. See Decontamination in Children
    5. Immediate Management Indications (Antidotes)
       1. Severe Nerve Agent casualty if circulation intact
       2. Unconscious, convulsing, post-ictal or flaccid
       3. Difficult breathing or apnea
       4. Intact breathing and mentation with severe symptoms
    6. Minimal Management Indications
       1. Patient walking, talking with normal Vital Signs and no Miosis
       2. More reassuring if exposure to vapor Nerve Agent
    7. Delayed Management Indications
       1. Severe exposure post-stabilization
20. Management: Emergency Department
    1. See Poisoning
    2. See Personal Protection Equipment
    3. See Contaminated Casualty Management
    4. See Decontamination
    5. See Decontamination in Children
    6. Supportive Care
       1. ABC Management
       2. Observe for Cardiac Arrhythmia
       3. Ingestions
          1. Immediate Activated Charcoal may be given in awake, alert patients able to swallow
          2. Do not induce Vomiting
       4. Mechanical Ventilation
          1. Do NOT use Succinylcholine (metabolized by acetylcholinesterase)
             1. Results in prolonged effects
             2. Use Rocuronium instead
          2. Usually required for 30 minutes to 3 hours
          3. Airway resistance high (50-70 cm of water)
             1. Improves after Atropine
    7. Antidotes in the emergency department (see field kits above)
       1. Atropine (Preservative-free) for bronchorrhea, bronchospasm, Bradycardia (muscarinic effects)
          1. Goal: Drying of secretions (will not reverse neuromuscular effects, Muscle Weakness or Respiratory Failure)
             1. Repeat doses until Shortness of Breath and Wheezing resolve and excess secretions reduce
          2. Adult: 1-2 mg slow IV push (up to 2-5 mg IV) every 15 minutes as needed
             1. May be given as often as every 3-5 minutes, doubling dose
             2. Most effective for pulmonary symptoms in adults
             3. Very high doses (e.g. 40 mg) may be needed
          3. Child <12 years: 0.015 to 0.05 mg/kg slow IV push (up to 0.1 mg/kg) every 15 minutes as needed
             1. May be given as often as every 3-5 minutes, doubling dose
             2. Most effective for CNS symptoms in children
          4. Taper dose, and discontinue by 24 hours
          5. Atropine may be continued as drip at 0.5 to 2.4 mg/kg/h
             1. Indicated for persistent symptoms (up to 48 hours may be needed in severe cases)
       2. Pralidoxime chloride (2-PAMCl)
          1. Goal: Reverse muscle Fasciculations, Muscle Weakness to Flaccid Paralysis and coma (nicotinic effects)
          2. Most effective if given within minutes (to maximum of hours) of exposure
             1. Nerve Agents irreversibly bind acetylcholinesterase over time ("aging")
             2. May have effect at 24-48 hours
             3. Liberally administer doses even with mild effects (Neurotoxins may have delayed effect)
             4. Treatment may need to be continued longer (esp. fat soluble compounds)
                1. May continue as infusion (e.g. in adults, 500 mg/h IV)
          3. Adult
             1. Dose: 2 g IM or 1 to 2 g IV (in 100 ml saline as infusion)
             2. May repeat in 30-60 minutes (if Muscle Weakness not improved), then every 6-8 hours as needed
          4. Child
             1. IV: 25 mg/kg up to 1 g in 200 ml D5W or NS IV over 15 min OR
             2. IM: 50 mg/kg up to 2 g IM
             3. May repeat in 30-60 minutes (if Muscle Weakness not improved), then every 6-8 hours as needed
    8. Other specific agents
       1. Diazepam (Valium) for Seizures
          1. May use other Benzodiazepines (e.g. Midazolam, Lorazepam)
          2. Non-Benzodiazepine anticonvulsants are not effective for Cholinergic crisis
          3. Adult: 5-10 mg IV push q5-10 minutes up to 30 mg
          4. Child >5 years: 0.2 to 0.5 mg/kg q5 minutes to 10 mg
          5. Child <5 years: 0.2 to 0.5 mg/kg q5 minutes to 5 mg
       2. Furosemide (Lasix) for pulmonary congestion has been used
          1. Maximize Atropine prior to Furosemide use
          2. Dose: 40 to 160 mg IV prn pulmonary congestion
    9. Disposition
       1. Symptomatic Exposure
          1. Observe >8 hours for respiratory decompensation
       2. Asymptomatic Exposure
          1. Observe for 4 to 6 hours and may discharge if continues to be asymptomatic
21. Management: Return to work recommendations
    1. Nerve Agent LD50 decreases for a second exposure
    2. Return when cholinesterase activity >75% baseline
       1. Severe exposure results in <30% activity
       2. Severe exposure requires >45 days for recovery
       3. Mild to moderate exposure is less reliably predicted
    3. Medically observe severe exposures for >1 week
22. Prevention
    1. Protective gear
       1. Chemical protective mask with Activated Charcoal
       2. Charcoal in chemical protective over-garment
       3. Butyl Rubber in chemical protective gloves and boots
    2. Antidotal Enhancement ("Pretreatment")
       1. Pyridostigmine Bromide 30 mg PO q8h before exposure
    3. Research topics
       1. Seizure protection
          1. More reliable alternatives to Valium (e.g. Versed)
          2. Neuro-protective agents
       2. Nerve Agent antidotes
          1. Circulating bio-scavengers for Nerve Agent
23. Complications: Long-term
    1. Neurotoxicity symptoms may be delayed 1 to 3 weeks after exposure (rare)
    2. Neuropsychiatric changes may persist weeks to months
    3. Polyneuropathy
    4. Cognitive changes associated with prolonged Seizures
24. Resources
    1. Nerve Agents (Wikipedia)
       1. https://en.wikipedia.org/wiki/Nerve_agent
25. References
    1. (2016) CALS Manual, 14th ed, p. I-135-7
    2. Seeyave (2015) Crit Dec Emerg Med 29(5): 13-21
    3. Tomaszewski (2020) Crit Dec Emerg Med 34(10): 24
    4. Koh (2017) Crit Dec Emerg Med 31(5): 24
    5. Medical Response to Chemical Warfare and Terrorism
       1. US Army Medical Research Institute Chemical Defense
       2. Video-Teleconference: 4/20/00 to 4/22/99
       3. Video-Teleconference: 12/5/00 to 12/7/00
       4. Text: 3rd Edition, December 1998