Nerve Agents
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  • 1. 3 ER Cases
    • Which patient has nerve agent poisoning?
    • 9 year-old with miosis, agitation, copious secretions, uncontrolled urination. HR 120. RR 16/shallow. Sat 83%
    • 15 year-old with generalized seizure, tongue fasciculations, absent gag, absent reflexes
    • 2 year-old old with fussiness/diarrhea progressing to impaired consciousness, hypotonia
  • 2. Nerve Agents in Children
    • Josh Rotenberg MD MMS
    • Fellow, Pediatric Neurology
    • Staff Pediatrician, WRAMC & NNMC
    • Assistant Professor of Pediatrics, USUHS
  • 3. Nerve Agents in Children
    • Background: Scope of the Problem
    • Background: The agents
    • Diagnosis
    • Isolation/Decon
    • Treatment
    • Pediatric Issues
  • 4. Background : Scope of the Problem
    • CWA in US
      • the most important act of terrorism in which CWA was attempted to use a was the World Trade Center bombing in 1993.
    • the explosive used by the terrorists contained sufficient cyanide to contaminate the entire structure.
    • Fortunately, the cyanide was destroyed by the blast
  • 5. Background : Scope of the Problem
    • Police foil terror plot to use sarin gas in London (Filed: 18/02/2001)
    • Bin Laden British cell planned gas attack on European Parliament (Filed: 16/09/2001)
  • 6. Background: Scope of the Problem
    • Iran-Iraq war (1984-1988)
      • UN confirmed that Iraq used Tabun and other organophosphorous nerve agents
    • Sarin and Sulphur mustard used on Kurds in Northern Iraq
    • Iraq has weaponized VX - 4 tons
    • Gulf-War: large, urban civil popualation threatened for first time since WW1
  • 7. Sarin Attacks in Japan
    • Matsumoto Japan, June 1994
        • 7 died, 58 admitted, 600 injured
    • Tokyo Subway March 1995
        • Sarin released at several points in the Tokyo subway
        • 11 killed, 5,500 injured
        • secondary contamination of the house staff in more than 20%
  • 8. Background: The agents
    • Nerve agents include:
      • Tabun (GA)
      • Sarin (GB)
      • Soman (GD), and
      • VX
  • 9. Background: The agents
    • Originally developed as insectisides
        • more powerful than organophosphates
    • Tabun is easiest and cheapest to manufacture.
      • Described as a starter agent for CW program. Some consider most likey to be used as terrorist agent.
    • Sarin has been used in terrorist attacks
    • VX “only exists in military stockpiles”
  • 10. Background: The agents
    • Exist as a liquid or a gas
    • Liquid is colorless (g-type) amber-colored (VX)
    • Gas can be odorless, fruity (tabun) or slight camphor odor (soman)
    • Vary in volatility – some more persistent than others
      • Sarin as volatile as water
      • VX very persistent
  • 11. Background: The agents
    • Toxic effects depend on the concentration of the agent inhaled and the time exposed to the agent.
      • LD50 - 100 mg/m3 for 1 minute is equivalent to 50 mg/m3 for 2 minutes
    • Note the vapor density
      • Sarin 4.86
      • VX 9.2
  • 12.  
  • 13.
    • When would you launch a sarin attack?
  • 14. How do nerve agents work?
    • Irreversible phosphorylation of cholinesterase enzymes at acetycholine receptors
      • Nicotinic
      • Muscarinic
      • CNS
      • Adrenal
  • 15. Nerve Agents-Mucosal Absorption
    • Nature and onset of signs and symptoms vary by route of absorption.
      • Gases may be absorbed through any part of the respiratory tract: mucosa of the nose and mouth to the alveoli of the lungs.
    • Aerosol particles
      • > than 5 µm tend to remain in the upper respiratory tract
      • < than 1 µm tend to be breathed in and out again, although some of these smaller particles may be retained.
    • They may also be directly absorbed by the eye/skin/GI tract
  • 16. Nerve Agents - Absorption via Skin
    • Agents which penetrate the skin may form temporary reservoirs so that delayed absorption may occur (less so, that OPP).
    • Even the vapor of some agents can penetrate the intact skin and intoxication may follow.
    • Wounds/abrasions (even minor injuries caused by shaving ) present areas which are more permeable than intact skin.
    • The penetration of agents through the GI tract or abrasions may not neccessarily be accompanied by irritation or damage to the surfaces concerned.
  • 17. Neuromuscular Effects
    • Twitching
    • Weakness
    • Paralysis
    • Respiratory failure
  • 18. Autonomic Nervous System Effects
      • Reduced Vision
      • Small pupil size
      • Drooling
      • Sweating
      • Diarrhea
      • Nausea
      • Abdominal pain
      • Vomiting
  • 19. Eyes -- Miosis
    • most common finding
    • Matsumoto - 134/219 -2.5 mm or less
        • improved with atropine
        • Resolved in a month
      • Impaired acuity in 124/219
      • Blurry vision
    • Visual Darkness
    • Ocular pain
  • 20. Central Nervous System Effects
      • Headache
      • Convulsions
      • Coma
      • Respiratory arrest
      • Confusion
      • Slurred speech
      • Depression
      • Respiratory depression
  • 21. Delayed (Chronic) CNS Effects
    • Giddiness, anxiety, jitteriness, restlessness, emotional lability, excessive dreaming, insomnia, nightmares, headaches, tremor, withdrawal and depression,
    • drowsiness difficulty concentrating, slowness on recall, confusion, slurred speech, ataxia.
    • bursts of slow waves of elevated voltage in EEG, especially on hyperventilation,
  • 22. Cause of death
    • In the absence of treatment
      • anoxia resulting from airway obstruction, weakness of the muscles of respiration and central depression of respiration.
    • Airway obstruction
      • due to pharyngeal muscular collapse,
      • upper airway and bronchial secretions,
      • bronchial constriction and
      • occasionally laryngospasm and paralysis of the respiratory muscles.
  • 23. Cause of death
    • With adequate pulmonary support/toilet and atropine, the individual may survive several lethal doses of a nerve agent.
    • However, if the exposure has been many times the lethal dose, death may occur despite treatment as a result of respiratory arrest and cardiac arrhythmia.
    • When overwhelming doses of the agent are absorbed quickly, death occurs rapidly without orderly progression of symptoms.
  • 24. Other symptoms
    • Headache
    • cough
    • sore throat
    • Can persist for weeks
  • 25. Differential Diagnosis
    • Sudden Mass casualties - no sign of trauma
      •  Suspect airborne toxin
    • Hypoxemic, miosis, profuse secretions  Anti -Cholinesterase agent
    • Unconscious, non-hypoxemic  Cyanide
      • venous blood gasses arterialized
    • Less acute causes of respiratory problems
      •  Bo-tox - paralysis, absent reflexes
      •  ARDS like picture- anthrax,plague,phosgene
  • 26. Diagnosis :
    • Treatment: institute rapidly based on clinical judgment
    • Can measure RBC levels of acetycholinesterase
      • Assess treatment and recovery.
      • Insensitive as a screen
        • Matsumoto: ChE decreased in 43% of severely affected
        • Tokyo: decreased in 74% of admiitted
        • 4% have genetic low levels
        • Have genetic high levels, lose 50%, still be nl
        • One call to lab, 3 send outs-time is critical
    • Clinical presentation is likely to vary in children.
  • 27.  
  • 28. Isolation/Decon
    • Decontamination is necessary
    • Dogma
      • 0.05% bleach- people
      • 0.5% household bleach - equipment
    • Truth: Use what is available
      • Good results can be obtained with such widely differing means as talcum powder, flour, soap and water, or special decontaminants.
  • 29. Isolation/Decon
    • Isolation and Decon are necessary in the field
      • Hot, Warm, Cold Zone - Triage in hot and cold zones
      • Tokyo: Most casualties arrive in POV
    • First responders may also be early casualties
      • Rotate health care workers in “hot zone”
    • 23 % health care workers had some sort of physical disorder, though mild.
      • symptoms included ocular pain, headache, sore throat, dyspnea, nausea, dizziness, and nose pain
      • none was seriously affected
  • 30. Triage: Tokyo Subway, St. Lukes
    • Mild severity
      • miosis, rhinorrhea, and mild headache
    • Moderate severity
      • victims were immobile or complained of moderate degree dyspnea, vomiting, severe headache or with neurologic complication like fasciculation
    • Critical severity
      • victims had cardiac or respiratory arrest.
  • 31. Treatment
    • Atropine, respiratory support (secretion management)
    • Antidotes must be given quickly
      • But may still be effective if given late, even in extremis
  • 32. Treatment
    • Atropine -give liberally to dry secretions
      • average total dose in adult 50 mg
    • Pralidoxime 1 g over 5-10 min
    • Fasciculations, Seizures treated with benzodiazepines
    • IM not optimal but acceptable
  • 33. Mark 1 - USA/USAF
    • Atropine - 2 mg (0.7 ml)
    • 2 PAM Cl autoinjector dispenses 600 mg/2 ml
  • 34. Prophylaxis
    • Pyridostigmine
    • Military use only
  • 35. Supportive therapy for CWA exposure include
    • Pulmonary treatment/toilet
      • supplementary oxygen
      • bronchodilators
    • Fluids, elctrolytes, nutrition
    • Hypothermia
    • Eye care
    • Attention to skin lesions,
    • Treatment of complicating infections
  • 36. Pediatric considerations/guidance
    • Antidotes - Dosages
    • Organ System Specific
    • Tokyo Subway, 1995
      • 16 children
      • 5 pregnant women
    • Matsumoto, 1994
      • age 3-89
      • mean 33 y.o .
  • 37. Treatments: Pediatric Dosage
    • Atropine - ACLS protocol
      • 0.02 to 0.05 mg/kg to a maximum of 2 mg. May repeat q 10 minutes to reverse cholinergic symptoms.
        • Min dose – 0.1 mg
        • Max dose - 0.5 mg child; 1 mg adolescent
    • Should we be liberal
        • with atropine?
    • ACLS dosing may
    • not be sufficient
  • 38. Atropine Poisoning in Israeli Children
      • n=268, 92% of pediatric ER’s
      • Most cases accidental; 7.5% intentional by parents expecting exposure
      • doses of 0.01 to 0.17 mg/kg
      • no fatalities,seizures
      • 0.045 to 0.17 mg/kg - mild effects
  • 39. Treatments: Pediatric Dosage
    • Pralidoxime (US) 2-PAM, Protopam
      • 20-50 mg/kg x 1 im/iv/sc. May repeat in 1 hour to relieve muscle weakness (nicotinic)
      • Watch for muscle rigidity, laryngospasm, tachycardia
      • n.b. others used in Europe and Israel
      • Some studies suggest continuous infusion may be better
        • no data in kids
  • 40. Treatments: Pediatric Dosage
    • Diazepam – For severe seizures/status epilepticus
    • 30d to 5 y – 0.05 to 0.3 mg/kg IV to a max of 5mg/dose. May repeat q15-30 minutes
    • 5 y.o. – 0.05 to 0.3 mg/kg IV to a max of 10 mg/dose.
  • 41. CNS
    • Carbamate and Organophosphate poisoning in young children -- Pediatric Emerg Care, April 1999
          • age 2-8, Median 2.8
        • Stupor/Coma 100%
        • Hypotonia 100%
        • Miosis 56%
        • Diarrhea,, Bradycardia, Salivation 25-37%
        • Pulmonary edema 37%
    • Predominance of CNS findings in children?
      • Immaturity of blood brain vs. developmental effect on CNS cholinesterase
  • 42. Pulmonary
    • Increased minute volume and vapor density increases dose of vapor to children
    • Smaller airway will be more easily obstructed
      • bronchoconstriction and secretions
  • 43. Dermatologic
    • Skin absorption of liquid may be significant consideration in infants.
    • Large surface to volume ratio in children compared to adults
    • Fat soluble agents (less than OPP)
    • Breaks in skin may permit easier penetration of agent.
      • Incidence of atopy is approx 4%.
  • 44. Dermatologic
    • Decontamination - Bleach is a mild to moderate mucosal irritant.
    • 0.5% bleach may cause contact dermatittis
    • In children can present like “prickly heat”, erythema, edema, blistering.
  • 45. Environmental Exposure/ Temperature Regulation :
    • Hypothermia - Patients will be fully disrobed before decontamination
      • cold water/bleach solution.
    • Adequate cover, clothing, diapers should be available for parents and children.
    • Watch for delayed effects with warming
  • 46. Feeding
    • No information is available regarding breast feeding.
      • However, nerve agents are less lipid soluble than OPP.
    • Breast feeding mothers should be encouraged to pump and discard.
      • Until when? No research done
    • Institutions should be ready to support infant feedings
  • 47. Developmental-Triage and care
    • Mild and early symptoms may be missed due to a child’s inability to communicate symptoms of pain and pressure.
    • Alternatively, a physician might dismiss signs symptoms such as sleepiness, hypotonia, cramps, rhinnorhea as typical of other childhood illnesses and behavior.
    • What will we do with the mother/infant pairs in decon?
    • Unescorted children?
  • 48. Long-Term Effects :
    • CNS: Organophospate poisoning literature suggests chronic CNS (neurocognitive/cerebellar) and PNS impairment
    • Carcinogenicity: Limited data in animals suggests no effect. One study suggests genotoxicity in human lymphocytes
    • Reproductive Effects: Limited data in animals suggests no effect.
      • Tokyo - well babies
  • 49. Take Home Goodies
    • Mass cas + no trauma=Inhalant
    • Presentation varies with:
        • agent, state, absorption, temperature
    • Autonomic, CNS, muscular symptoms
    • Start treatment based on suspicion
      • atropine, respiratory support
      • Consider diazepam, pralidoxime
    • Pediatric Issues: acute and chronic
  • 50. AAP Guidelines