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Nerve Agents


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Nerve Agents

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