New Jersey Preparedness Training Consortium

1. New Jersey Preparedness Training Consortium Continuing Education for health care professionals “modulechemv1” Chemical Agents of Terror

2. Background: Recent Chemical Warfare Agents Terrorist Events • 1993 World Trade Center Bombing • Explosive used contained sufficient cyanide to contaminate entire bldg. • Cyanide destroyed in blast • 1995 Aum Shinrikyo sect released Sarin vapor into Tokyo Subway • 12 deaths, 5,500 casualties (4,000 w/o clinical manifestation of injury)

3. Background (continued) • Sarin gas was released in the Tokyo subway system by the Aum Shinrikyo Cult, creating more than 5,000 victims and causing 12 deaths. • The same cult had released sarin in an apartment complex in Matsumoto in 1994, killing seven and injuring more than 600 people. • In Tokyo, sarin was concealed in lunch boxes and bags. The terrorists punctured the bags with umbrellas and ran out of the subway tunnel.

4. Background (continued) • Iraq reportedly used tabun and maybe sarin in the Iran-Iraq war (1984–1988). • Iranian soldiers had atropine auto-injectors. • Many had atropine overdoses from misuse of their auto-injectors.

5. Preparing public health agencies for chemical attacks • Enhance epidemiologic capacity for detecting and responding to chemical attacks. • Enhance awareness of chemical terrorism among emergency medical service personnel, police officers, firefighters, physicians, and nurses. • Stockpile chemical antidotes. • Develop and provide means to detect and diagnosis chemical injuries. • Prepare educational materials to inform the public during and after a chemical attack

6. Chemical agents • Range from warfare agents to toxic chemicals commonly used in industry. • Criteria for determining priority chemical agents include • chemical agents already known to be used as weaponry • availability of chemical agents to potential terrorists • chemical agents likely to cause major morbidity or mortality • potential of agents for causing public panic and social disruption • agents that require special action for public health preparedness Source CDC

7. Potential Terrorism Risks from Chemical Warfare Agents • Detonation of CWA-containing munitions • Atmospheric Dispersal • Contamination of Food Supplies • Contamination of Water Supplies • Product Tampering • Low Probability/High Consequence Event

8. Sources of CW Agents • Foreign governments • Internet recipes • Crime and corruption in former Soviet Union • U.S. Chemical plants (e.g. Cl, Phosgene, etc) • U.S. Military Stockpile • (est. 30,600 tons of nerve agents and vesicant at 8 sites across U.S.) • 1985 law directed DoD destroy stockpile by 1994 …extended to 2004) • U.S. Military non-stockpile • (outdated CWA and recovered weapons…buried at 215 sites)

9. Sources (continued) • The United States has over 30,000 tons of VX and sarin. • The government is planning the destruction of this stock and has already destroyed small batches. • Dupont Chemical is negotiating for the contract to destroy 1,200 tons of VX stored in the Newport chemical depot. • There is an ongoing discussion about the best way to dispose of the end products.

10. CWA Characteristics • Volatility • Tendency to evaporate from liquid to gas form • Greater volatility= shorter persistence • Vapor Density • Weight of the vapor or mist relative to air • All CWA’s (except HCN) heavier than air • Persistence • Most evaporate > 24 hours • Present increased risk for skin exposure to victims and risk to responders

11. Toxicity of CWA’s • Potential to cause injury in biologic systems • LD50 – single dose causing death in 50% of animals • ED50 – dose where 50% of exposed population will exhibit signs or symptoms • LD50 and ED50 limited use for toxicity of agents inhaled or absorbed across mucous membranes • Concentration-time (Ct) used for CW Agents • Concentration in air x time exposed • Represented as milligrams/minute/cubic meter • Latency – time delay between exposure and clinical signs/symptoms (sulfur mustard and pulmonary have longest…nerve agents and cyanides shortest)

12. Clues suggesting release of a chemical agent • An unusual increase in the number of patients seeking care for potential chemical-release--related illness; • Unexplained deaths among young or healthy persons • Emission of unexplained odors by patients • Clusters of illness in persons who have common characteristics, such as drinking water from the same source • Rapid onset of symptoms after an exposure to a potentially contaminated medium (e.g., paresthesias and vomiting within minutes of eating a meal)

13. Clues suggesting release of a chemical agent • Unexplained death of plants, fish, or animals (domestic or wild) • Syndrome (i.e., a constellation of clinical signs and symptoms in patients) suggesting a disease associated commonly with a known chemical exposure (e.g., neurologic signs or pinpoint pupils in eyes of patients with a gastroenteritis-like syndrome or acidosis in patients with altered mental status).

14. Classes of Chemical Agents • Nerve Agents • Inhibit acetylcholinesterase (AChE) causing Ach accumulation and excessive cholinergic stimulation • Incapacitating Agents • Irritation and extreme pain to affected organs • Pulmonary Agents • Impair ability to function- not permanent • Lacrimators, sternutators, vomiting • Vesicants/Blistering/Vomiting Agents • Extensive irreversible tissue damage • Blood Agents • Interfere with cellular respiration

15. General Treatment Guidelines • Nerve Agents • Atropine, pralidoxime chloride (2-PAMCl), or diazepam • Incapacitating Agents • Remove to fresh air, decon w/water, 6% bicarbonate solution • Pulmonary Agents • Supplemental oxygen, restrict physical activity, medical attention • Vessicants/Blister Agents • Remove to fresh air, remove clothing, decontaminate skin, supplemental oxygen, hospitalization, extensive irrigation of eyes • Blood Agents • Amyl nitrate, sodium nitrate, sodiumthiosulfate

16. Patient Management and Treatment • Focus on Airway, Breathing, Circulation (ABCs) • Personal Protective Equipment (resp, skin) • Clothing Removal • Decontamination of Patient • Copious water w/any liquid soap • 0.5-2% bleach solution (controversial) • Soft sponges (no abrasive cleaners) • Plain water or normal saline for eyes • Do not delay irrigation

17. Chemical Warfare Agent Detection • Ionization Instruments • Flame Ionization Detectors (FID) • Poor range of detection • Not selective • Photo Ionization Detectors (PID) • Good range of detection • Not Selective

18. Chemical Warfare Agent Detection • Ionization Instruments • Ion Mobility Spectrometry (IMS) • Excellent range of detection • Moderately selective

19. Chemical Warfare Agent Detection • Surface Acoustic Wave (SAW) • Very Good range of detection • Fairly Selective • Filter Based Infrared Spectroscopy(FBIS); or Non-Dispersive Infrared (NDIR) • Very Good range of detection • Fairly Selective

20. Chemical Warfare Agent Detection • Colorimetric Tubes • Very good range of detection • Fairly Selective • Electrochemical Sensors • Poor range of detection

21. Nerve Agents Nerve • Tabun (GA) • Sarin (GB) • Soman(GD) • Cyclosarin (GF) • VE • VG • V-Gas • VM • VX

22. Health Effects of Nerve Agents • Toxic by inhalation, absorption or ingestion in very small amounts • Effects after dermal exposure may be delayed for as long as 18 hours. • Effects - runny nose, chest tightness, pinpoint pupils, shortness of breath, excessive salivation and sweating, nausea, vomiting, abdominal cramps, involuntary defecation and urination, muscle twitching, confusion, seizures, paralysis, coma, respiratory paralysis, and death.

23. Nerve Agents • Incapacitating effects occur within 1 to 10 minutes and fatal effects can occur within 1 to 10 minutes for GA, GB, and GD, and within 4 to 42 hours for VX. • Fatigue, irritability, nervousness, and memory defects may persist for as long as 6 weeks after recovery from an exposure episode. • We do not know if exposure to the nerve agents GA, GB, GD, or VX might result in reproductive effects in humans. • Source: ATSDR

24. Nerve Agents • “Nerve agents” are aptly named, since they affect the nervous system. • Structural name for these agents is organic phosphorous compounds (OPCs) • Term “nerve agents” commonly used to refer to a specific military class of OPCs • soman, sarin, tabun, VX

25. Nerve Agents • In fact, the OPCs also include several hundred “nonmilitary” OPCs. • Malathion • Parathion • Others • Used commonly as insecticides, where military OPCs are used to kill humans • Both can kill humans, just differently • Nerve agents are used in the treatment of myasthenia gravis and anticholinergic drug poisoning

26. Physical Properties • Liquids with varying volatility and persistence • VX is the least volatile but the most persistent; “oily.” Soman is odorless. • Tabun, sarin, and soman have significant volatility. Sarin is the most volatile. • Absorbed via skin, mucus membranes, lungs, and gastrointestinal system.

27. Toxicity • Dermal toxicity: One drop of VX,1–10 ml of the G agents may be fatal. • Onset of symptoms may be delayed several hours from exposure to the liquid form, especially VX (up to 18 hours). • Rapid development of symptoms after exposure is more likely.

28. Lethality of VX • An amount of VX equal in size to one column of the building depicted on the back of this penny would be lethal.

29. Mechanism of Action • Nerve agents bind and inhibit acetylcholine esterases. • Acetylcholine esterase breaks down acetylcholine (ACh). • ACh mediates neurotransmission at • nicotinic muscular junctions, • autonomic nicotinic synaptic junctions (sympathetic and parasympathetic), and • muscarinic end-organ synapses (GI tract, glands, bladder, pupils).

30. Autonomic Nervous System Somatic Central Parasympathetic Sympathetic AutonomicGanglia N N N N ACh ACh ACh ACh M ACh M M A A N End Organ Brain ACh ACh Epinephrine Norepinephrine ACh Glands Bladder Gut Heart Heart Blood Pressure Neuromuscular Junction Sweat Glands

31. Mechanism of Action (continued) • Enzyme inhibition is reversible within a certain period of time that is agent dependent. • This time period in which structural changes to the enzyme occur is called “aging.” • Soman ages within minutes, whereas sarin takes hours. • After aging occurs, the enzyme is inactivated. Enzyme regeneration usually takes several weeks. • Excess ACh at all these synapses accounts for the clinical presentation.

32. Clinical Presentation Muscarinic: SLUDGE— BBBs— Salivation Bradycardia Lacrimation Bronchorrhea Urination Bronchospasm Diaphoresis GI distress (diarrhea, vomiting) Emesis Miosis

33. Clinical Presentation (continued) • Nicotinic: MTWThF • Mydriasis • Tachycardia • Weakness • Hyperthermia • Fasciculation

34. Clinical Presentation (continued) • Military class OPCs (sarin, soman, etc.) • Preferential affinity for nicotinic receptors • Muscle paralysis • Effective battlefield weapon • Insecticide class OPCs (malathion) • Preferential affinity for muscarinic receptors • SLUDGE • BBBs

35. Clinical Presentation (continued) • Dim vision and eye pain from ciliary spasm or direct cortical effect? • Cardiovascular effects are less predictable and range from bradycardia with AV blocks to tachycardia.

36. Clinical Presentation (continued) • Compared with adults, children exposed to nerve agents are thought to be less likely to have miosis and more likely to have increased secretions. • Children are also thought to have more seizures, hypotonia, and weakness than adults. • No studies have been done on nerve agents and children, even though historical incidents have affected children. • Assumptions about children and nerve agents are based on knowledge of organophosphates and of characteristics of children such as lower weight, less active metabolism (paroxanase activity), and greater ventilatory rate.

37. Differential Diagnosis for Nerve Agent Poisoning • Gastroenteritis • Ingestion of muscarinic mushrooms (Amanita muscaria, Clytocybe, Inocybe) • Pesticide poisoning • Carbamate overdose • Metal ingestion

38. Diagnostic Workup • No lab workup is useful for acute nerve agent poisoning. • RBC and plasma cholinesterase (butylcholinesterase) levels may be checked. These results are usually not immediately available.

39. Prehospital Care and Decontamination • First responders: Respirators, goggles, protective clothing • Self-contained breathing apparatus (SCBA) is recommended in response to any nerve agent vapor or liquid. • Butyl rubber gloves (most agents are lipophilic) • 20% of healthcare workers in Tokyo had mild symptoms after taking care of patients. These symptoms included nausea, eye pain, and headache.

40. Prehospital Care and Decontamination (continued) • Inhalation exposure: removal from exposure • Dermal: wash with soap and water or mild (0.5%) sodium hypochlorite (bleach) solution if availability of water is limited • Ingestion: no charcoal as these patients are at risk for vomiting and aspiration

41. Antidotes: Atropine • Muscarinic receptor antagonist. • Only treats muscarinic symptoms. • Given IV, IM, or by ET tube. • Dose is 2 mg every 5–10 minutes. End point is resolution of bronchorrhea. • For children, give 0.5–1.0 mg IM/IV every 5–20 minutes. For children < 6 months old, the dose is 0.05 mg/kg, with the minimum dose being 0.1 mg. Same end point. • If given early, atropine may prevent seizures. • Glycopyrrolate may also be used but does not penetrate the CNS.

42. Antidotes: Oximes • Reverses the binding of the nerve agent to the enzyme, especially if given prior to aging. Also acts as a scavenger and inactivates circulating nerve agents. • Pralidoxime: Slow IV bolus. Dose is 25–50mg/kg in children or 2 g in adults, targeting a serum level of > 4 mg/L. If given IM using the auto-injector, level is achieved in 8 minutes. • May repeat dose in 1 h. Effect is lost after 3 h of exposure to sarin because of aging.

43. Antidotes: Oximes (continued) • Side effect: elevated BP and EKG abnormalities • Other oximes (such as obidoxime and P2S) are used in other countries and have variable efficacy. • There is ongoing research to develop better agents.

44. Antidotes: Benzodiazepines • Used to treat the seizures • Diazepam IM/IV appears to be better than other benzodiazepines. • Dose is 5 mg IV/IM. May be repeated every 5–15 minutes.

45. Antidotes: Pyridostygmine • Subjects pretreated with pyridostigmine will be less vulnerable to nerve agents. • The U.S Army used pyridostigmine during the Gulf War. • Pyridostigmine is a carbamate that binds reversibly to AChE. It does not cross the CNS. • Pretreated individuals will have a store of AChE that is bound to pyridostigmine and is protected from the nerve agent.

46. Antidotes: Pyridostygmine (continued) • Bound pyridostigmine-AChE spontaneously breaks after several hours, releasing normal AChE. Administration of 2-PAM stimulates release of AChE that was protected from the nerve agent by pyridostigmine.

47. Antidotes: Pyridostigmine

48. Antidotes: MARK I Kit • Contains pralidoxime (600 mg) and atropine (2 mg) self injectors

49. Psychological Impact • Psychological impact has been seen after exposure to nerve agents as well as other terrorist attacks. • Post traumatic stress disorder seen in 60% of victims of the Tokyo sarin gas attack at 6months. • Fear of riding the subway, nightmares, and depression were some of the common symptoms (Kawana N, Ishimatsu S, Kanda K. Psycho-physiological effects of the terrorist sarin attack on the Tokyo subway system. Military Medicine 166(12 Suppl):23–6, 2001 Dec.).

50. Experimental Therapies for Nerve Agent Exposure • Exogenous choline esterases to bind the nerve agents • Paroxinases that degrade the nerve agents • Hl-6 thought to work better than pralidoxime for exposure to soman, which ages quickly. HI-6 has been shown to work when it is administered to rats up to 2 hours before exposure (Kassa J, Fusek J. The influence of oxime selection on the efficacy of antidotal treatment of soman-poisoned rats. Acta Medica 45(1):19–27, 2002).