Chemical Agent Poisoning

1. Chemical Agent Poisoning Anthony J. Tomassoni, MD, MS, FACEP, FACMT Maine Medical Center Department of Emergency Medicine Medical Director Northern New England Poison Center Southern Maine Regional Resource Center for Emergency Preparedness

2. How to avoid misdiagnosis or delayed diagnosis Outline: What tests When to angio When should you transfer Once you consider the dx, what is an efficient way to rule it in or out. AAA-what tests Back pain and syncope-what tests Dissection-delayed dx-how to prevent Dissection vs. aneurysm How to avoid misdiagnosis or delayed diagnosis Outline: What tests When to angio When should you transfer Once you consider the dx, what is an efficient way to rule it in or out. AAA-what tests Back pain and syncope-what tests Dissection-delayed dx-how to prevent Dissection vs. aneurysm

3. Objectives Describe pathophysiology and clinical manifestations Discuss management of toxicity Health care provider self-protection Patient decontamination Patient treatment

4. Why we need to be prepared

5. History of Chemical Weapons Peloponnesian War - 423 BC smoke from lighted coals, sulfur, and pitch WWI Chlorine, phosgene, chloropicrin gases; sulfur mustard; riot control agents; cyanide WWII Sulfur mustard; cyanide Iran-Iraq War - 1980s Sulfur mustard; nerve agents; cyanide Tokyo Sarin gas terrorist attack - 1995

6. Overview of Chemical Weapons Exist as solids, liquids, or gases Primarily dispersed as liquid or an aerosol 5 classes of agents will be discussed

7. Classification of Chemical Agents TOXIC AGENTS (producing injury or death) PULMONARY AGENTS (choking agents) Chlorine (CL), phosgene (CG) “BLOOD” AGENTS (cyanogens): AC and CK BLISTER AGENTS (vesicants) Mustard (H), Lewisite (L), phosgene oxime (CX) NERVE AGENTS (anticholinesterases) GA,GB,GD,GF,VX INCAPACITATING AGENTS (producing temporary effects) BZ, Agent 15, CN, CS, capsaicin [riot-control agents]

8. Do you carry a tox lab in your pocket?

11. Toxidrome A constellation of clinical clues to the identity of a poison. Concept by Mofenson & Greensher, 1970 Present in whole or in part Vital signs, Mental Status, Symptoms, Signs, Labs

12. Toxidromes: In Whole or In Parts

13. What’s the poison? Putting the toxidrome together: Vital signs T P R BP What’s the fifth vital sign? Other autonomic indicators: Pupils, bowel sounds, secretions and fluids

14. Nerve Agents Overview Most toxic of known chemical agents Inhaled LD50 is 1 mg Can cause symptoms within seconds and death within minutes Include: tabun (GA), sarin (GB), soman (GD), GF, and VX Colorless, odorless liquids with high volatility at room temperature

18. Iraqi Chemical Weapons

19. Nerves Talk

20. Mechanism of Toxicity Cf. organophosphate pesticides Inactivate acetylcholinesterase Acetylcholine accumulates at cholinergic and nicotinic nerve terminals Irreversible AChE inhibition occurs with time (“aging”) Antagonize GABA neurotransmission Stimulate glutamate-NMDA receptors Bind nicotinic and muscarinic receptors directly

21. Cholinergic Nerve Terminal

23. Latent Period Rate of onset and severity of toxicity depends on dose and route of exposure Vapor: peak effects within minutes after exposure Liquid exposure: effects from 30 min to 18 hrs

24. Clinical Manifestations Mild poisoning: eye pain, blurred vision, miosis, rhinorrhea, salivation, headache, mild dyspnea, chest tightness. Moderate poisoning: N/V, coughing, wheezing, SOB, muscle fasciculations and weakness, agitation Severe poisoning: apnea, LOC, seizures, flaccid paralysis, incontinence, tachycardia Death: most commonly due to respiratory arrest

25. Tokyo Sarin Gas Attack

26. Tokyo, March 20, 1995 5 bags of sarin punctured in 5 subway trains 12 dead 5500 “sick” patients St. Luke’s Hospital (520 beds) Treated 500 patients in first hour; 640 on first day ~10% arrived via EMS

27. Tokyo Experience Vapor exposure Moderate to severe poisoning Tachycardia and HTN common Bradycardia and bronchorrhea uncommon Clinical Manifestations Miosis 99% Headache 75% Dyspnea 63% Nausea 60% Eye pain 45% Blurred vision 40% Vomiting 37%

28. Vesicants

30. Overview Both vapor and liquid threat to exposed skin and mucous membranes Effects are delayed, occurring 4-24 hrs after exposure Include: sulfur mustards (HD, H), lewisite (L) Exist as oily amber liquid with odor of burning garlic Irreversibly bind with tissue cellular components within 2 min of exposure Low case-fatality rate of 2-4%; high morbidity

31. Mechanism of Toxicity Once absorbed, mustards form highly reactive episulfonium compounds Bind irreversibly (alkylate) nucleic acids and proteins Result in DNA strand-breaking, inhibited protein synthesis Depletion of NAD+ Mustards bind and deplete cellular glutathione Cell death from lipid peroxidation, cell inflammation Rapidly dividing cells most susceptible to injury

32. Clinical Manifestations Sites of injury: eye, skin, respiratory tract, bone marrow, GI tract Skin: erythema, edema, vesication, skin necrosis Eye: miosis, lacrimation, keratoconjunctivitis, lid and corneal edema, iritis, chemosis, blindness from corneal opacification/scarring Respiratory tract: bleeding, necrosis, and sloughing of airway mucosa, rhinosinusitis, cough, sputum, laryngitis, bronchitis, pseudomembrane formation Pancytopenia 5-10 days post-exposure GI: mucositis, N/V/D

33. Mustard: Blind leading blind

34. Mustard Skin Lesions

37. Cyanide

38. Overview Exists as liquid in munitions; detonation causes vaporization Toxicity typically from inhalation of vapor Effects occur within seconds to minutes of exposure Include: hydrogen cyanide and cyanogen chloride (AC, CK) Erroneously referred to “blood agents” by US military Least toxic of “lethal” CW agents

39. Mechanism of Toxicity Cyanide binds to ferric (Fe3+) iron of mitochondrial cytochrome oxidase Produces cellular hypoxia Prevents electron transport and oxidative phosphorylation Lactic acid accumulates and severe AGMA develops Brain and myocardium (tissues with greatest oxygen demand) most profoundly affected

40. Nitrites: affect heme causing methemoglobinemia antidote: methylene blue Carbon monoxide (CO): affects heme and cytochrome oxidase antidote: oxygen and hyperbaric oxygen Hydrogen cyanide (HCN): affects heme & cytochrome oxidase antidotes: sodium thiosulfate, amyl/sodium nitrite, hydroxocobalamin Hydrogen sulfide (H2S): affects heme and cytochrome system; also has irritant properties antidote: oxygen, ?HBO, amyl/sodium nitrite, albuterol

41. Oxidative Phosphorylation Chain (Terminal End) with CN-

45. Clinical Manifestations Low Concentration exposure: Anxiety, agitation, hyperventilation, headache, dizziness, N/V, mild hypertension High Concentration exposure: Transient hyperpnea and anxiety followed by rapid LOC and seizures within 30 sec. Apnea by 2-4 min. Patients may develop mydriasis, hypotension, arrhythmias, cardiovascular collapse and asystole by 4-8 min.

49. Choking or Pulmonary Agents Overview Lung injury from inhalation of vapor Effects occur minutes to hrs after exposure Include: chlorine, phosgene, diphosgene (CL, CG) Injury depends on gas concentration, duration of exposure, water content of tissue

50. Mechanism of Toxicity Chlorine: reacts with tissue water to form HCl and oxygen free radicals - corrosive effects Phosgene: reacts with tissue water (slowly) to form HCl and carbonyl (C=O), which acylates proteins at alveolar-capillary membranes

51. Chlorine- Mechanism of Injury Reaction 1: generation of HCL Cl2 + H2O HOCl + HCl Reaction 2: oxygen free radical generation HOCl OCl- + O2-

52. Phosgene - Mechanism of Injury Reaction 1: hydrolysis, generation of HCl CG + H2O CO2 + 2HCl Reaction 2: acylation, X = NH, NR, O, S CG + X COX2 + 2HCl

53. Clinical Manifestations Asymptomatic latent period 4-24 hrs after phosgene exposure Acute effects: lacrimation, mucosal irritation, cough, dyspnea, chest tightness, cyanosis, hemoptysis, hypotension, pulmonary edema (noncardiogenic) Chronic: ARDS

54. CXR Progression: Phosgene

55. Riot Control Agents Overview Also called lacrimating agents or tear gases Typically dispersed as a smoke or suspended solid particles or liquid aerosol Effects occur immediately Include: chloroacetophenone (CN or Mace), CS, and capsaicin (pepper spray) Injury depends on gas concentration, duration of exposure

56. Mechanism of Toxicity Pulmonary irritants and mild corrosives CS and CN injure tissue by alkylating tissue enzymes (e.g., LDH, Pyruvate DeHase) CS causes tissue bradykinin release Capsaicin: alkaloid that stimulates substance P release and then blocks its synthesis and transport (counterirritant)

57. Clinical Manifestations Pain, burning, irritation of exposed mucous membranes (e.g., eye, throat) and skin Lacrimation, blepharospasm, corneal abrasions and edema Rhinorrhea, sneezing, skin erythema N/V Dyspnea, RAD, SOB, rare pulmonary edema and death

59. Incapacitating AgentAnticholinergic 3-quinuclidinyl benzilate (QNB, BZ) - Affects PNS and CNS: psychotomimetic - Atropine-like effects and LD 50 ~= 100 mg - Onset of action ~ 1 hour, peak effects at 8 hours - Effects gradually subside over 2-4 days - ICt50 (concentration in air of QNB necessary to incapacitate 50% of unprotected exposed individuals via inhalation per unit time) ~=100 mg·min/m3

61. Incapacitating AgentOpioid Toxidrome Fentanyl and analogs Supportive care: Airway management Antidote: naloxone or other opioid antagonist

63. Evaluation DECONTAMINATE VICTIMS IMMEDIATELY! Must protect health care workers and facilities first Consider circumstances: Degree of exposure & contamination Prehospital decontamination Life threatening injuries History Document amount, time, nature, and duration of exposure Document time of onset, nature, progression, severity of symptoms Physical Focus on VS, neuromuscular, and cardiopulmonary function

64. Management Overview Implement disaster plans Self-protection of health care providers Patient decontamination Establish and maintain ABCs Continuous cardiac and oxygen sat monitoring for all victims ACLS and ATLS measures as appropriate Administer antidotes, coma cocktail when necessary CXR, ECG, ABG analysis often necessary along with standard and specialized ancillary laboratory testing

65. Personal Protective Equipment (PPE) for health care providers encountering chemical hazards: Trained personnel performing decontamination: Level B or C PPE - chemically resistant, nonencapsulated suit, nitrile gloves, boots, appropriate respiratory protection Personnel caring for decontaminated patient: Standard gown, mask, nitrile or neoprene gloves

66. Self-protection of health care providers

68. Treatment Most patients just need decon Some may need oxygen and supportive care A few will need specific antidotes This will vary by agent Nerve agents Cyanide

69. Patient Decontamination Gross decontamination Brush off powder; remove all clothing and jewelry Copious irrigation of eyes, exposed skin Eyes: warm water Skin: Triple wash - tepid water Waste water should be collected

71. “Dry Decon” Wiping May smear agent over unexposed areas May drive agent into skin or wounds Adsorption Resins from M291 kit Fuller’s earth, clay, flour, etc. Must be followed by mechanical removal such as rinsing or scraping

72. Agent specific treatment Nerve Agents Atropine, 2-PAM, diazepam Vesicants Experimental: mustard scavengers, NAD+-stabilizers, anti-inflammatories, nitric oxide synthase inhibitors Cyanide Amyl or sodium nitrite, sodium thiosulfate, hydroxycobalamin Choking Agents Humidified O2, bronchodilators, ventilatory support with PEEP

73. Nerve Agent Treatment Atropine Cumulative doses of 10-20 mg Titrate to oral and pulmonary secretions Oxime therapy 2-PAM: start with 1-2 g IV and then 3.4 mg/kg/hr infusion HI-6: more effective against soman Diazepam 0.2-0.4 mg/kg or 10 mg IV empirically Experimental therapy GK-11 (gacyclidine), glutamate antagonist promising in primate studies

74. MARK 1 Auto-Injector Spring powered injectors Atropine, 2 mg/0.7 ml 2-PAMCl, 600 mg/2 ml

75. Which of these items might be useful to treat each toxidrome? Albuterol Atropine Calcium chloride Diazepam Methylene blue Pralidoxime Pyridoxine Sodium bicarbonate Sodium thiosulfate