Managing Chemical Exposure

1. Managing Chemical Exposure Kevin O. Rynn, PharmD, FCCP, DABAT Clinical Associate Professor Clinical Pharmacy Specialist Emergency Medicine

2. Awakening of America

3. Objectives: • Identify agents potentially used in a terrorist attack • Understand the pharmacology and toxicology of these agents • Understand the management of exposed patients • Identify unique potential threats to New Jersey residents • Better appreciate our role as pharmacists

4. Introduction: Chemical Warfare • Spartans, 429 BC • World War I: Germany • April 22nd 1915: chlorine gas against allies • Belgium, Hundreds killed, troops retreated • July 12th, 1917: Sulfur mustard • Injuries >>> fatalities • World War II: Germany • December 2nd 1943: Mustard bombs destroyed in Italy • Yemen war • Egypt: riot control agents, mustards, nerve agents • Vietnam • US: Tear gas and chemical herbicides

5. Introduction: Chemical Terrorism • Aum Shinrikyo Cult

6. Introduction: Chemical Terrorism • Matsumoto: 1994 • Sarin: residential neighborhood • Fatalities: 7 • Hospital visits: 500 • Tokyo: 1995 • Sarin, subway system during rush hour • Fatalities: 12 • Hospital visits: > 5,000 Subway riders injured in Aum Shinrikyo sarin gas attack, Tokyo, March 20, 1995. (AP Photo/Chikumo Chiaki )

7. Eye Miosis 99% Eye pain 45% Blurred vision 40% Dim vision 38% Tearing 9 % Chest Dyspnea 63% Cough 34% Wheezing 6% Tachypnea 32% ENT Runny nose 25% Sneezing 9% GI Nausea 60% Vomiting 37% Diarrhea 5% Neurologic Headache 75% Weakness 37% Fasciculations 23% Numbness 19% Decreased LOC 17% Vertigo/dizziness 8% Seizures 3% Psychologic Agitation 33% Signs & Symptoms of 111 Moderately or Severely Injured Patients on Admission Okumura T, et al Ann Emerg Med 1996;28(2):129-35

8. Chemical Weapons

9. Chemical Weapons

10. Nerve Agents • Physical characteristics and toxicity • Mechanism: • Cholinesterase inhibitors, excess buildup of Acetycholine (Ach) • Muscarinic effects • Postganglionic parasympathic • Nicotinic effects • Autonomic ganglia • Preganglionic sympathetic & parasympathetic • Neuromuscular junction • Excess Ach in CNS

11. Muscarinic Diarrhea Salivation Urination Lacrimation Miosis**Urination Bradycardia Defecation Bronchorrhea GI symptoms Bronchospasm Emesis Emesis Lacrimation Nicotinic Tachycardia Hypertension Mydriasis Neuromuscular junction** Fasciculation Weakness paralysis CNS Anxiety, confusion, ataxia, dysarthria Coma, Seizures**, Resp depression** Results of Cholinesterase Inhibition ** Most important after nerve agent

12. Key Findings Based on Route of Exposure

13. RBC & Plasma Cholinesterase Levels • Clinical utility limited • Related to clinical effect, but not consistently • Normal value range • Workplace usage • Do not wait on these for treatment!

14. RBC Difficult assay inhibited preferentially by VX and sarin 2-PAM: regenerates levels Regeneration rate: 1% per day (erythrocyte production) Plasma Easier assay An acute phase reactant (liver protein) Affected by low protein conditions Declines faster acutely and regenerates faster Cholinesterase Levels

15. Treatment: Decontamination • Selective protective measures • Lipophyllic agents can penetrate latex and vinyl • Nitrile, neoprene, butyl rubber gloves • Leather • Shared Breathing air • Irrigation • Water • Hypochlorite solution • Alkaline soap

16. Atropine • Competitive MUSCARINIC antagonist • Peripheral > central • Blood brain barrier • Dosing- IV or IM • Initial Adult 2mg Peds 0.02mg/kg (min 0.1mg) • Repeat Every 2 - 5 minutes • Endpoints • Reversal of muscarinic signs of toxicity Mod. to Severe 2-3 times this

17. Atropine • Dosing in comparison to organic phosphorus insecticide. • Tokyo subway sarin attack (N=111) • Doses > 2mg 18.9% • Max dose administered 9 mg • Adverse effects • Dry mouth&skin, mydriasis, paralysis of accommodation, tachycardia Okumura T. et al Ann Emerg Med 1996;28(2):129-35

18. Aerosolized Ophthalmic Miosis reversal Causes photophobia and loss of accommodation Glycopyrolate IV administration of EMS sources Opthtalmic Veterinary Powder preparation Atropine: Alternative Routes and Supply Sources

19. Geller RJ, Lopez G, Cutler S, Lin D, Bachman GF, Gorman SE. Ann Emerg Med 2003;41:453-6. 110 6mg syringes ~ 60 minutes 8 week testing 5˚C: USP standards + 5% Pyrogen free 4 week testing Room Temp: USP standards + 5% Kozak RJ, Siegel S, Kuzma J. Ann Emerg Med 2003;41:685-8. 100 6mg syringes ~ 30 minutes 3 week testing USP standards + 5% microbiologic sterility testing Cost Advantage $11 vs $5,000 Rapid Atropine Reformulation From Bulk Powder

20. Pralidoxime:Protopam®(2-PAM) • Cholinesterase reactivator • Dosing: IM or IV • Adult: 1-2 gms over 15-20 minutes then q6h for 24 hrs • Peds: 25mg/kg to max 1gm • C.I.: Adult 500mg/hr, peds 25mg/kg/hr • Improves all cholinergic symptoms • Aging • Covalent bond between nerve agent and enzyme • Irreversible dealkylation

21. Nerve Agent Aging:

22. Treatment: Continued • Mark 1 Kits • CANA • Convulsion antidote for nerve agents • Diazepam • NAPS • Nerve agent pre-treatment tablets • Pyridostigmine

23. Nerve Agent Antidote ProgramChemPack

26. Vesicants

27. Vesicant Agents: Symptoms

28. Decontamination Water, hypochlorite solutions Avoid scrubbing and hot water Topical Calamine/other soothing lotions Antibiotics Systemic analgesia Ocular injures Irrigation Mydriatics: homatropine or other anticholinergics Anesthetics Ophthalmic ointments Constant reassurance Respiratory Antitussives: Bronchodilators/mucolytics Antibiotics Intubation Treatment

29. Treatment: BAL • British Anti-Lewisite: Dimercaprol • Metal chelating agent • BAL combined with lewisite forms stable 5 member ring • Dosing • 3 -5 mg q4hr x 4 doses • Adverse effects • GI, Hypertension, tachycardia • Peanut allergy

30. Blood Agents: Cyanides • Antiquated term • Carried via blood to exert it’s effect • French • Franco-Prussian war: Napoleon III first to use • WWI: French and British • Hydrogen cyanide and cyanogen chloride used on battlefields • WWII: • German genocidal agent • Iran-Iraq war and Iraq’s suppression of Kurds • Apparent use with mass casualties reported

31. Cyanide: Tampering • 1982: Chicago Tylenol • 7 deaths • 1988: Yogurt • 1989: Dept of Agriculture • Cyanide traces on fruit from Chile, possible terrorist threat

32. Cyanide • Routes • Inhalation, ingestion, topical • Primary site of action • Cells rather than blood • Interruption of cellular respiration in mitochondria

33. Cyanide: Mechanism of Toxicity • Binding of CN- to cytochrome a3 in mitochondria • Stable but not irreversible • CN- has higher affinity for the Fe3+ in methemoglobin • Interruption of oxidative phosphorylation • Decreased aerobic energy production(ATP) • Final results: cellular hypoxia

34. Cyanide Vapor Exposure

35. Cyanide • Homicidal and suicidal use • Judicial execution • Combustion of plastics, cigarettes, vehicle exhaust • Household products • Silver polish, acetonitriles • Industry: chemical syntheses • Hospital • Sodium nitroprusside

36. Cyanide Toxicity: Treatment

37. Cyanide: Treatment • Healthcare worker protection • Supportive therapy • Antidotal therapy • Displace CN- from cytochrome A3 • Nitrite therapy • Enzymatic conversion of CN- to thiocyanate • Thiosulfate therapy

38. Sodium Nitrite • Converts Hb(Fe2+ ) to MetHb (Fe3+) • Preferential binding of CN- • Goal MetHb = 20 - 30% • Adverse effects • Excessive methemoglobin production • Vasodilatation: hypotension

39. Sodium Thiosulfate • Enzymatic (rhodanese) reaction with CN- • Formation of thiocyanate (SCN-) • Irreversible reaction • Renal elimination • Adverse effects - minimal • N/V • Arthralgias

40. Dosing

41. Pulmonary Agents: Chlorine and Phosgene • Increased permeability • Delayed pulmonary edema • WWI: Primary chemical agents • Chlorine: yellow-green cloud, pungent • Phosgene: colorless, fresh hay

42. Pulmonary Agents

43. Pulmonary agents- Phosgene • Low-solubility = deeper lung penetration • Symptoms within 4 hrs • Worse prognosis • ICU admission • No chest x-ray changes within 8 hours • Acute lung injury unlikely • Delayed serious symptoms • 15 -18 hours

44. Pulmonary Agents: Treatment • Decontamination • Irrigation of eyes and skin • Oxygen • Endotracheal Intubation • Hoarseness, stridor, upper-airway burns, wheezing, altered mental status • Bronchodilators • Nebulized sodium bicarbonate • Neutralize chlorine derivatives • Efficacy data lacking

45. Pulmonary Agents: Treatment • Bed rest • Physical exertion exacerbates lung inflammation • Corticosteroids • Moderate to severe exposures • Positive End Expiratory Pressure (PEEP) • Antibiotic prophylactic use • Not recommended

46. Riot Control Agents • Tear gas or lacrimators • Aerosolized solids • Intense immediate self-limiting symptoms • Prolonged exposure with underlying lung disease • Bronchospasm and acute lung injury

47. Riot Control Agents • Chloroacetophenone - CN • o-chlorobenzilidene malononitrile - CS • Symptoms • Lacrimation, photophobia, blepharospasm • Chest tightness, wheezing, coughing, secretions • Dermal burning, erythema, vesiculation • Recovery: 15 - 30 minutes post removal

48. Riot Control Agents: Treatment • Removal from exposure • Remove clothing and placed in airtight bags • Irrigation • Symptomatic treatment • Ophthalmic anesthetics, bronchodilators, antihistamines • Capsaicin-induced dermatitis • Oil immersion

49. Prevalent New Jersey HazMat Threats • Terrorist attack likely to involve conventional explosives & hazardous materials • New Jersey likely target • Densely populated state • Many companies/manufacturers • Most New Jerseyans live/work within short distances to chemical plants Marcus, S, Ruck B. New Jersey Medicine 2004;101(9):34-43.

50. New Jersey Department of Environmental Protection (DEP) • New Jersey Toxic Catastrophe Prevention Act (TCPE) • > 100 companies • Implement risk management plan (RMPs) • NJ DEP list chemicals and threshold quantities http://www.nj.gov/dep/rpp/tcpa/