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Managing Chemical Exposure Kevin O. Rynn, PharmD, FCCP, DABAT Clinical Associate Professor Clinical Pharmacy Specialist Emergency Medicine Awakening of America QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Quic kTime™ and a TIFF (Unc ompres sed) dec ompres sor are needed to see this pic ture. 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 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 Introduction: Chemical Terrorism Aum Shinrikyo Cult 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 ) Signs & Symptoms of 111 Moderately or Severely Injured Patients on Admission Eye GI Miosis 99% Eye pain 45% Blurred vision 40% Dim vision 38% Tearing 9 % Chest Dyspnea 63% Cough 34% Wheezing 6% Tachypnea 32% Runny nose 25% Sneezing 9% Nausea 60% Vomiting 37% Diarrhea 5% Neurologic ENT Headache 75% Weakness 37% Fasciculations 23% Numbness 19% Decreased LOC 17% Vertigo/dizziness 8% Seizures 3% Psychologic Agitation 33% Okumura T, et al Ann Emerg Med 1996;28(2):129-35 Chemical Weapons Agent Common Name Code Nerve Agents Tabun Sarin Soman VX Mustard Lewisite Phosgene oxime Bis-2-chloroethylsulfide GA GB GD VX HD L CX T Vesicants Chemical Weapons Agent Common Name Code Blood Agents Hydrogen cyanide Cyanogen chloride AC CK Pulmonary Agents Phosgene Chlorine CG CL Riot Control Agents Mace CR,CS, CN,CA 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 Results of Cholinesterase Inhibition Muscarinic Diarrhea Urination Miosis** Bradycardia Bronchorrhea Bronchospasm Emesis Lacrimation Salivation Lacrimation Urination Defecation GI symptoms Emesis ** Most important after nerve agent Nicotinic Tachycardia Hypertension Mydriasis Neuromuscular junction** Fasciculation Weakness paralysis CNS Anxiety, confusion, ataxia, dysarthria Coma, Seizures**, Resp depression** Key Findings Based on Route of Exposure Route & Onset Mild Vapor/aeroso Rhinorrhea, l secretions, slight dyspnea Immediate Topical Immediate or delayed Localized sweating & fasciculations Moderate Severe Miosis, eye pain, dim vision, pronounced dyspnea Coma, convulsions, fasciculations, paralysis Vomiting, diarrhea, secretions Miosis, coma, convulsions, generalized fasciculations 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! Cholinesterase Levels 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 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 Atropine Competitive MUSCARINIC antagonist Peripheral > central Mod. to Severe Blood brain barrier 2-3 times this 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 Atropine Dosing in comparison to organic phosphorus insecticide. Tokyo subway sarin attack (N=111) Doses > 2mg 18.9% Max dose administered 9 mg Okumura T. et al Ann Emerg Med 1996;28(2):129-35 Adverse effects Dry mouth&skin, mydriasis, paralysis of accommodation, tachycardia Atropine: Alternative Routes and Supply Sources Aerosolized Ophthalmic Miosis reversal Causes photophobia and loss of accommodation Glycopyrolate IV administration of EMS sources Opthtalmic Veterinary Powder preparation Rapid Atropine Reformulation From Bulk Powder 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 Kozak RJ, Siegel S, Kuzma J. Ann Emerg Med 2003;41:685-8. USP standards + 5% 5˚C: USP standards + 5% Pyrogen free 4 week testing Room Temp: USP standards + 5% 100 6mg syringes ~ 30 minutes 3 week testing microbiologic sterility testing Cost Advantage $11 vs $5,000 ® 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 Nerve Agent Aging: Nerve Agent GA (Tabun) Aging t1/2 in Humans > 14 hrs GB (Sarin) 3 - 5 hrs GD (Soman) 2 - 6 min VX 48 hrs Treatment: Continued Mark 1 Kits CANA Convulsion antidote for nerve agents Diazepam NAPS Nerve agent pre-treatment tablets Pyridostigmine Nerve Agent Antidote Program ChemPack Vesicants Common Name Sulfur mustard Lewisite Code H, HD L Phosgene oxime CX QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. 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Vesicant Agents: Symptoms Mild Moderate Severe Onset 4-24 hrs 2-6hrs 1-2 hrs Ocular Tearing, itching burning Reddening, swelling, pain Marked swelling, cornea damage, severe pain Airway Hoarseness, hacking cough, runny nose, sneezing, nosebleeds Worsening symptoms Severe productive cough, SOB Skin Erythema, blistering Worsening symptoms Worsening symptoms Treatment 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: 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 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 Cyanide: Tampering 1982: Chicago Tylenol QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. 7 deaths 1988: Yogurt 1989: Dept of Agriculture Cyanide traces on fruit from Chile, possible terrorist threat Cyanide Routes Inhalation, ingestion, topical Primary site of action Cells rather than blood Interruption of cellular respiration in mitochondria 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 Cyanide Vapor Exposure Moderate Severe Exposure Increased rate and depth of breathing Dizziness, N/V, HA < 1min: Transient increased breathing 30 sec: Seizures 2-4 min: Cessation of respiration 4-8 min: Cessation of heartbeat Cyanide QuickT ime ™an d a TIFF ( Uncomp res sed) deco mpre ssor ar e need ed to see this pictur e. Homicidal and suicidal use Judicial execution Combustion of plastics, cigarettes, vehicle exhaust Household products Silver polish, acetonitriles Industry: chemical syntheses Hospital Sodium nitroprusside Cyanide Toxicity: Treatment QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Cyanide: Treatment Healthcare worker protection Supportive therapy Antidotal therapy QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Displace CN- from cytochrome A3 Nitrite therapy Enzymatic conversion of CN- to thiocyanate Thiosulfate therapy Sodium Nitrite Converts Hb(Fe2+ ) to MetHb (Fe3+) Preferential binding of CNGoal MetHb = 20 - 30% Adverse effects Excessive methemoglobin production Vasodilatation: hypotension Sodium Thiosulfate Enzymatic (rhodanese) reaction with CN Formation of thiocyanate (SCN-) Irreversible reaction Renal elimination Adverse effects - minimal N/V Arthralgias Dosing Adult Na Nitrite 3% Na Thiosulfate 25% Pediatric 300mg 10mg/kg (0.33 ml/kg) (10ml) IVP (Dose adjusted in anemic patients) 12.5 gms 412 mg/kg (1.65 (50 ml) ml/kg) IVP Pulmonary Agents: Chlorine and Phosgene Increased permeability Delayed pulmonary edema WWI: Primary chemical agents Chlorine: yellow-green cloud, pungent Phosgene: colorless, fresh hay QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Pulmonary Agents Mild Symptoms Phosgene and Chlorine Moderate to Severe Symptoms Nose and throat Laryngitis, wheezing, irritation, cough, stridor, laryngeal chest tightness edema, Acute lung injury 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 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 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 Riot Control Agents QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. Tear gas or lacrimators Aerosolized solids Intense immediate self-limiting symptoms Prolonged exposure with underlying lung disease Bronchospasm and acute lung injury 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 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 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. 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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/ New Jersey’s Top 10 List Ammonia Chlorine Difluoroethane Hydrogen chloride Hydrogen fluoride Hydrogen sulfide Ozone Pentane Toluene diisocyanate Vinyl Acetate monomer Ammonia Background Refrigerant, fertilizer, explosives, synthetic fiber, petroleum industry, manufacture of chemicals including methamphetamine Signs and Symptoms Ocular and respiratory Treatment Supportive Copious amounts of water Chlorine Background Bleaching fabrics, rubber and plastic manufacturing, production of chemicals, meds, and pesticides, water purification, sanitizing Reacts with water to form HCl and hypochlorous acid Signs & Symptoms Ocular and respiratory Treatment Supportive Cautious supplemental O2 Hydrogen Fluoride Background Electronic circuits and plastics production Glass, metal, stone, porcelain etching Cleaning products Fluoride ion responsible for tissue damage Readily penetrates and causes deep tissue destruction/burns Hypocalcemia Signs & Symptoms Derm: Burns, erythemia, pain GI: N/V abdominal pain Hydrogen Fluoride: Treatment Assess electrolyte and cardiac status Irrigation Calcium gluconate Forms insoluble precipitate of calcium fluoride, preventing absorption of F ion Alleviate pain and prevent extension Topical, intra-dermal, intra-arterial Inhalation New Jersey Conclusions Many Locations that house chemicals Risks to citizens working in or living near Health care works prepare to manage these exposures Protocols should be available Conclusions Hospital roles Pharmacist roles Poison center roles QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
