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Managing Chemical Exposure
Kevin O. Rynn, PharmD, FCCP, DABATClinical Associate ProfessorClinical Pharmacy Specialist Emergency Medicine
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Objectives:
Identify agents potentially used in a terrorist attackUnderstand the pharmacology and toxicology of these agentsUnderstand the management of exposed patientsIdentify unique potential threats to New Jersey residentsBetter appreciate our role as pharmacists
Introduction: Chemical Warfare
Spartans, 429 BCWorld 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 Shinrikyosarin gas attack, Tokyo, March 20, 1995. (AP Photo/Chikumo Chiaki )
Signs & Symptoms of 111 Moderately or Severely Injured Patients on Admission
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%
Okumura T, et al Ann Emerg Med 1996;28(2):129-35
Chemical WeaponsAgent Common Name Code
Nerve Agents
TabunSarinSomanVX
GAGBGDVX
Vesicants MustardLewisitePhosgene oximeBis-2-chloroethylsulfide
HDLCXT
Chemical WeaponsAgent Common Name Code
Blood Agents
Hydrogen cyanideCyanogen chloride
ACCK
Pulmonary Agents
PhosgeneChlorine
CGCL
Riot Control Agents
Mace CR,CS,CN,CA
Nerve AgentsPhysical characteristics and toxicityMechanism: 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 InhibitionMuscarinic
Diarrhea Salivation
UrinationLacrimation
Miosis** Urination
Bradycardia Defecation
Bronchorrhea GI symptoms
Bronchospasm Emesis
Emesis
Lacrimation
NicotinicTachycardiaHypertensionMydriasisNeuromuscular junction**
FasciculationWeaknessparalysis
CNSAnxiety, confusion, ataxia,
dysarthriaComa, Seizures**, Resp
depression**** Most important after nerve agent
Key Findings Based on Route of Exposure
Route & Onset
Mild Moderate Severe
Vapor/aerosol
Immediate
Rhinorrhea, secretions, slight dyspnea
Miosis, eye pain, dim vision, pronounced dyspnea
Coma, convulsions, fasciculations, paralysis
TopicalImmediate or
delayed
Localized sweating & fasciculations
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 antagonistPeripheral > 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 Severe2-3 times this
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
Atropine: Alternative Routes and Supply Sources
AerosolizedOphthalmic 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 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
Pralidoxime:Protopam® (2-PAM)
Cholinesterase reactivatorDosing: 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 symptomsAging Covalent bond between nerve agent and
enzyme Irreversible dealkylation
Nerve Agent Aging:
Nerve Agent Aging t1/2 in Humans
GA (Tabun) > 14 hrs
GB (Sarin) 3 - 5 hrs
GD (Soman) 2 - 6 min
VX 48 hrs
Treatment: Continued
Mark 1 KitsCANA Convulsion antidote for nerve agents Diazepam
NAPS Nerve agent pre-treatment tablets Pyridostigmine
Nerve Agent Antidote ProgramChemPack
Common Name Code
Sulfur mustard H, HD
Lewisite L
Phosgene oxime
CX
Vesicants
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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 7 deaths
1988: Yogurt1989: Dept of Agriculture Cyanide traces on fruit from Chile,
possible terrorist threat
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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 breathingDizziness, N/V, HA
< 1min: Transient increased breathing30 sec: Seizures2-4 min: Cessation of respiration4-8 min: Cessation of heartbeat
Cyanide
Homicidal and suicidal useJudicial executionCombustion of plastics, cigarettes, vehicle exhaustHousehold products Silver polish, acetonitriles
Industry: chemical synthesesHospital Sodium nitroprusside
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Cyanide Toxicity: Treatment
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Cyanide: Treatment
Healthcare worker protectionSupportive therapyAntidotal therapy Displace CN- from cytochrome A3
Nitrite therapy Enzymatic conversion of CN- to
thiocyanate Thiosulfate therapy
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Sodium Nitrite
Converts Hb(Fe2+ ) to MetHb (Fe3+)Preferential binding of CN-
Goal MetHb = 20 - 30%Adverse effects Excessive methemoglobin production Vasodilatation: hypotension
Sodium Thiosulfate
Enzymatic (rhodanese) reaction with CN-
Formation of thiocyanate (SCN-)
Irreversible reactionRenal eliminationAdverse effects - minimal N/V Arthralgias
DosingAdult Pediatric
Na Nitrite3%
300mg (10ml) IVP
10mg/kg (0.33 ml/kg)(Dose adjusted in anemic patients)
Na Thiosulfate25%
12.5 gms (50 ml) IVP
412 mg/kg (1.65 ml/kg)
Pulmonary Agents: Chlorine and Phosgene
Increased permeability Delayed pulmonary edema
WWI: Primary chemical agentsChlorine: yellow-green cloud, pungentPhosgene: colorless, fresh hay
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Pulmonary Agents
Mild Symptoms
Moderate to Severe Symptoms
Phosgene and Chlorine
Nose and throat irritation, cough, chest tightness
Laryngitis, wheezing, stridor, laryngeal 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
DecontaminationIrrigation of eyes and skinOxygenEndotracheal Intubation Hoarseness, stridor, upper-airway burns,
wheezing, altered mental status
BronchodilatorsNebulized 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
Tear gas or lacrimatorsAerosolized solidsIntense immediate self-limiting symptomsProlonged exposure with underlying lung disease Bronchospasm and acute lung injury
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Riot Control Agents
Chloroacetophenone - CNo-chlorobenzilidene malononitrile - CSSymptoms Lacrimation, photophobia, blepharospasm Chest tightness, wheezing, coughing,
secretions Dermal burning, erythema, vesiculation
Recovery: 15 - 30 minutes post removal
Riot Control Agents: Treatment
Removal from exposureRemove clothing and placed in airtight bagsIrrigationSymptomatic treatment Ophthalmic anesthetics, bronchodilators,
antihistamines
Capsaicin-induced dermatitis Oil immersion
Prevalent New Jersey HazMat Threats
Terrorist attack likely to involve conventional explosives & hazardous materialsNew 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
AmmoniaChlorineDifluoroethaneHydrogen chlorideHydrogen fluoride
Hydrogen sulfideOzonePentaneToluene diisocyanateVinyl 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
ChlorineBackground 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 statusIrrigationCalcium 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 exposuresProtocols should be available
Conclusions
Hospital roles
Pharmacist roles
Poison center roles
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