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

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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