Medical Treatment of
Chemical Warfare Casualties

MAJ Tom Garigan
Last Update: 5 April 1996

Overview:

Purpose:

• To Prepare the Military Physician for Clinical Responsibilities in the Medical Care of Chemical Casualties
  
• To Enable the Military Physician to plan and supervise the logistical preparation of field medical units for possible chemical casualties.
  
• To enable the Military Physician to recognize and treat industrial toxin exposures.

Chemical Warfare Agents Defined:

United Nations 1969 - " ... chemical substances, whether gaseous, liquid or solid, which might be employed because of their direct toxic effects on man, animals and plants ... ".

Toxins, i.e., poisons produced by living organisms and their synthetic equivalents:
Are covered by the Biological and Toxin Weapons Convention of 1972.

20th century- @ 70 different chemicals used or stockpiled as CW agents.
Only a few of these are of practical interest:

• Must not only be highly toxic but also "suitably highly toxic" so that it is not too difficult to handle.
• Capable of being stored for long periods in containers without degradation and without corroding the packaging material.
• Relatively resistant to atmospheric water and oxygen so that it does not lose effect when dispersed.
• Withstand the heat developed when dispersed.

General Characteristics:

• Gas vs. Liquid vs. Solid
• Liquid: can also be Aerosol or Evaporating
• Volatile vs. Persistent
• Lethal vs. Incapacitating*

*less than 1/100 of the lethal dose causes incapacitation, e.g., nausea, visual problems

History:

WW1- Chemical weapons caused 1.3 million casualties, 92,000 deaths

• 1914- Haber devises chlorine gas
• 1915- April - First "gas attack" at Ypres, Belgium with chlorine gas
• - Dec - Germans use phosgene
• 1916- British have chlorine and phosgene
• 1917- Livens projector fielded
  Germans use mustard gas at Ypres, Belgium
  ----------->1 million shells on Armentieres
  Cyanide
  Riot control agents
  
  
• 1925- Geneva Protocol
• 1936- Italy uses mustard gas against Ethiopians
• 1936-1944 Schrader develops three nerve agents
• 1938-In its war with Ethiopia, Italy used both nerve gases and mustard gas.
• 1937-45 Japan's Unit 731 in China
• 1943- Germans attack USS John Harvey- cargo ship in the Italian port of Bari; Carrying mustard gas; >600 casualties
• 1952- British discover VX at Porton Down
• 1956- North Africa- children injured when playing with mustard gas shell
• 1984-1988-Iran-Iraq War: Mustard agents
• 1988- Iraq drops Nerve agents on Kurds
• Baltic Sea fishermen- exposure to mustard agent from WW2 munitions dumped off the Danish and Swedish coasts.
• 1995- Tokyo Subway

Known to possess chemical weapons:

US, France, Iraq

Suspected of having chemical weapons:

Burma, China, India, Pakistan, Egypt, Israel, Ethiopia, Kuwait, Libya, North Korea, South Korea, Thailand, Taiwan, Syria, Vietnam

Nerve Agents (Organo-phosphorus compounds)

History

• Dr Gerhard Schrader- chemist at IG Farben
• -------------> pesticide development
• Discoveries with military implications had to be reported to the military authorities
• 1936- TABUN- (GA)
• 1938- SARIN - (GB)
• 1944- SOMAN - (GD)

These are called "G" Agents (for "German")

• All clear, colorless liquids with high boiling points
• Vapors are denser than air ---> stay close to ground

At the end of World War 2- Russians captured Duhernfurt facility and personnel ---> moved to Russia

After World War 2:

• "V" Agents- More stable
• 1952- VX- approximately 10X more poisonous than SARIN
• 1961- US begins production of VX
• VR-55 Russian counterpart to VX

Only known hostile uses of Nerve Agents: Iraq against Iran, Kurds; Tokyo Subway

1990- US began destroying its stockpile

Types of Nerve Agents

• TABUN (GA)- -easiest to manufacture
• SARIN (GB)- volatile (=water) inhalation; thickener can increase persistence
• SOMAN (GD)-taken up by inhalation or skin contact. Pralidoxime does not work as well
• GF- taken up through skin contact and inhalation
• VX- Most Persistent; The best one taken up through skin contact ; 300 times more lethal than TABUN on skin oily liquid form that is persistent for weeks or longer in the environment

Rapid hydrolysis in alkaline solutions

Mechanism of Action: Acetylcholinesterase inhibition

• Acetylcholine accumulation
• Stimulation of nerve, then paralysis
• Under optimum conditions, each enzyme molecule hydrolyzes about 15 000 acetylcholine molecules per second.

Cholinergic Synapses:

• CNS
• Termination of Somatic Nerves
• Ganglionic synapses of autonomic nerves
• Parasympathetic nerve endings
• Some sympathetic nerve endings e.g. sweat glands

Step 1 ==== Reversible binding
Step 2 ==== Irreversible binding
Step 3 ==== Aging"- no possible reactivation by oximes

T1/2 of Aging

• SOMAN=minutes
• SARIN=5 hrs
• TABUN & VX= >40 hrs

Restoration of AChE= at least two weeks

Other possible binding of Nerve Agents

• Cardiac muscarinic (M2) receptors
• CNS GABA-ergic antagonism

Muscarinic Receptors & Results of Nerve Agent Action-

• Gland secretions
  • Salivation
  • Sweating
  • Tearing
  • Bronchial hypersecretion
• Smooth Muscle Contraction- Bronchial
  • Wheezing
• Smooth Muscle Contraction- GI
  • Nausea, vomiting, diarrhea
  • Intestinal cramping
• Incontinence
• Cardiac= Bradycardia
• CNS
• Miosis

Nicotinic Receptors & Results of Nerve Agent Action-

• Autonomic Ganglia---> tachy, HTN
• Skeletal Muscles---> muscle fasciculations and twitching, weakness, paralysis

  ---

Types of Exposures to Nerve Agents

Low Vapor Doses

• Eyes, Nose Airways
• Sx Within seconds

Skin exposure
Very low dose-

• up to several hours delay
• Site dependent (faster on face)
• Temperature dependent (faster with warmth)

Local effects-

• local fasciculations
• local sweating

Higher dose

• Systemic effects may be sudden

High Vapor Dose

• Systemic effects may be sudden

Nerve Agents Cause Death By:

• Paralysis ofDiaphragm
• Depression of CNS respiratory center

  ---

EFFECTS OF NERVE AGENTS BY ORGAN SYSTEM

CNS EFFECTS

• Seizures
• Respiratory Depression
• Mental Status Changes
• Irritability
• Nervousness
• Fatigue
• Lethargy
• Memory impairment
• Depression
• Hallucinations
• Slurred Speech
• Ataxia
• Headache

PULMONARY EFFECTS

• Hypersecretions
• Bronchospasm

CARDIAC EFFECTS

• Bradycardia
• Dysrhythmias

EYES

• Miosis
• Vision Dimness

Upon inhalation- the symptoms in order of occurrence:

• Runny nose
• Bronchial secretions
• Tightness in the chest
• Dimming of vision
• Pin-Point Pupils
• Drooling
• Excessive perspiration
• Nausea, Vomiting
• Involuntary defecation, urination
• Muscle tremors, convulsions
• Coma
• Death

"SLUDGE"

• Salivation
• Lacrimation
• Urination
• Defecation
• Gastric Emesis

Medical Treatment of Nerve Agent Casualties

Decon

• Water, Sodium hypochlorite 0.5 % (bleach= 5%) or alkalinic solutions

ABC's

• Respiratory Support [possibly exhaled nerve agent (up to 10%)]
• This is most important;
  • bodily functions will gradually return

MARK I Kit- Q5-8 minutes

• Atropine 2 mg & 2-PAM Cl 600 mg

Atropine

• Far more effective at muscarinic sites
• minimum 2 mg IM or IV or ET
• Severe cases- LOC and/or severe signs in 2 or more organ systems
• except eye, rhinorrhea
• Begin with 6 mg IM or IV or ET
• But don't give IV if hypoxic
• Children 0.02-0.08 mg/kg

Give atropine until:

• skin is dry
• secretions are minimal
• adequate ventilation (decreased airway pressures)
• consciousness and spontaneous ventilation regained
  • Nerve agent casualties-- usually take <20 mg
  • Insecticide poisoning- may take hundreds of mg's
• Do not use pupils and HR as guides
• Muscle fasciculation may persist (nicotinic sites)
• Give 6 mg initially if moderate to severe exposure- LOC and/or severe signs in 2 or more organ systems except eye, rhinorrhea

If NOT exposed to Nerve Agent:
2 mg of Atropine------>up to 4-6 hrs of:

• increase in HR of 35;
• drying of airway secretions;
• blurring of vision (can last up to 24 hrs);
• inhibition of sweating

2 PAM Cl or HI-6= Oximes-

• Reactivate AchE
• Poor penetration capacity into the brain

2 PAM Cl (protopam)-

• 1-2 gm IV over 20-30 minutes
• not better--> immediately repeat
• better--> repeat 60-90 minutes later
• May cause HTN, tachycardia, N/V, visual change
• Children 15-25 mg/kg
• OR dilute to 300 mg/ml---> give 2 ml (600 mg) IM with first 3 atropine doses
• Does NOT Rx SOMAN
• No benefit at muscarinic sites

HI-6

• 3-5x more effective than 2 PAM Cl

Valium-

• If Seizures
• If 3 each MARK 1's given (6mg atropine)
• 5-10 mg IV
• 0.24-0.4 mg/kg IV in children

Pretreatment with p.o.?

• 10 mg tab 30 min before
• peak effect in 2 hrs

Observe Nerve Agent Casualties for 18+ hours
Until free of symptoms except miosis

OTHER MEDS:

• IV beta blocker to counteract tachycardia of atropine
• Eye pain from miosis-- ophtho atropine, homatropine, etc

Pyridostigmine

• Pretreatment for organophosphate nerve agent exposure
• inhibits acetylcholinesterase (@25 per cent)
• --->protects the enzyme against inhibitory effects of nerve agents
• 1-2 per cent of functional enzyme is sufficient to have a functioning synapse.
• 30 mg 3 times a day for a maximum of 7 days before a nerve agent attack
• Effectiveness has not been demonstrated in humans. (increases LD50 in monkeys)
• Not effective for SARIN or VX
• Does not reduce effects of nerve agents alone-
• helps for SOMAN when antidotes are given after exposure
• No CNS penetration
• After exposure- Carbamates worsen the situation
• 99% compliance in ODS

Side Effects of Pyridostigmine:

• Flatus, cramps, soft stools, urinary urgency, headaches, vivid dreams?
• Decrease HR by 5 bpm
• <0.1% had to discontinue the medication
• Overdose (2+ tabs) ---> cholinergic crisis
• Occasional hypertensive crisis

Blood testing if needed to confirm Nerve Agent Poisoning

• RBC acetylcholinesterase activity
• Metabolites/Products of the hydrolysis:
  • methylphosphonic acid (MPA)
  • isopropyl methylphosphonic acid (iPMPA)

Lung Agent= Phosgene (CG)

• Smell- like newly mown hay
• Commonly used by industry-- foamed plastics
• (Chlorine = Lung Agent)

Clinical Effects:

• Pulmonary Edema
• Bronchial injury

Onset of Sx- 10-24 hrs

ABG findings

• early= hyperventilation
• later- hypoxia

CXR findings

• 20-30 min= air trapping
• Later= ARDS

Medical RX

• No prophylaxis available
• Steroids do not help
• RX= ABC's
• Observe for at least 4 hrs then: Exam, CXR, ABG

Vesicants/Blister Agents

• Mustard (H,HD,HQ, yellow cross, yperite)
  Persistent, lipid soluble
  More volatile with increasing temperature
  Mustard or Garlic odor
• HT (60% HD, 40% T)

See Later Sections for:

• Lewisite (L) (an arsine)
• Phosgene Oxime (CG) (an urticant)

History

Produced 1822; Simple to make
Harmful effects discovered in 1860.

First World War

• Eyes- 86%; Resp- 75%; Skin 80-90%

Iran-Iraq War (1979-1988)-

• Resp, Eyes >90%; Skin 83%; CNS 83%; GI 68%
• About 5 000 Iranian soldiers reported KIA, 10-20 per cent by mustard agent.

Mechanism of Action:

Alkylating Agent- reacts with proteins, nucleic acids, cell membranes
Cells repair DNA using NAD-----> NADdepletion---->inhibited cellular glycolysis---> cell necrosis
Mustard agent interacts with intracellular glutathion. (small peptide which takes care of the free radicals)

Clinical Effects

Skin-
Biphasic response

• 1- fibroblasts, vessel endothelium disrupted
• 2- DNA damage
• Latent period- 1 hr to several days

Itching, +/- dryness & pallor-->Erythema--> vesicles--> bullae--> necrosis and ulceration--> hyperpigmentation

• Healing of erythema: 3-7 days
• Healing of ulcers: 6-8 weeks
• Skin injuries are more severe in humid and warm climates
• Most severe at warm & moist sites (intertriginous areas)

Eye-

• pain
• lacrimation
• photophobia
• swelling
• blepharospasm
• ulceration
• weeks of healing
• opacification

Lung-

• Most common cause of death
• Sx=pressure across the chest, sneezing and hoarseness
• may have delayed onset: 2-36 hrs
• Irritation- tracheobronchitis
• pulmonary edema, hemorrhage
• bronchopneumonitis

Chronic pulmonary changes:

• bronchiectasis
• chronic bronchitis
• bronchial hyperreactivity
• emphysema

Upper Airway

• Sinusitis
• hoarseness
• sore throat
• pseudo membrane formation

GI-

• N/V/D

Heme-

• Leukopenia at day 7-10

CNS-

• "Intellectual dullness or stupidity"

Medical Treatment of Mustard Casualties:

Decontaminate:

M258 Kit Towelletes:

• ethanol, phenol, sodium hydroxide, ammonia
• chloramine B, ethanol, zinc chloride

Soap and water
Absorption-

• charcoal slurry
• flour
• powdered milk
• albumin

Basic solutions-

• Ammonia
• Lye
• Bleach

Flush
Topical vs. Systemic Steroids---May slow healing
Cooling skin with ice bags- to slow chemical reaction

Treat as a burn:

• Fluid & Electrolytes
• Prevent secondary infection
• Silvadene, Sulfamylon, Bacitracin
• Do not give prophylactic antibiotics
• Wound Care
• Biosynthetic dressings
• Daily Debridement, cleansing

Other Rx:

• Antihistamines- for itching, edema, cough, vomiting
• Anti-emetics
• NSAIDS
• beware of renal effects

TREATMENT WITH ANTAGONISTS:

Sodium Thiosulfate

• 50 ml of a 25% solution (12.5 gm total) IV over 10 minutes

Mucomyst

• Oral loading dose: 140 mg/kg then 40 mg/kg Q4 hrs for 17 doses total

Vitamin E?

Also Give Tetanus Toxoid
Treat Ingestion:

• Activated charcoal

Treatment of Eyes:

• Saline irrigation
• Ointment to prevent lid sticking
• Local anesthetic 1-2x (may cause corneal damage)
• Ophth. Antibiotic
• Mydriatic (e.g. homatropine)
• Ophtho consultation
• Ocular steroids?

Respiratory:

• ABC's
• moistenedO2
• Beta agonists
• Mucomyst
• Cough suppressant

Testing:
Urine: thiodiglycol (metabolite)

Arsines

Types

• Lewisite is a colorless to brown liquid
• Fruity or geranium-like odor
• Adamsite is a nasal and throat-irritating powder.

Clinical Effects

• Similar to Mustard injuries
• BUT- Pain occurs immediately.
• Blisters within 12 hrs.
• Increased risk of bleeding
• Rapid eye damage

Medical Treatment

• BAL=British Anti-Lewisite (chelator)
• Apply topically (ointment)5 minutes after exposure
• Inject IM 10 % solution at a dose of 0.025 mL/kg Q4hrs up to 4 to 6 total injections
• BAL ophthalmic ointment

Phosgene Oxime (an urticant) (CX)

Immediate pain, then necrosis
Eye irritation
Lung effects- ? Like Mustard Agent?

Treat:

• Ulceration
• Pain control

CYANIDES

Hydrogen cyanide (AC) = gas
Cyanogen chloride (CK)
Zyklon B- was used in Nazi gas chambers.

• bitter almond odor
• colorless liquid - boils at 26°C (volatile)
• best used in confined spaces
• Cyanide: Found in many industrial processes and materials e.g. X-Ray film

Mechanism of Action:
Inhibits mitochondrial cytochrome oxidase- [cellular respiration]---->anaerobic metabolism

CNS, Heart-- most sensitive

Clinical Effects of Cyanide:

Sequence of Signs and Symptoms:

• Dryness and burning of the throat
• Dyspnea, shortness of breath
• Hyperpnea, rapid shallow breathing followed by:
• Apnea, lack of breathing
• Convulsion & coma
• Cardiovascular collapse

OR: another acronym:

• Flushing
• Elevated RR
• Erratic Respirations
• LOC
• Seizure
• Breathing Cessation
• Arrhythmias
• Death

Physical Findings:

• Pink Skin
• Red Venous blood
• Bitter almond odor
• Fundi- arterioles and veins- same color red
• mydriasis
• Muscle weakness, failure
• red engorged veins
• nausea, vomiting
• salivation
• Ataxia
• Weakness

Laboratory Findings:

• Lactic Acidosis/high anion gap
• Increased venous oxygen

Medical Treatment:

• Oxygen
• Amyl Nitrate (not available) crushable ampules (inhaled)
• Sodium Nitrate (300 mg [10 ml]) IV 10 cc of 3% solution
  Results in formation of Methemoglobin (which binds cyanide)
• Sodium thiosulfate (50 cc of 25% solution= 12.5 mg) IV. May repeat 1/2 dose x 1

Oxygen potentiates these processes

Metallic ions bind cyanide:

• Vitamin B12-(cobalt)
• EDTA

Pre-Treatment: Methemoglobin-forming meds-

• 8-aminoquinoline (US)
• PAPP, para-aminopropiophenone (UK)

Incapacitating Agents

Types

• Atropine-like drugs
  • BZ- US destroyed its weapons in 1980's
  • like atropine: anticholinergic
• lasts 1-6 days
• Barbiturates
• Volatile anesthetics
• Narcotics/tranquilizers
• LSD

Riot Control Agents & Vomiting Agents

Not recognized by US as chemical weapons

Types:

• CS
• CN- WW1; Mace
• CA- Obsolete
• CR- New; British Agent
• DM (Adamsite), DA, DC- "Vomiting Agents" (see below)

Potency:
CR>CS>CN>DM

Clinical Effects:

Irritation of:

• Eyes
• Upper Airway
• Lungs
• Skin
• GI

Potential Complications:

• Corneal Damage
• Bronchospasm
• chronic laryngitis, tracheitis
• Dermatitis- incl. contact, allergic

Clinical Effects of "Vomiting Agents"

sx may take minutes to develop
Last 20-120 minutes
headache, chills, N/V/D, malaise
upper resp tract sx
rhinorrhea, salivation
Rx= chloroform inhalation

Medical RX-

Do not use bleach

Decon with water, soap

Skin lotions
Topical steroids
Vesicles: topical antibiotics

Bronchodilators
Assisted ventilation

Eye:

• Flush eyes
• Ophtho consult
• Look for impacted particle

U.S. Army Modernization Plan, May '94 ASTMP Chapter III

c. Demonstrations Supporting System of Medical Chemical Defense

Cyanide Pretreatment (91-99)
Methemoglobin former= oral pretreatment
Methemoglobin preferentially binds cyanide.
Lead candidate compound = 8-aminoquinoline

M291 skin decontaminating kit- activate resin mixture- black.
1- absorbent
2- sulfonic acid
3- hydroxy amine
Will train with actual kit. Non-irritating

Topical Skin Protectant (TSP) (90-96).
Used with MOPP Gear and the M291 skin decon kit,
To prevent or significantly reduce the toxicity of chemical warfare agent

Nerve Agent Antidote, Multi-Chambered Auto injector (MA) (90-97)
Injects both through a single needle.

New Nerve Agent Antidote System (NAAS) (91-98).
Replaces MARK 1

• Atropine
• HI-6.
  
  
  

  ---

Current US Army Chemical Casualty Treatment Kit:

• Includes the following medications:
• atropine
• 2-PAM Cl
• Valium
• Sodium Nitrite
• Sodium Thiosulfate

Bibliography

WWW:

• PTS Home Page, @opcw
• U.S. Army Modernization Plan, May '94 ASTMP Chapter III

Medical Management of Chemical Casualties Course
USAMRICD, Sept 1995 Aberdeen Proving Ground, MD
Lecture Notes:

Sidell, Frederick R.- Nerve Agents, Cyanide, Riot Control Agents, Incapacitating Agents
Hurst, Charles G.- Vesicants
Urbanetti, John S.- Phosgene

ed. Somani, S. M. Book of Chemical Warfare Agents Academic Press, Inc 1992
Sidell, Frederick R. Chapter 6 pp155-194
Sidell, Frederick R. Chapter 3 "Clinical Considerations in Mustard Poisoning" pp51-66

Smith, William J., & Dunn, Michael A. "Medical Defense Against Blistering Agents" Arch Dermatol Vol. 127 pp1207-1213

Dunn, Michael A., & Sidell, Frederick R.; "Progress in Mdical Defense Against Nerve Agents" JAMA Vol 262:5 August 4, 1989 pp. 649-652

Keeler, Jill R., Hurst, Charles G., Dunn, Michael A.; "Pyridostigmine Used as a Nerve Agent Pretreatment Under Wartime Conditions" JAMA Vol 266:5 August 7, 1991 pp. 693-695

Borak, Jonathan, &Sidell, Frederick R.; "Agents of Chemical Warfare: Sulfur Mustard" Annals of Emerg Med, Vol 21:3 March 1992 pp303-308

Sidell, Frederick R., & Borak, Jonathan; "Agents of Chemical Warfare: Sulfur Mustard" Annals of Emerg Med, Vol 21:7 July 1992 pp865-871