A slide presentation describing Chemical Agents and their treatment.

1. Combat
Toxicology
Frank W. Meissner, MD, FACP, FACC, FCCP
Emergency Medicine

2. History
●Iran - Iraq War emphasized the risk of
chemical weapons on the modern
battlefield
●Planning for ChemWar, complicated
Desert Storm Operations
●Recent Urban terrorist attacks in Japan
have emphasized the THREAT

3. Large scale conventional
combat operations
●Air Force bases susceptible to chemical
attack
●Geographicaly fixed & limited targets
●Chemical agent concentrations are in the
realm of tactical feasibility
●High value targets ideal for suprise
attack

4. Large scale conventional
combat operations
●High probability of disruption of combat
operations
●High density of personnel and technically
complicated resources
●Communication Nodes, Command and
Control, Combat Analysis
●Non-combatant philosophy of technically
oriented staff

5. Ground attack/defense forces
fewer susceptibilities
●Density of personnel much less than Air
Force Base
●High penalties for attacker - mobility and
fields of fire/observation

6. Ground attack/defense forces
fewer susceptibilities
●Uncertainty of defenders position in time
and space
●Larger areas to saturate with the
chemical munition
●Chemical agent concentrations are lower
than in the fixed target

7. Toxicological definitions
●Dose: Quantity of compound (mg/kg)
●Vaporized chem-agent dose = conc *
time (exposure)
Ct (mg*min/m3)
●LD50: Dose that 50% population dies
●ID50: Dose that 50% of population
incapacited

8. Routes of absorption
●Gases, vapors, aerosols absorbed in
total respiratory tract
●Aerosol particles > 5µ tend to be
retained in upper respiratory tract
●Aerosol particles < 1 µ tend to be in
exchanged gases

9. Routes of absorption
●Liquids absorbed from skin surface &
mucous membranes
●Chemical agents contaminate food
stuffs/water - GI tract absorption

10. Classes of Chemical Weapons
●Nerve agents
●Vesicants
●Lung damaging agents
●Cyanogen agents
●Incapacitating agents

11. Nerve Agents - History
●At end of WWII stocks of new type
German chemical weapon discovered
●This compound labeled by the Germans
as TABUN
●Entire group of agents developed from
this prototypical compound

12. Physical & chemical properties
●Organophosphorus esters related to
insecticides such as parathion
●These compounds are liquids varying in
volatility
●Volatility range between petrol and heavy
lubricating oil
●Freezing points approx -40° C

13. Physical & chemical properties
●Appearance- liquid nerve agents are
pale yellow to colorless
●Almost odorless
●Stability- moderate solubility in H2O/high
solubility in lipids
●Rapidly destroyed strong alkalies &
chlorinating compounds

14. Toxicity
●Depends on animal species and route of
entry
●IV in rabbits LD50 10-20 µgm/kg (GA
80µgm/kg)
●Percutaneous toxicity dependent on
volatility
○25 µgm/kg for VX
○20 µgm/kg for GB

15. Inhalation route
●LCt50 of G agents in rats - 200
mg*min/m3 for 10 minutes
●LCt50 of G agents for man 100
mg*min/m3
○Approx 400 mg needed to kill 50 % theater
audience

16. Inhalation route
●LCt50 of VX aerosol for man 50
mg*min/m3
●ID50 aproximately 50% of LD50 or LCt50

17. Acetylcholine
●Most ubiquitious and important neural
transmitter
●Motor end plate
●Muscarinic receptor
●Nicotinic receptor

18. Parasympathomimetic (muscarinic) receptor
●Nonvascular smooth muscle
○Increased propulsive gastrointestinal activity
("the shits", "the barfs" )
○Bladder constriction ("the wizzes")
○Bronchiole constriction ("the wheezes")
○Pupillary constriction ("the squints")

19. Parasympathomimetic (muscarinic) receptor
●Exocrine glands
○Increase in salivation ("the drools")
○Increase in perspiration ("the sweats")
○Increase in rhinorrhea ("the drips")
●Cardiovascular
○UNPREDICTABLE EFFECTS

20. Sympathomimetic (nicotinic) receptor
●Effects first described for the tobacco
alkaloid nicotine
●Cardiovascular effects
○Vasoconstriction & cardiac stimulation
○Liberates adrenal medullary amines
(catecholamines)

21. Voluntary nerve-muscle junction
●Voluntary muscle contraction

22. Acetylcholinesterase
●Enzyme found in postsynaptic side of
neuromuscular junction
●Action of the enyzme
●Inactivates Acetylcholine

23. Cholinesterase inhibitors
●Reversible inhibitors
○Used for a number of medical indications
Postoperative ileus and urinary retention
Glaucoma
Termination of the action of curare
Myasthenia Gravis

24. Cholinesterase inhibitors
●Irreversible inhibitors: organophosphates
●Insecticides, e.g. malathion
●Nerve gases

25. Signs and symptoms
●Irreversible inhibition of cholinesterase
inhibitor
●Results in uncontrolled stimulation at
acetylcholine receptors

26. Symptoms of acetylcholine action
●Mild to moderate exposure
○"the squints"; "the drools"; "the sweats"; "the
drips"; "the wheezes"
●Severe exposure
○"the barfs"; "the shits"; "the wizzes";"the
drops" (syncope)
○"the shakes" (seizures); "the end"
(respiratory arrest & death)

27. Treatment
●General supportive care & BCLS/ACLS
●Ventilator support & cardiac monitoring &
inhaled beta-agonist
●Requirements for optimal care of one
apneic, seizing, hypoxic patient
○one medical corps officer & two support
personnel

28. Atropine -the first line of
therapy
●A potent acetylcholine inhibitor
●Acts by competitive inhibition of Ach at
the neuromuscular junction
○Atropine Dosage
2 mg IV q 5 minutes until signs of atropinization

29. Effective Atropinization
●Red face
●Dry mouth
●Mydriasis (wide-open pupils)
●Tachycardia

30. Pralidoxime chloride- reserve forces
●Partially reactivates acetylcholinesterase
●Effective within first 36 hours of exposure
●Unlike atropine has actions at nicotinic & muscarinic
receptors helps relieve skeletal neuromuscular
blockade
●No reversal of inhibition after exposure to GD (Soman)

31. Pralidoxime chloride
●Dose
○Pralidoxime moderate poisoning
1 gram 2-Pam Cl in 10 ml at 500mg/min IV
○Pralidoxime severe poisoning
2 gram 2-Pam Cl in 10 ml at 500mg/min IV
●Precautions
○Hypertension during infusion self-limited but
may be severe, thus, monitor B/P

32. "The Chemical Battlefield"
Acetylcholine
receptor
P
r
e
s
y
n
a
p
t
i
c
Ach
Ach-esteras
e
Cholinesterase
inhibitor
Pralidoxim
e
Atropine

33. Vesicants (Blister Agents)-
History
●Mustard most well known agent
●First synthesized 1822
●Vesicant properties=> mid-19th century
●First employed as a chemical weapon
near Ypres 1917
●HD symbol in NATO nomenclature

34. Properties
●Mustards are liquid agents with high
persistence in temperate and cold
climates
●Toxicity
○LCt50 vapor, inhalation (mg*min/m3)
HD - 1500
HN1 - 1500
HN2 - 3000
HN3 - 1500

35. Toxicity
●LCt50 vapor, skin (mg*min/m3)
HD - 10000
HN1 - 20000
HN3 - 10000
●LD50 liquid, skin (mg/kg) 1 hr contact time
HD - 60
HN1 - 10
●Total absorption of 6 µg/cm2 causes 50% of
white human subjects to blister

36. Mode of action
●Alkylating and electrophylic properties
●Modify the structure of nucleic acids,
cellular membranes, and proteins
●Overall reactions of mustard with cellular
molecules
●Used clinically as chemotherapy agents

37. Signs and symptoms
●Cutaneous syndrome- divided into 4
phases

38. Latent
●Skin penetration not noticed because
painless
●Average duration of 4-8 hrs after
exposure
●Duration of latent period dependent on
humidity, temperature, and dose

39. Erythema
●Intensive itching in association with
erythema

40. Vesication
●Begins 12 - 48 hours after exposure
●Coalescence of vesicles form large
blisters
●Blisters generally more than 1 cm2 in
area

41. Necrosis
●Blisters rupture spontaneously turn into
suppurating & necrotic wounds
●Prolonged period of healing of these
wounds may take as long as weeks to
months

42. Ocular syndrome
●1-4 hours after exposure
●Intense pain, photophobia, and
blepharospasm
●Usually blistering of external ocular
structures and periorbital structures
●May result in blindness

43. Respiratory tract
●Mustard attacks all mucous membranes
●Latent period 4-6 hours in duration
●Profuse nasal secretions, burning pain in
throat
●Abundantly productive cough
●ARDS

44. Gastrointestinal tract
●Nausea & vomiting
●Pain
●Bloody diarrhea
●Shock

45. Systemic effects
●Headache, N/V, anorexia, epigastric
pain, leukopenia, anemia
●CNS depression, seizures
●Cardiac arrythmias, Cardiac arrest

46. Other Vesicants
●Lewisite
○Arsenical
○Similar clinical picture
○Reduced period of latency

47. Halogenated oximes
●CX most toxic of this class of agents
●No period of latency
●Low boiling point limits this agents
military usefulness

48. Treatment
●Prevention of exposure
●Supportive care & meticulous nursing
●No specific therapy

49. Choking Agents- History
●Phosgene(CG) first used combat in 1915
●80% of all combat causalities in WWI
●CG is the only significant chemical threat
in this class

50. Physical & chemical properties
●Colorless gas under conditions of
ordinary temperature & atmospheric
pressure
●Odor of newly mown hay
●Limit of perception by smell 22 mg/m3

51. Toxicity
●Minimal concentration irritation of eyes
and throat 12.5-20 mg/m3
●Serious lung damage-inhalation 50
mg/m3 over an hour period
●200 mg/m3 rapidly fatal
●LCt50 = 3000 mg*min/m3

52. Mode of action
●Poorly understood=> diffuse damage to
pulmonary membranes
●Severe pulmonary edema- 12-24 hrs
post exposure
●Lethal exposure usually results in death
within 24 hrs
●SurvivalX2-3 days=> good prognosis

53. Signs and symptoms
●Immediate exposure symptoms
○Lacryamation, dry throat, coughing,
tightness in chest
○Nausea & vomiting, headache
●Latent period of 2-6 hours after exposure
○Hypoxia, cyanosis, and productive cough
○Shock and respiratory arrest

54. Treatment
●General supportive care
●Enriched O2 & ventilator support with
PEEP for fulminant cases
●Rx the patient as an ARDS patient

55. Cyanogen Agents- History
●Cyanogen halides only compounds of
military importance
●WWI hydrocyanic acid & cyanogen
chloride used by French
●Cyanogen bromide used by Austrians

56. Properties
●Physical & Chemical
○Vapor at room temperature
○smell of "bitter almonds"
●Toxicity
○Percutaneous LD50 100mg/kg
○Ocular LD50 1-2 mg/kg
○Oral LD50 .9 mg/kg

57. Haber's Law= LCt50 is a constant
●Blood agents do not follow Haber's Law
○LCt50 600 mg*min/m3 15 sec exposure
○LCt50 1000 mg*min/m3 60 sec exposure
○LCt50 2000 mg*min/m3 10 min exposure
○LCt50 4500 mg*min/m3 30 min exposure
●Time concentration variablity limit their
military usefulness

58. Mode of action
●Cyanide high affinity- Fe++ in ferric state
●Binds to cytochrome oxidase
●Inhibits electron transport chain
●Intracellular hypoxia
●O2 cannot be utilized within the cell
●Progressive severe Acidosis

59. Signs and symptoms
●Tachypnea
●Headache
●Convulsions
●"bitter almond" smell on breath

60. Treatment
●Amyl nitrate by inhalation
●Sodium nitrate(4-5 mg/kg or 10 ml 3%
solution in 1 min) by infusion
●Converts hemoglobin=> methemoglobin
●Competes for cyanide ion

61. Treatment
●Thiosulfate (50ml of a 25% aqueous
solution(200 mg/kg))
●Thiocyanate excreted in urine
●Hyperbaric oxygen adjunctive therapy for
drug therapy

62. Incapacitants- History
Not known to be previously
used in combat

63. CNS Depressants
●BZ cholinergic compound
○Toxicology
Dose ≤ 1mg/kg can cause delirium of several day
duration
Safety margin (lethal/incapacitating dose)= 30
●Mode of action
○Similiar to atropine

64. BZ- Signs & symptoms
●Dry as a bone
●Hot as a hare
●Mad as a hatter

65. BZ- Treatment
●High risk for heat stroke as patient
cannot sweat
●Physostigmine salicylate 1 mg/20 kg IM
repeat dose in 40 min if inadequate
result
●Maintenance dose 2-5 mg po q 1-2 hrs
●Titrate therapy to HR = 70-80 bpm

66. Tetrahydrocannabinols
●Toxicity
○No deaths reported from this agent
○Synthetic analogs can have effects for days
after dose
●Mode of action
○Unknown

67. Tetrahydrocannabinols
●Signs & symptoms
○feelings of unreality, intensification of
sensations, difficulty in concentration
○lethargy, sedation, orthostatic hypotension
(synthetic analogs)
●Treatment
○No treatment necessary

68. CNS Stimulants- LSD & Mescaline
●Toxicity
○D-lysergic acid diethylamide most potent
biologicaly active indole
○Minimal dose 50 µgm
○Doses of 2-5 mg taken without sequelae
○Mescaline < potent toxic range 300-600 mg
○Max effects 2-3 hrs & further effects 4-8 hrs

69. LSD
●LSD is a serotonin antagonist
●Enhances neural activity in the reticular
activating system
○Signs & symptoms
Sympathetic stimulation,
Mental excitement
●Symptomatic treatment

70. Conclusions
●Chemical threat is REAL
●Weapons are cheap to make & utilize
●Terrorist threat is OBVIOUSLY high
●Air Force Bases @ increased risk
●Poor weapon against prepared troops in
the defense