1. NERVE AGENTS & PRETREAMENT
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES
NERVE AGENTS & PRETREAMENT
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE

2. DEFINITION
A substance that causes biological effects by inhibiting acetylcholinesterase
Acetylcholine accumulates
Effects are due to excess acetylcholine

3. EXAMPLES Carbamates Organophosphates Physostigmine (Antilirium)
Neostigmine (Prostigmine)
Pyridostigmine (Mestinon)
Sevin (insecticide)
Organophosphates
Malathion
Diazinon
“Nerve Agents” 4 3

4. NERVE AGENTS
GA (Tabun)
GB (Sarin)
GD (Soman) GF VX

5. GA
CH3
CH2 O P N CN

6. GB
CH3 O P F CH

7. GD
CH3 O P F CH C

8. VX O
CH3
CH(CH3)2 S
CH2
CH2 N P
CH(CH3)2
CH3
CH2 O

9. HISTORY Germany, WW II, nerve agent munitions Used by Iraq
CONTINUED
HISTORY
Germany, WW II, nerve agent munitions
Used by Iraq
In stockpiles

10. TERRORIST USE
Matsumoto, 1994
7 deaths
Tokyo, 1995
12 deaths

11. PHYSICAL PROPERTIES
Clear, colorless liquids (when fresh), not “nerve gas”
Tasteless, most are odorless
Freeze/melt <0º C
Boil >150º C
Volatility GB>GD>GA>GF>VX
Penetrate skin, clothing 9 8

12. TOXICITY LCt50 LD50 mg-min/m3 mg/70kg GA 400 1,000 GB 100 1,700GD GF VX

13. CHOLINESTERASE Blood Tissue Acetyl (red cell, erythrocyte, “true”)
Butyryl (plasma, pseudo)
Tissue
Tissue acetylcholinesterase (at cholinergic receptor sites) 11 10

14. EXPOSURE INDICATORS Inhibition of Acetylcholinesterase (RBC)
most sensitive for nerve agent
Butyrylcholinesterase (plasma)
more sensitive for most insecticides

15. PHYSIOLOGY: NORMAL Electrical impulse goes down nerve
Impulse causes release of neurotransmitter, acetylcholine
ACh stimulates receptor site on organ
Causes organ to act
ACh is destroyed by AChE
No more organ activity 12 11

16. Nerve Transmission: Nerve to Nerve
ACh

17. Nerve Transmission: Nerve to Nerve
ACh

18. Nerve Transmission: Nerve to Nerve
ACh

19. Nerve Transmission: Nerve to Skeletal Muscle

20. Nerve Transmission: Nerve to Smooth Muscle

21. Nerve Transmission: Nerve to Exocrine Gland

22. Impulse Termination: The Role of AChE

23. Impulse Termination: The Role of AChE

24. PHYSIOLOGY: NERVE AGENT
Enzyme (AChE) is inhibited
Does not destroy ACh
Excess ACh continues to stimulate organ
Organ overstimulation 13 12

25. Exposure to Nerve Agent
AChE
ACh

26. Exposure to Nerve Agent
ACh
AChE

27. Effects on Striated (Skeletal) Muscle
AChE
ACh

28. Effects on Smooth and Cardiac Muscle
AChE
ACh

29. Effects on Exocrine Glands
AChE
ACh

30. ORGANS Muscarinic Nicotinic Both Smooth muscles Exocrine glands
Cranial nerves (vagus)
Nicotinic
Skeletal muscles
Pre-ganglionic nerves
Both
CNS 14

31. EFFECTS Muscarinic Smooth muscles Glands Heart, bradycardia (vagal)
Airways - constrict
GI tract - constrict
Pupils - constrict
Glands
Eyes, nose, mouth, sweat, airways, GI
Heart, bradycardia (vagal) 15 14

32. NICOTINIC Skeletal muscles Pre-ganglionic
Fasciculations, twitching, fatigue, flaccid paralysis
Pre-ganglionic
Tachycardia, hypertension 16 15

33. ACh at Receptors Nicotinic Nicotinic Preganglionic synapses in ANS
Skeletal muscle
ACh
ACh
Muscarinic
Muscarinic
Synapses in CNS
Smooth muscle
Exocrine glands
ACh

34. HEART RATE Muscarinic (vagal) decreases
Nicotinic (ganglionic) increases
May be high, low, normal 17 16

35. CNS Acutely, large exposure Loss of consciousness Seizures Apnea Death18 17

36. CNS Acutely, small exposure Minor CNS effects
CONTINUED
CNS
Acutely, small exposure
Minor CNS effects
Slowness in thinking and decision making
Sleep disturbances
Poor concentration
Emotional problems
Other minor problems

37. CNS Minor CNS effects May last for 3 to 6 weeks
CONTINUED
CNS
Minor CNS effects
May last for 3 to 6 weeks
May follow any exposure
Not always present
Very slight, subtle

38. VAPOR
Small exposure
Eyes: Miosis; injection; dim, blurred vision; pain; maybe nausea, vomiting
Nose: Rhinorrhea
Mouth: Salivation
Airways: Shortness of breath 20 19

39. VAPOR - NOSE and MOUTH Runny nose Mouth Worse than cold or hay fever
Leaking faucet
Mouth
Excessive saliva
May run out corners

40. VAPOR - RESPIRATORY TRACT
Small exposure
Tight chest
Moderate exposure
Severe breathing difficulty
Gasping, irregular breathing
Compounded by excessive secretions

41. VAPOR - GASTROINTESTINAL
Exposure to a large but not lethal concentration may cause:
Nausea, vomiting
Pain in abdomen
Diarrhea, involuntary defecation or urination

42. VAPOR - CARDIAC Heart rate Increase or decrease
Blood pressure - increase
Not an indicator for care

43. VAPOR Onset of effects: seconds to minutes After removal from vapor
CONTINUED
VAPOR
Onset of effects: seconds to minutes
After removal from vapor
Effects do not worsen
May improve
No late-onset effects

44. VAPOR Large exposure Previously listed effects plus...
CONTINUED
VAPOR
Large exposure
Previously listed effects plus...
Loss of consciousness
Seizures
Apnea
Flaccid paralysis
Death

45. LIQUID ON SKIN Small droplet: local effects
Sweating, fasciculations
Medium droplet: systemic effects GI
Large droplet: CNS
Loss of consciousness, seizures, apnea, flaccid paralysis, death 23 22

46. LIQUID ON SKIN Onset of effects Small, medium drop As long as 18 hours
CONTINUED
LIQUID ON SKIN
Onset of effects
Small, medium drop
As long as 18 hours
Large, lethal drop
Usually <30 minutes

47. LIQUID ON SKIN Onset time, penetration Skin site Temperature Moisture
CONTINUED
LIQUID ON SKIN
Onset time, penetration
Skin site
Temperature
Moisture

48. LIQUID ON SKIN Effects may occur despite initial decontamination
CONTINUED
LIQUID ON SKIN
Effects may occur despite initial decontamination
Effects may worsen

49. MIOSIS Almost always after vapor After liquid on skin: Small: no
Moderate: maybe
Severe: yes 27

50. MANAGEMENT ABCs Drugs Decontamination Supportive
Not necessarily in that order 28

51. MANAGEMENT MOST IMPORTANT Protect self Protect medical facility
CONTINUED
MANAGEMENT
MOST IMPORTANT
Protect self
Protective gear
Decontaminate casualty
Protect medical facility

52. DETECTION M256A1 Chemical Agent Monitor M8 and M9 paper
M8A1 Automatic Chemical Agent Alarm

53. PROTECTIVE POSTURE
MOPP 4!!!!!!

54. SKIN DECONTAMINATION Early is best, within 1 to 2 minutes
Little benefit after 30 minutes
Physical removal is best
Forceful flush with water
Stick, dirt, cloth, M291
Solutions (hypochlorite, etc.)
Detoxify after many minutes 30

55. VENTILATION Possibly less need after pyridostigmine
None forward of Battalion Aid Station
Very high airway resistance until atropine is given 31

56. ANTIDOTES Too much acetylcholine Enzyme inhibited
Block excess acetylcholine
Enzyme inhibited
Reactivate enzyme 32

57. ATROPINE A cholinergic blocking drug Blocks excess acetylcholine
An anticholinergic
Blocks excess acetylcholine
Clinical effects at muscarinic sites
Dries secretions
Reduces smooth muscle constriction 33

58. Atropine at Receptors Nicotinic Nicotinic Atropine Atropine Muscarinic

59. ACh and Atropine at Receptors
Nicotinic
Nicotinic
Atropine
ACh
ACh
Muscarinic
Muscarinic
Atropine
ACh

60. ATROPINE Side effects in unexposed Starting dose 2 mg or 6 mg
CONTINUED
ATROPINE
Side effects in unexposed
Starting dose 2 mg or 6 mg
More, 2 mg every 5 to 10 minutes
Until
Secretions drying
Ventilation improved
Usual dose: (severe casualty) 15 to 20 mg
1000s of mgs in insecticide

61. ATROPINE Not for Skeletal muscle effects Miosis, unless used topically
CONTINUED
ATROPINE
Not for
Skeletal muscle effects
Miosis, unless used topically
Use will cause blurred vision for 24 hours

62. Action of Atropine on Smooth Muscle
AChE
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
ACh
Atr
Atr
Atr

63. Effects on Exocrine Glands
Atr
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
ACh
Atr
Atr

64. Effects on Striated (Skeletal) Muscle: None!
Atr
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
ACh

65. OXIMES Effects at nicotinic sites
Increase skeletal muscle strength
No clinical effects at muscarinic sites 36

66. Action of Pralidoxime Chloride (2-PAM Cl)
AChE
Nerve Agent
2-PAM Cl

67. ACTION OF PRALIDOXIME CHLORIDE (2-PAM Cl)
AChE
2-PAM Cl
Nerve Agent

68. OXIMES Remove agent from enzyme, unless aging has occurred
CONTINUED
OXIMES
Remove agent from enzyme, unless aging has occurred
Aging: agent-enzyme complex changes
Oximes cannot reactivate enzyme
Aging times: GD 2 min GB 3 to 4 hours Others longer

69. Aging of the Nerve Agent-AChE Complex

70. Introduction of 2-PAM Cl after Aging

71. OXIMES Other countries have different ones England: P2S
CONTINUED
OXIMES
Other countries have different ones
England: P2S
Some European countries: obidoxime
Israel: TMB4
Japan: 2-PAMI

72. 2-PAMCL DOSE NAAK (MARK I): contains 600 mg
One or three Combopens; repeat in one hour
IV: One gram slowly (20 to 30 min)
Repeat in one hour 39

73. SEIZURES Without pyridostigmine Prolonged after pyridostigmine
Not prolonged
Anticonvulsant seldom necessary
Prolonged after pyridostigmine
Possible brain damage from prolonged seizures
Anticonvulsant needed (diazepam)
Give diazepam to any severe casualty 40

74. ARRHYTHMIAS Initial, transient from agent, atropine
Terminal after hypoxia
V-fib if atropine given IV with hypoxia 41

75. RECOVERY Severe casualty:
Without complications, conscious, breathing, in 2 to 3 hours 42

76. RETURN TO DUTY Dose-dependent, need dependent
Could be hours with minor exposure, great need
Many days after severe exposure
Consider:
Vision
Minor, subtle mental effects 43

77. LONG TERM EEG changes not detected in individuals
Minor changes detected in an averaged group
Significance unknown 44

78. MARK I Spring powered injectors Atropine, 2 mg/0.7 ml
2-PAMCl, 600 mg/2 ml 45

79. MARK I AUTO-INJECTOR

80. MILD VAPOR EXPOSURE Miosis, rhinorrhea
Rx: Probably none unless rhinorrhea is severe
Atropine IM will not help miosis 46

81. MODERATE VAPOR EXPOSURE
Miosis, rhinorrhea, moderate or severe dyspnea
Walking and talking
Rx: 1 MARK I (if dyspnea is quite severe: 2 MARK Is) 47

82. SEVERE VAPOR EXPOSURE Conscious or unconscious Seizing or post-ictal
Breathing or not
Or effects in two or more systems (airway, GI, muscular, CNS) 48

83. SEVERE VAPOR EXPOSURE Rx: 3 MARK Is and diazepam ASAP Ventilation
Rx even after cardiac arrest 48

84. MILD LIQUID EXPOSURE Localized twitching, sweating
Rx: 1 MARK I (agent has been absorbed) 49

85. MODERATE SKIN EXPOSURE
GI effects: vomiting, diarrhea, cramps
Rx: 1 MARK I
Watch carefully for 18 hours 50

86. SEVERE SKIN EXPOSURE Conscious or unconscious Seizing or post-ictal
Breathing or not
Or effects in two or more systems (airway, GI, muscular, CNS) 51

87. SEVERE SKIN EXPOSURE Rx: 3 MARK Is and diazepam Ventilation
Rx after cardiac arrest 51

88. NERVE AGENTS A Case Study From the Tokyo Subway Incident
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES
NERVE AGENTS A Case Study From the Tokyo Subway Incident
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE

89. Tokyo Subway Victim 35-year-old man
Exposed to sarin during the Tokyo subway attack 20 MAR 95
For approximately 7 minutes after exposure:
Had tonic-clonic convulsions
Episodes of dyspnea, during which he needed artificial respiration
In the hospital emergency room he was comatose and mildly cyanosed
Both pupils were constricted to 1.5 mm
Had increased oral and nasal secretions and profuse sweating and vomiting
Slide set: Tokyo subway victim
“A 35-year-old man was exposed to sarin during the Tokyo subway attack 20 MAR 95. For approximately 7 minutes after exposure, he had tonic-clonic convulsions and episodes of dyspnoea, during which he needed artificial respiration. In the hospital emergency room he was comatose and mildly cyanosed. Both pupils were constricted to 1.5 mm. He had increased oral and nasal secretions and profuse sweating and vomiting.” 2

90. Tokyo Subway Victim
Atropine sulphate and pralidoxime iodide were given intravenously
The patient began to regain consciousness 8 hours after exposure
Regained full mobility after 54 hours
He was, however, disoriented and had an impaired short-term memory
His electroencephalogram showed mild slowing of alpha activity, intermittent theta bursts, and the development of delta busts during hyperventilation
disappeared 3 months after exposure
CT and MRI imaging showed no focal lesions
Plasma cholinesterase activity, which was markedly low at 6% of normal levels after exposure, was normal within 3 weeks
RBC cholinesterase activity was normal after 3 months
Slide set: Tokyo subway victim
“Atropine sulphate and pralidoxime iodide were given intravenously. The patient began to regain consciousness 8 hours after exposure and regained full mobility after 54 hours. He was, however, disoriented and had an impaired short-term memory. His electroencephalogram showed mild slowing of alpha activity, intermittent theta bursts, and the development of delta busts during hyperventilation, which disappeared 3 months after exposure. CT and MRL imaging showed no focal lesions. Plasma cholinesterase activity, which was markedly low at 6% of normal levels after exposure, was normal within 3 weeks, and RBC cholinesterase activity was normal after 3 months.” 2

91. Tokyo Subway Victim
Neuropsychological tests 6 months after exposure showed no global intellectual impairment or defects in immediate recall
All his errors on the Mini Mental State were related to recall and temporal orientation
Performance was particularly impaired on the Logical Memory and Associate Learning scales from the Wechsler Memory Scale-Revised
Ability to copy the Rey-Osterrieth complex figure was normal (36/36)
However, when he was asked to reproduce the drawing 3 and 30 minutes later, his performance was worse (18/36 and 3/36, respectively)
These results suggest a defect in his ability to consolidate new learning and memory
Furthermore, without confabulation, he showed retrograde amnesia that extended to 70 days before exposure to sarin
Personality changes characterized by passivity and shallow affect were also evident
Slide set: Tokyo subway victim
“Neuropsychological tests 6 months after exposure showed no global intellectual impairment or defects in immediate recall. All his errors on the Mini Mental State were related to recall and temporal orientation. Performance was particularly impaired on the Logical Memory and Associate Learning scales from the Wechsler Memory Scale-Revised. Ability to copy the Rey-Osterrieth complex figure was normal (36/36). However, when he was asked to reproduce the drawing 3 and 30 minutes later, his performance was worse (18/36 and 3/36, respectively). These results suggest a defect in his ability to consolidate new learning and memory. Furthermore, without confabulation, he showed retrograde amnesia that extended to 70 days before exposure to sarin. Personality changes characterized by passivity and shallow affect were also evident.” 2

92. Tokyo Subway Victim
The extent and consequences of brain injury and incapacity due to nerve gas poisoning in human beings are not understood
Patient had amnesia similar to that caused by severe acute hypoxia
Hypoxia may have been a factor in our patient during the first 7 minutes after exposure
Defects such as retrograde amnesia and character changes might be associated with the direct effects of excess choline
Hatta K et al., Lancet 347:1343, 1996
Slide set: Tokyo subway victim
The extent and consequences of brain injury and incapacity due to nerve gas poisoning in human beings are not understood. Our patient had amnesia similar to that caused by severe acute hypoxia. Hypoxia may have been a factor in our patient during the first 7 minutes after exposure, although defects such as retrograde amnesia and character changes might be associated with the direct effects of excess choline.”
--Hatta K et al., Lancet 347:1343, 1996 2

93. PRETREATMENT FOR NERVE AGENT POISONING
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE

94. TERMINAL OBJECTIVE
Apply principles of pyridostigmine use in enhancing drug therapy for nerve agent intoxication 2

95. WHY? Major threat agent: Soman
Therapy for soman: relatively ineffective 3

96. CARBAMATES Transient carbamylation of AChE
Protects site from OP (nerve agent)
Carbamylation of only small amount of AChE needed 4

97. Action of Pyridostigmine
AChE
Pyridostigmine

98. Action of Pyridostigmine
AChE
Pyridostigmine

99. Action of Pyridostigmine
Nerve Agent
AChE
Pyridostigmine

100. Action of Pyridostigmine
AChE
Pyridostigmine

101. Pretreatment Pretreatment alone, without therapy provides no benefit
Pretreatment followed by antidotes after nerve agent: beneficial 9

102. Protective Ratio LD50 (treated) LD50 (untreated) PR =
PR of 1.0: No effect
PR of 5.0 desirable for the battlefield
PR of antidotes against GD: 1.6

103. PR Study in Rhesus Monkeys
Group LD50 of GD PR
Control mcg/kg 1.0
Mark I only mcg/kg 1.6
NAPP + Mark I > 617 mcg/kg > 40

104. UTILITY OF PRETREATMEN T
Helpful against: GD, GA
No added benefit: GB, GF, VX 11

105. BEFORE USE Efficacy Safety Short-term Long-term Side Effects
Performance
Long-term

106. SHORT TERM Side effects: <5% of those taking it
Performance: No decrements in military tasks (including shooting, flying, driving, physical tasks) 13

107. LONG TERM Animal studies Myasthenia gravis patients
Starting dose usually 60 mg q8h, can go much higher
Usual course of treatment is years, not weeks 14

108. DOSE REGIMEN Dose: 30 mg Interval: 8 hours Dosing: 30 mg every 8 hours
Based on RBC-ChE
Inhibition
Interval: 8 hours
Based on pharmacokinetics of pyridostigmine
Dosing: 30 mg every 8 hours
Commander starts, stops use 15

109. WHAT DO YOU SAY IF YOUR COMMANDER ASKS:
How long after I order pyridostigmine do I have to wait until my troops are protected?
How soon after I order them to stop taking it can I consider them at risk?

110. PYRIDOSTIGMINE: USE Mestinon : five decades for myasthenia gravis
Regonal : anesthesia

111. PYRIDOSTIGMINE Insignificant binding to plasma proteins
Bioavailability after oral dose: 8 to 29%
Elimination: <75% in urine
Maximal plasma concentration: 1.5 to 2.0 hours
Elimination half time: 3.5 hours

112. PYRIDOSTIGMINE: USE IN GULF WAR
Compliance unknown
High incidence (>50%) of side effects
Most related to pharmacology of drug
GI >50%
GU 5 to 30%
Medical assistance 1%
Discontinuance drug <0.1%

113. Israeli Study Effects of Pyridostigmine on troops in field conditions
Done under FTX conditions at basic training on 80 troops
Half of them given pyridostigmine 30 mg q8h or placebo
Studied before and after 8-day period on drug or placebo
Study design is double blinded but not crossover

114. Results of the Israeli study
Pyridostigmine-treated soldiers had “mild” GI symptoms in most cases
Pyridostigmine-treated soldiers had changes on order of 10% in their scores on vertical addition and four-choice (perceptual speed) tasks.
Other neuropsychiatric parameters were unaffected.
The two groups had no difference in their endocrine or stress tests including cortisol

115. Conclusions:
Soldiers did as well functionally with as without pyridostigmine
Functional significance of neuropsychiatric changes is unclear
Commanders and their troops had no complaints and those with mild changes were functionally unaware of them.
Limitation:
No systematic long-term follow-up
MAJ Givoni
Israeli Defence Force

116. PYRIDOSTIGMINE
After pretreatment, nerve agent, antidotes: breathing and seizures continue
Potential brain damage
Anticonvulsant (diazepam) needed (10 mg via auto-injector)

117. Effects of Long-term Administration
In vitro and in vivo evidence of myopathy
Complaints of weakness, fatigue, etc.
U.K. 60-day study
U.S. doctrine does not advocate long-term use

118. PYRIDOSTIGMINE: SUMMARY
Pretreatment, not a substitute for treatment
“Hides” or protects a fraction of AChE (creates a “reserve force”
Increases the amount of nerve agent a person can be exposed to and survive
Causes predictable side effect profile
Does not interfere with military function

119. U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES
SUMMARY ANY QUESTIONS?
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE