NERVE AGENTS

1
NERVE AGENTSPRETREAMENT
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES

• U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL
  DEFENSE

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DEFINITION

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

3
EXAMPLES

• Carbamates
• Physostigmine (Antilirium)
• Neostigmine (Prostigmine)
• Pyridostigmine (Mestinon)
• Sevin (insecticide)
• Organophosphates
• Malathion
• Diazinon
• Nerve Agents

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NERVE AGENTS

• GA (Tabun)
• GB (Sarin)
• GD (Soman)
• GF
• VX

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GA
6
GB
7
GD
8
VX
O
CH(CH3)2
CH3
N
CH2
S
CH2
P
CH(CH3)2
CH3
CH2
O
9
HISTORY
CONTINUED

• Germany, WW II, nerve agent munitions
• Used by Iraq
• In stockpiles

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TERRORIST USE

• Matsumoto, 1994
• 7 deaths
• Tokyo, 1995
• 12 deaths

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PHYSICAL PROPERTIES

• Clear, colorless liquids (when fresh), not nerve
  gas
• Tasteless, most are odorless
• Freeze/melt lt0º C
• Boil gt150º C
• Volatility GBgtGDgtGAgtGFgtVX
• Penetrate skin, clothing

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TOXICITY

• LCt50 LD50
• mg-min/m3 mg/70kg
• GA 400 1,000
• GB 100 1,700
• GD 70 50
• GF 50 30
• VX 10 10

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CHOLINESTERASE

• Blood
• Acetyl (red cell, erythrocyte, true)
• Butyryl (plasma, pseudo)
• Tissue
• Tissue acetylcholinesterase (at cholinergic
  receptor sites)

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EXPOSURE INDICATORS

• Inhibition of
• Acetylcholinesterase (RBC)
• most sensitive for nerve agent
• Butyrylcholinesterase (plasma)
• more sensitive for most insecticides

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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

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Nerve Transmission Nerve to Nerve
ACh
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Nerve Transmission Nerve to Nerve
ACh
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Nerve Transmission Nerve to Nerve
ACh
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Nerve Transmission Nerve to Skeletal Muscle
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Nerve Transmission Nerve to Smooth Muscle
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Nerve Transmission Nerve to Exocrine Gland
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Impulse Termination The Role of AChE
AChE
ACh
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Impulse Termination The Role of AChE
AChE
ACh
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PHYSIOLOGY NERVE AGENT

• Enzyme (AChE) is inhibited
• Does not destroy ACh
• Excess ACh continues to stimulate organ
• Organ overstimulation

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Exposure to Nerve Agent
AChE
ACh
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Exposure to Nerve Agent
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Effects on Striated (Skeletal) Muscle
AChE
ACh
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Effects on Smooth and Cardiac Muscle
AChE
ACh
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Effects on Exocrine Glands
AChE
ACh
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ORGANS

• Muscarinic
• Smooth muscles
• Exocrine glands
• Cranial nerves (vagus)
• Nicotinic
• Skeletal muscles
• Pre-ganglionic nerves
• Both
• CNS

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EFFECTS

• Muscarinic
• Smooth muscles
• Airways - constrict
• GI tract - constrict
• Pupils - constrict
• Glands
• Eyes, nose, mouth, sweat, airways, GI
• Heart, bradycardia (vagal)

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NICOTINIC

• Skeletal muscles
• Fasciculations, twitching, fatigue, flaccid
  paralysis
• Pre-ganglionic
• Tachycardia, hypertension

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ACh at Receptors
Nicotinic
Nicotinic
Preganglionicsynapses in ANS Skeletal muscle
ACh
Muscarinic
Muscarinic
Synapses in CNS Smooth muscle Exocrine glands
ACh
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HEART RATE

• Muscarinic (vagal) decreases
• Nicotinic (ganglionic) increases
• May be high, low, normal

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CNS

• Acutely, large exposure
• Loss of consciousness
• Seizures
• Apnea
• Death

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CNS
CONTINUED

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

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CNS
CONTINUED

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

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VAPOR

• Small exposure
• Eyes Miosis injection dim, blurred
  vision pain maybe nausea, vomiting
• Nose Rhinorrhea
• Mouth Salivation
• Airways Shortness of breath

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VAPOR - NOSE and MOUTH

• Runny nose
• Worse than cold or hay fever
• Leaking faucet
• Mouth
• Excessive saliva
• May run out corners

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VAPOR - RESPIRATORY TRACT

• Small exposure
• Tight chest
• Moderate exposure
• Severe breathing difficulty
• Gasping, irregular breathing
• Compounded by excessive secretions

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VAPOR - GASTROINTESTINAL

• Exposure to a large but not lethal concentration
  may cause
• Nausea, vomiting
• Pain in abdomen
• Diarrhea, involuntary defecation or urination

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VAPOR - CARDIAC

• Heart rate
• Increase or decrease
• Blood pressure - increase
• Not an indicator for care

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VAPOR
CONTINUED

• Onset of effects seconds to minutes
• After removal from vapor
• Effects do not worsen
• May improve
• No late-onset effects

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VAPOR
CONTINUED

• Large exposure
• Previously listed effects plus...
• Loss of consciousness
• Seizures
• Apnea
• Flaccid paralysis
• Death

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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

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LIQUID ON SKIN
CONTINUED

• Onset of effects
• Small, medium drop
• As long as 18 hours
• Large, lethal drop
• Usually lt30 minutes

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LIQUID ON SKIN
CONTINUED

• Onset time, penetration
• Skin site
• Temperature
• Moisture

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LIQUID ON SKIN
CONTINUED

• Effects may occur despite initial decontamination
• Effects may worsen

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MIOSIS

• Almost always after vapor
• After liquid on skin
• Small no
• Moderate maybe
• Severe yes

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MANAGEMENT

• ABCs
• Drugs
• Decontamination
• Supportive
• Not necessarily in that order

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MANAGEMENT
CONTINUED

• MOST IMPORTANT
• Protect self
• Protective gear
• Decontaminate casualty
• Protect medical facility
• Decontaminate casualty

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DETECTION

• M256A1
• Chemical Agent Monitor
• M8 and M9 paper
• M8A1Automatic Chemical Agent Alarm

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PROTECTIVE POSTURE

• MOPP 4!!!!!!

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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

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VENTILATION

• Possibly less need after pyridostigmine
• None forward of Battalion Aid Station
• Very high airway resistance until atropine is
  given

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ANTIDOTES

• Too much acetylcholine
• Block excess acetylcholine
• Enzyme inhibited
• Reactivate enzyme

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ATROPINE

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

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Atropine at Receptors
Nicotinic
Nicotinic
Atropine
Atropine
Muscarinic
Muscarinic
Atropine
Atropine
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ACh and Atropine at Receptors
Nicotinic
Nicotinic
Atropine
ACh
Muscarinic
Muscarinic
ACh
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ATROPINE
CONTINUED

• 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

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ATROPINE
CONTINUED

• Not for
• Skeletal muscle effects
• Miosis, unless used topically
• Use will cause blurred vision for 24 hours

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Action of Atropine on Smooth Muscle
Atr
Atr
Atr
Atr
Atr
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
ACh
Atr
Atr
Atr
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Effects on Exocrine Glands
Atr
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
Atr
ACh
Atr
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Effects on Striated (Skeletal) Muscle None!
Atr
Atr
AChE
Atr
Atr
Atr
Atr
Atr
Atr
ACh
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OXIMES

• Effects at nicotinic sites
• Increase skeletal muscle strength
• No clinical effects at muscarinic sites

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Action of Pralidoxime Chloride (2-PAM Cl)
AChE
NerveAgent
2-PAM Cl
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ACTION OF PRALIDOXIME CHLORIDE(2-PAM Cl)
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OXIMES
CONTINUED

• 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

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Aging of the Nerve Agent-AChE Complex
NerveAgent
AChE
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Introduction of 2-PAM Cl after Aging
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OXIMES
CONTINUED

• Other countries have different ones
• England P2S
• Some European countries obidoxime
• Israel TMB4
• Japan 2-PAMI

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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

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SEIZURES

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

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ARRHYTHMIAS

• Initial, transient from agent, atropine
• Terminal after hypoxia
• V-fib if atropine given IV with hypoxia

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RECOVERY

• Severe casualty
• Without complications, conscious, breathing, in
  2 to 3 hours

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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

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LONG TERM

• EEG changes not detected in individuals
• Minor changes detected in an averaged group
• Significance unknown

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MARK I

• Spring powered injectors
• Atropine, 2 mg/0.7 ml
• 2-PAMCl, 600 mg/2 ml

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MARK I AUTO-INJECTOR
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MILD VAPOR EXPOSURE

• Miosis, rhinorrhea
• Rx Probably none unless rhinorrhea is severe
• Atropine IM will not help miosis

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MODERATE VAPOR EXPOSURE

• Miosis, rhinorrhea, moderate or severe dyspnea
• Walking and talking
• Rx 1 MARK I(if dyspnea is quite severe 2 MARK
  Is)

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SEVERE VAPOR EXPOSURE

• Conscious or unconscious
• Seizing or post-ictal
• Breathing or not
• Or effects in two or more systems(airway, GI,
  muscular, CNS)

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SEVERE VAPOR EXPOSURE

• Rx 3 MARK Is and diazepam ASAP
• Ventilation
• Rx even after cardiac arrest

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MILD LIQUID EXPOSURE

• Localized twitching, sweating
• Rx 1 MARK I (agent has been absorbed)

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MODERATE SKIN EXPOSURE

• GI effects vomiting, diarrhea, cramps
• Rx 1 MARK I
• Watch carefully for 18 hours

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SEVERE SKIN EXPOSURE

• Conscious or unconscious
• Seizing or post-ictal
• Breathing or not
• Or effects in two or more systems(airway, GI,
  muscular, CNS)

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SEVERE SKIN EXPOSURE

• Rx 3 MARK Is and diazepam
• Ventilation
• Rx after cardiac arrest

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NERVE AGENTSA Case Study From the Tokyo Subway
Incident
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES

• 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

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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

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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

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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 3471343, 1996

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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

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WHY?

• Major threat agent Soman
• Therapy for soman relatively ineffective

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CARBAMATES

• Transient carbamylation of AChE
• Protects site from OP (nerve agent)
• Carbamylation of only small amount of AChE needed

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Action of Pyridostigmine
AChE
Pyridostigmine
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Action of Pyridostigmine
AChE
Pyridostigmine
99
Action of Pyridostigmine
NerveAgent
AChE
Pyridostigmine
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Action of Pyridostigmine
AChE
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Pretreatment

• Pretreatment alone, without therapy provides no
  benefit
• Pretreatment followed by antidotes after nerve
  agent beneficial

102
Protective Ratio

• 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 15.3 mcg/kg 1.0
• Mark I only 25.1 mcg/kg 1.6
• NAPP Mark I gt 617 mcg/kg gt 40

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UTILITY OF PRETREATMEN T

• Helpful against GD, GA
• No added benefit GB, GF, VX

105
BEFORE USE

• Efficacy
• Safety
• Short-term
• Side Effects
• Performance
• Long-term

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SHORT TERM

• Side effects lt5 of those taking it
• Performance No decrements in military tasks
  (including shooting, flying, driving, physical
  tasks)

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

108
DOSE REGIMEN

• Dose 30 mg
• Based on RBC-ChE
• Inhibition
• Interval 8 hours
• Based on pharmacokinetics of pyridostigmine
• Dosing 30 mg every 8 hours
• Commander starts, stops use

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?

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PYRIDOSTIGMINE USE

• Mestinon? five decades for myasthenia gravis
• Regonal? anesthesia

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PYRIDOSTIGMINE

• Insignificant binding to plasma proteins
• Bioavailability after oral dose 8 to 29
• Elimination lt75 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 (gt50) of side effects
• Most related to pharmacology of drug
• GI gt50
• GU 5 to 30
• Medical assistance 1
• Discontinuance drug lt0.1

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
SUMMARYANY QUESTIONS?
MEDICAL MANAGEMENT OF CHEMICAL CASUALTIES
U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL
DEFENSE