nerve agents & pretreament

USAMRICDPROTECT, PROJECT, SUSTAIN

MEDICAL MANAGEMENT OF CHEMICAL CASUALTIESMEDICAL MANAGEMENT OF CHEMICAL CASUALTIES

NERVE AGENTS&

PRETREAMENT

U.S. ARMY MEDICAL RESEARCH INSTITUTE OF CHEMICAL DEFENSE

NERVE AGENTS

USAMRICDPROJECT, PROTECT, SUSTAIN

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DEFINITION

• A substance that causes biological effects by inhibiting acetylcholinesterase

• Acetylcholine accumulates

• Effects are due to excess acetylcholine

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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

CH3 CH2 O

O

P

CH3

CH3

N

CN

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GB

CH3

O

OP

CH3

CH3F

CH

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GD

CH3

O

OP

CH3

CH3F

CH C

CH3

CH3

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VX

CH3O

SP CH2N

CH(CH3)2

CH2

CH3CH2O

CH(CH3)2

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HISTORY

• Germany, WW II, nerve agent munitions

• Used by Iraq

• In stockpiles

CONTINUEDCONTINUED

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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 <0º C

• Boil >150º C

• Volatility GB>GD>GA>GF>VX

• 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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ACh

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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

ACh

AChE

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Impulse Termination: The Role of AChE

ACh

AChE

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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

ACh

AChE

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Exposure to Nerve Agent

ACh

AChE

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Effects on Striated (Skeletal) Muscle

ACh

AChE

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Effects on Smooth and Cardiac Muscle

ACh

AChE

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Effects on Exocrine Glands

ACh

AChE

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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

ACh

ACh ACh

ACh

Nicotinic Nicotinic

Muscarinic Muscarinic

Preganglionicsynapses in ANS

Skeletal muscle

Synapses in CNS

Smooth muscle

Exocrine glands

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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

• Acutely, small exposure– Minor CNS effects

• Slowness in thinking and decision making• Sleep disturbances• Poor concentration• Emotional problems• Other minor problems

CONTINUEDCONTINUED

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CNS

• Minor CNS effects

– May last for 3 to 6 weeks

– May follow any exposure

– Not always present

– Very slight, subtle

CONTINUEDCONTINUED

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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

• Onset of effects: seconds to minutes

• After removal from vapor

– Effects do not worsen

– May improve

• No late-onset effects

CONTINUEDCONTINUED

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VAPOR

• Large exposure

• Previously listed effects plus...– Loss of consciousness

– Seizures

– Apnea

– Flaccid paralysis

– Death

CONTINUEDCONTINUED

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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

• Onset of effects

– Small, medium drop

• As long as 18 hours

– Large, lethal drop

• Usually <30 minutes

CONTINUEDCONTINUED

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LIQUID ON SKIN

• Onset time, penetration

– Skin site

– Temperature

– Moisture

CONTINUEDCONTINUED

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LIQUID ON SKIN

• Effects may occur despite initial

decontamination

• Effects may worsen

CONTINUEDCONTINUED

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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

• MOST IMPORTANT

• Protect self

– Protective gear

– Decontaminate casualty

• Protect medical facility

– Decontaminate casualty

CONTINUEDCONTINUED

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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

NicotinicNicotinic

Muscarinic Muscarinic

Atropine

AtropineAtropine

Atropine

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ACh and Atropine at Receptors

ACh

ACh

ACh

Nicotinic

Muscarinic

Atropine

Nicotinic

Muscarinic

Atropine

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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

CONTINUEDCONTINUED

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ATROPINE

• Not for

– Skeletal muscle effects

– Miosis, unless used topically

• Use will cause blurred vision for 24 hours

CONTINUEDCONTINUED

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Action of Atropine on Smooth Muscle

ACh

AChE

AtrAtr

AtrAtr

Atr

Atr

Atr

Atr

Atr

Atr

Atr

Atr

AtrAtr

Atr

Atr

Atr

Atr

Atr

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Effects on Exocrine Glands

ACh

AChE

AtrAtrAtr

Atr

Atr

AtrAtr

Atr

Atr

AtrAtr

AtrAtr

Atr

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Effects on Striated (Skeletal) Muscle: None!

ACh

AChE

Atr

Atr

Atr

Atr

Atr

Atr

Atr

Atr

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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)

AChE

2-PAM Cl

Nerve Agent

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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

CONTINUEDCONTINUED

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Aging of the Nerve Agent-AChE Complex

AChE NerveAgent

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Introduction of 2-PAM Cl after Aging

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OXIMES

• Other countries have different ones

– England: P2S

– Some European countries: obidoxime

– Israel: TMB4

– Japan: 2-PAMI

CONTINUEDCONTINUED

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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



NERVE AGENTSA Case Study From the Tokyo

Subway Incident


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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 347:1343, 1996


PRETREATMENT FOR NERVE AGENT POISONING


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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

Pyridostigmine

AChE

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AChEPyridostigmine

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AChEPyridostigmine

NerveAgent

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AChEPyridostigmine

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Pretreatment

• Pretreatment alone, without therapy provides no benefit

• Pretreatment followed by antidotes after nerve agent: beneficial

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Protective Ratio

• PR =

• PR of 1.0: No effect

• PR of 5.0 desirable for the battlefield

• PR of antidotes against GD: 1.6

LD50 (treated)

LD50 (untreated)

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PR Study in Rhesus Monkeys

GroupGroup LD50 of GDLD50 of GD PRPR

ControlControl 15.3 mcg/kg15.3 mcg/kg 1.0 1.0

Mark I onlyMark I only 25.1 mcg/kg25.1 mcg/kg 1.6 1.6

NAPP + Mark I NAPP + Mark I > 617 mcg/kg> 617 mcg/kg > 40 > 40

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UTILITY OF PRETREATMEN T

• Helpful against: GD, GA

• No added benefit: GB, GF, VX

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BEFORE USE

• Efficacy

• Safety– Short-term

• Side Effects• Performance

– Long-term

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SHORT TERM

• Side effects: <5% of those taking it

• Performance: No decrements in military tasks (including shooting, flying, driving, physical tasks)

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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

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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

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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: <75% in urine

• Maximal plasma concentration: 1.5 to 2.0 hours

• Elimination half time: 3.5 hours

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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%

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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

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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

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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

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PYRIDOSTIGMINE

• After pretreatment, nerve agent, antidotes: breathing and seizures continue

• Potential brain damage

• Anticonvulsant (diazepam) needed (10 mg via auto-injector)

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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

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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


SUMMARYANY QUESTIONS?



nerve agents & pretreament

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