What neurologists should know about NERVE AGENTS Grand Rounds Department of Neurology University of Cincinnati College of Medicine 18 November 2015.

What neurologists should know about

NERVE AGENTSGrand Rounds

Department of Neurology

University of Cincinnati College of Medicine

18 November 2015

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Jonathan Newmark, M.D., FAANCOL (ret.), MC, USA

Adjunct Full Professor of Neurology, Uniformed Services University of the Health Sciences

Consultant to the Surgeon General of the Army for Chemical Casualty Care, 2002-2012

MM candidate, composition, College-Conservatory of Music, University of Cincinnati

Special Government Employee, Office of Health Affairs, US Department of Homeland Security

Department of Neurology, School of Medicine, University of Cincinnati

Disclosures

The opinions are my own and not necessarily those of the Army, Department of Defense, nor of the Department of Homeland Security

No disclosures; if I had any, they would be violations of Federal law

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Resources

National Library of Medicine, Bethesda, Maryland Chemical Hazards Emergency Medical

Management web site: http://chemm.nlm.nih.gov

US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland Chemical Casualty Care Division web site:

http://ccc.apgea.army.mil Medical Management of Chemical-Biological

Casualties course

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Chemical and Biological Defense for Neurologists

Biological agents: Bacteria

Anthrax (meningitis) Viruses

VEE, other alphaviruses Toxins

Botulinum toxin Chemical agents:

Pulmonary intoxicants Cyanides Sulfur mustard and other vesicating agents Nerve agents

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Nerve agent: DEFINITION

A substance that causes biological effects by inhibiting acetylcholinesterase

Acetylcholinesterase, therefore, is the target of nerve agents

Acetylcholine accumulates

Effects are due to excess acetylcholine

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NERVE AGENTS

GA (tabun)

GB (sarin)

GD (soman)

GF

VX

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EXAMPLES OF ANTICHOLINESTERASES

Carbamates Physostigmine (Antilirium) Neostigmine (Prostigmine) Pyridostigmine (Mestinon) Sevin (insecticide)

Organophosphates Malathion Diazinon Nerve agents

Classical nerve agents: GA, GB, GD, VX

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GA

CHCH33CHCH2 2 OO PP NN

OO

CCNN

CHCH33

CHCH33

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GB

CHCH33 PP OO CH CH

OO

FF

CHCH33

CHCH33

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GD

CHCH33 PP OO CH C CH CH C CH33

OO

FF CHCH33 CHCH33

CHCH33

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VX

PP SS CH CH22CHCH22 NN

OOCHCH33

CHCH33CHCH22OO

CH(CHCH(CH33))22

CH(CHCH(CH33))22

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HISTORY

First synthesized by Gerhard Schrader, IG Farben,

Germany, 1936-8

Weaponized and stockpiled by Germany in WWII but never

used

Manufactured and stockpiled in quantity by USA, USSR,

Iraq, others

First used on the battlefield by Iraq, 1984-1987

First documented US battlefield casualties, Iraq, 2004

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TERRORIST USE

Matsumoto, 1994

7 deaths

Tokyo, 1995

12 .5 (!) deaths

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SARIN ATTACK, TOKYO SUBWAY, 1995

Syrian chemical attacks, August 2013

Claims that Bashar al-Assad used nerve agents against rebel-held residential areas

“1400 deaths” – Washington Post

Picture credit: The Guardian, UK

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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 / 70 kg

GA 400 1,000GB 100 1,700GD 70 50GF 50 30VX 10 10

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LD50 of VX

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NERVE AGENT PATHOPHYSIOLOGY

Target: Synaptic acetylcholinesterase (AChE)

Disabling AChE causes toxidrome of overstimulation at all cholinergic synapses

This is a form of cholinergic crisis

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CHOLINESTERASES: CIRCULATING AND NOT

Blood Acetyl (red cell, erythrocyte, “true”) Butyryl (plasma, pseudo) Easy to measure, not clinically relevant.

Tissue Tissue acetylcholinesterase (at cholinergic

receptor sites) This is the target of nerve agents!

Nerve agents will inhibit ALL of these.

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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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NEUROTRANSMISSION:NEURON TO NEURON

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IMPULSE TERMINATION:THE ROLE OF AChE

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PHYSIOLOGY:NERVE AGENTS

Enzyme (AChE) is inhibited

Does not destroy ACh

Excess ACh continues to stimulate organ

Organ overstimulation

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EXPOSURE TONERVE AGENT

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EFFECTS ON STRIATED (SKELETAL) MUSCLE

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EFFECTS ON SMOOTH AND CARDIAC MUSCLE

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EFFECTS ON EXOCRINE GLANDS

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TWO MAJOR TYPES OF CHOLINERGIC RECEPTORS

Muscarinic Smooth muscles Exocrine glands Cranial nerves (vagus)

Nicotinic Skeletal muscles Preganglionic nerves

Both CNS (brain and spinal cord) – roughly 9/1

muscarinic/nicotinic

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CHOLINERGIC MUSCARINICEFFECTS

Smooth muscles Airways - constrict GI tract - constrict Pupils - constrict

Glands Eyes, nose, mouth, sweat, airways, GI

Heart, bradycardia (vagal)

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CHOLINERGIC NICOTINICEFFECTS

Skeletal muscles Fasciculations, twitching, fatigue, flaccid

paralysis Note that flaccid paralysis is NEVER the first

sign!

Pre-ganglionic Tachycardia, hypertension

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CHOLINERGIC NICOTINIC EFFECTS

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HEART RATE

Muscarinic (vagal) decreases

Nicotinic (ganglionic) increases

May be high, low, or normal

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CNS

Acutely, large exposure

Loss of consciousness

Seizures

Apnea (central, due to inhibition of brain

center)

Death

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CNS

Acutely, small exposure: neurobehavioral syndrome May follow any exposure; not dose-dependent Poorly understood; few well-studied patients May last 3-6 weeks (some claim longer) Can be minimal Nonspecific in nature:

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

NB: This may be indistinguishable from post-traumatic stress disorder (PTSD)

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VAPOR

Small exposure Eyes: Miosis; injection; dim,

blurred vision; pain; maybe nausea, vomiting (from miosis

alone)

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

GI symptoms are the earliest symptoms in blood-borne NA exposure Possibly due to large

splanchnic circulation 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

Each individual has her/his own balance of vagal vs. sympathetic input to heart

Heart rate and blood pressure may increase or decrease

Usually HR increases early, then flattens

Not an indicator of efficacy of treatment! Individuals vary enormously!

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VAPOR: CNS (BRAIN)

Once nerve agent gets to the brain, symptoms include: Seizures Coma Central apnea (brain doesn’t tell the lungs to

breathe) Flaccid paralysis Death

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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

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VAPOR

Large exposure can go through all the preceding stages almost immediately, so first signs and symptoms may be: 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 NOTE: TAKES A LOT LONGER TO GO

SYSTEMIC than does vapor GI will be first system involved

Large droplet: CNS and lungs (also other organs, but those are not life-threatening): Respiratory failure, 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

Factors affecting this: location on skin,

temperature, moisture

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LIQUID ON SKIN

Effects may occur despite initial decontamination Effects may worsen

This is a major difference between vapor poisoning and liquid-on-skin poisoning

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MIOSIS

Almost always after vapor

After liquid on skin:

Small: no

Moderate: maybe

Severe: definitely

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NORMAL PUPILLARYRESPONSE

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PINPOINT PUPILS

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NERVE-AGENT EFFECTS:EYES

3

6

13

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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

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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

There is a use for MRE bread! Solutions (hypochlorite, etc.)

Detoxify, but only after many minutes

PRINCIPLE: NO KNOWN DECONTAMINANT TRUMPS PHYSICAL REMOVAL ON SKIN!

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VENTILATION

Possibly less need after pyridostigmine

None forward of battalion aid station

Very high airway resistance until atropine is given

Therefore, give atropine FIRST, then try to ventilate

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ANTIDOTES

Strategy ONE: Too much acetylcholine

Block excess acetylcholine

Antidote = atropine

Strategy TWO: Enzyme inhibited

Reactivate enzyme

Antidote = oxime (2-PAM Cl)

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ATROPINE

Cholinergic blocking drug = anticholinergic

Blocks excess acetylcholine

Clinical effects at muscarinic sites Dries secretions

Reduces smooth muscle constriction

This may be lifesaving!

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ATROPINE AT RECEPTORS

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ACh AND ATROPINEAT RECEPTORS

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ATROPINE

Smaller autoinjector (2 mg / 0.7 ml) of Mark I kit

Starting dose 2 mg or 6 mg (1-3 autoinjectors) More: 2 mg every 5 to 10 minutes

Until Secretions drying Ventilation improved

Usual dose in severe casualty: 15 to 20 mg 1000s of mgs in insecticide poisonings due to

lipid solubility of insecticides

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ATROPINE

Will NOT benefit

Skeletal muscle effects

Miosis, unless used topically

Use will cause blurred vision for 24 hours

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ACTION OF ATROPINEON SMOOTH MUSCLE

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EFFECTS OF ATROPINEON EXOCRINE GLANDS

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STOPPING ATROPINE

Endpoints Reduction in secretions (muscarinic effects) Reduction in chest tightness (muscarinic effects) Patient able to breathe comfortably on his/her own

Do not titrate to Heart rate (variable; not an indicator of severity of

exposure) Miosis (may persist for up to 6 weeks despite

atropine) Twitching or fasciculations (nicotinic effects)

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OXIMES

React with the complex formed by the combination of nerve agent and AChE

Result of reaction is: Normal, catalytic AChE Nerve agent broken into two harmless

fragments which the body rapidly breaks down

How oxime (2-PAM Cl) works

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OXIMES

Effects at nicotinic sites

Increase skeletal muscle strength

No additional clinical effects at muscarinic

sites

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OXIMES

Remove agent from enzyme unless aging has occurred

Aging = a reaction in which agent-enzyme bound complex changes

Oximes cannot reactivate enzyme after “aged” Aging T 1/2 = GD 2 min

GB 3 to 4 hours (so we may ignore aging clinically)

Others longer (so we may ignore aging clinically)

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INTRODUCTION OF 2-PAM ClAFTER AGING

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OXIMES

Other countries have different ones

United Kingdom: P2S

Germany, much of Europe, Iran: obidoxime (Toxigonin)

Israel: TMB4

Japan: 2-PAM Iodide

Canada: HI-6 (not yet approved by Health Canada)

Next generation American oxime may be MMB-4 (not yet

approved in USA)

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DOSE OF 2-PAM Cl

Larger autoinjector (600 mg / 2.0 ml) of Mark I kit 1-3 autoinjectors; may give additional 1 autoinjector

after one hour 2000+ mg of 2-PAM Cl may cause severe hypertension

IV: 1 gram slowly (over 20 to 30 min) Repeat in one hour

There is an UPPER BOUND to 2-PAM Cl treatment: no more than 1800 mg IM or 2000 mg IV in one hour

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MARK I AUTOINJECTOR

Spring-powered injectors

Atropine: 2 mg / 0.7 ml

2-PAM Cl: 600 mg / 2.0 ml

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ATNAA COMBINED AUTOINJECTOR CONTAINS 2.1 MG ATROPINE AND 600 MG

2-PAM ClThis item is replacing the MARK 1 kit!

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ATROPINE OPHTHALMICOINTMENT 1%

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SEIZURES

Without pyridostigmine Not prolonged Anticonvulsant seldom necessary

Prolonged after pyridostigmine (at least in animals) Possible brain damage from prolonged

seizures Anticonvulsant needed (diazepam)

Give diazepam to any severe casualty Dose: 10 mg im (CANA) In a seizing casualty 10 mg won’t be enough.

The combat medic/corpsman carries more. Next generation anticonvulsant = midazolam

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DIAZEPAM AUTOINJECTOR: CANADIAZEPAM AUTOINJECTOR: CANA

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ARRHYTHMIAS

Initial, transient from agent, atropine

Terminal after hypoxia

Ventricular fibrillation if atropine given

IV with hypoxia

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RECOVERY

Severe casualty:

Without complications, conscious, breathing, in 2 to 3 hours

IMPLICATION: A severe nerve agent casualty is a high priority for TREATMENT but is not a high priority for EVACUATION immediately. You should win the clinical battle for the patient’s life at YOUR echelon of care.

CHEMPACK program: COL N and Dr. Susan Cibulsky of DHHS, Glendale, Arizona, 2011

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PYRIDOSTIGMINE:SUMMARY

Pre-exposure or “pretreatment” Not a substitute for post-exposure 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; i.e., converts a lethal dose into a potentially survivable dose with antidotes

Causes predictable profiles of side effects Does not interfere with military function

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PYRIDOSTIGMINE:REGULATORY STATUS

Fully approved for pretreatment for soman ONLY by the Food and Drug Administration FEB 2003

FIRST DRUG EVER APPROVED USING THE ANIMAL RULE!

This means no IND or informed consent is necessary if the commander orders it to be used

Decision to use PB against potential nerve agent attack is driven by intelligence

I advised CENTCOM (7 MAR 03) that if the agent is not known, assume soman is possible and issue and order troops to take PB

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Upcoming and ongoing developments in nerve agent treatment

Replacement of MARK 1 by ATNAA Midazolam as a substitute for diazepam

(AAS) MMB-4 as a substitute for 2-PAM Cl (INATS) Bioscavengers Post-marketing studies on pyridostigmine Seizure monitor for the field Neuroprotectant for nerve agent poisoning

survivors

Butyrylcholinesterase: a stoichiometric bioscavenger

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DR. FREDERICK SIDELL

Resources

National Library of Medicine, Bethesda, Maryland Chemical Hazards Emergency Medical

Management web site: http://chemm.nlm.nih.gov

US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland Chemical Casualty Care Division web site:

http://ccc.apgea.army.mil Medical Management of Chemical-Biological

Casualties course

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SUMMARYANY QUESTIONS?