Transcript Neurological Agents of Bioterrorism

Between a Rock & a Hard Place:
A Review of the Neurological Aspects of
Bioterrorism
Amy Gutman MD
[email protected]
Overview
• Epidemiology of Bioterrorism
• Neurological Agents of Bioterrorism & Their
Mechanisms of Action
• Response to Bioterrorism
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Prehospital
Emergency Department
In-Patient Care
Chronic Care
Thoughts to Ponder
• “The American military
superiority presents a
paradox; potential
adversaries know they
can’t win a conventional
challenge to US forces,
so they’re likely to try
unconventional methods,
such as biologic or
chemical weapons.”
W. Cohen, Defense Secretary
Epidemiology of Bioterrorism
40,000 Metric Ton Russian Chemical Stockpile
(2005 United Nations Report )
Consider The Bioterrorism Sources In
Hamilton County
Likelihood of Agent Release
• Vapor / Aerosol
Inhalation:
– Potentially massive morbidity
& mortality
– Immediately affects those in
close proximity
– May have large affected area
due to weather conditions
• Liquid Release:
– Rapid onset of symptoms
limits potential victims even
in a large water source
– Either direct contact or via
ingestion
Exposure vs Contamination*
*Credited to Dr Leonard Singer
Neurotoxin Mechanisms of Action
• ACh released when impulse
reaches presynaptic neuron
– Ach travels in synaptic cleft to
postsynaptic membrane, binding
a muscarinic or nicotinic receptor
– ACh receptor activated generating
an action potential
– ACh detaches from receptor &
degraded by AChE regenerating
the receptor
• Neurotoxins inhibit ACh:
– Bind to the active site rendering
it incapable of deactivating ACh
• Undegraded ACh continues to
interact with receptors, resulting
in persistent & uncontrolled
stimulation until fatigued
– Same principle as neuromuscular
blocker succinylcholine
Pathophysiology
• Irreversibly inactivate AChE causing toxic accumulation of ACh at
muscarinic, nicotinic, & CNS synapses
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Muscarinic:
Miosis, bronchoconstriction, N/V/D, bradycardia,
glandular hypersecretion, urinary & fecal incontinence
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Nicotinic Skin:
Sweating
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Nicotinic Muscle:
Defasciculation then weakness & flaccid paralysis
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CNS Cholinergic:
Irritability, giddiness, fatigue, lethargy, amnesia,
ataxia, seizures, coma, & respiratory depression
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CNS Delayed:
behavioral changes (anxiety, emotional lability), ataxia,
insomnia, nightmares, depression, difficulty
concentrating, slow recall, confusion, slurred speech
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Adrenal Medulla:
Tachycardia & HTN
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GABA & NMDA:
Neurotransmission antagonized mediating
seizures & CNS neuropathology
Nerve Agent Pharmacologic Effects
“DUMBELS” or “M T W Th F”*
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Diarrhea
Urination
Miosis
Bronchorrhea / Bronchoconstriction
Emesis
Lacrimation
Salivation
• Alternative is “Days of The Week”
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Mydriasis
Tachycardia
Weakness
Hypertension
Fasciculations
*Common mnemonic "SLUDGE" does not include
bronchorrhea or bronchoconstriction
Bioterrorism Agents*
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Alphaviruses (viral encephalitis)
Arenaviruses (Lassa, Machupo)
Bacillus anthracis (anthrax)
Clostridium botulinum (botulism)
Clostridium perfringens
Brucella species
Burkholderia mallei (glanders)
Burkholderia mallei (meliodosis)
Chlamydia psittaci (psittacosis)
Coxiella burnetii (Q fever)
Escherichia coli 0157:H7
Filoviruses (Ebola, Marburg)
G Agents (Sarin, Soman)
Francisella tularensis (tularemia)
Hantavirus
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Hydrogen Cyanide
Nipah virus (encephalitis)
Organophosphates
Ricin toxin
Rickettsia prowazekii (typhus)
Salmonella species (salmonellosis)
Salmonella Typhi (typhoid fever)
Shigella (shigellosis)
Smallpox (variola major)
Staphylococcal enterotoxin B
V Agents (VX)
Variola major (smallpox)
Vibrio cholerae (cholera)
Yersinia pestis (plague)
*Chemical Weapons Convention of 1997 banned production, stockpiling & use of chemical
weapons, & provides for the monitoring of their destruction
V Agents: VX
• Developed by England in 1952
– Information traded with US for nuclear weapons technology
• Oily, odorless, amber liquid which does not readily
evaporate
– Must be aerosolized into tiny droplets
• Degrated products persist on the ground for 2 - 6 days
– Continue to have neurotoxic effects
• Enters body via skin or inhaled as a vapor
• V agents ~10X more poisonous than GB (sarin)
G “Deutsche Grun Drei” Agents
Agent
Base
Physical
Property
Odor
Color
Hazard
Degrade
Other
GA
Tabun
Cyanide
Oily
Fruity
Colorless
Direct
Contact <
Inhalation
1-2 Days
1st V agent;
discovered
by Nazis
GB
Sarin
Fluorine
Watery
Odorless
Colorless
Inhalation
>
Direct
Contact
1 Day to
stable,
non-toxic
product
Released on
Iranians,
Kurds &
Japanese
GD
Soban
Fluorine
Watery
Fruity or
Camphor
Colorless
Inhalation
>
Direct
Contact
¼ the rate
of water
1967 Yom
Kippur War
Botulism: Clostridium botulinum
• Paralytic illness caused by an anaerobic, gram
positive, spore-forming rod
• Lethal dose: one microgram is lethal to humans
• ~110 cases in US annually
– 72% are infant botulism
– 3% are wound botulism
– 25% are food born outbreaks due to home-canning
• The heat-labile toxin blocks ACh release at nerve
synapses
Symptoms & Diagnosis
• Symptoms at 12-48 hours:
– Dry mouth, double &/or blurred vision, difficulty swallowing, muscle
weakness, ptosis, SOB, slurred speech, vomiting, incontinence,
diarrhea then constipation (paralytic ileus)
– Death secondary to respiratory failure (8% case fatality rate)
– Long-term effects include: fatigue & SOB (decades)
• DDX:
– Guillain-Barré syndrome
– CVA
– Masthenia gravis
• Diagnostic Testing:
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CT, MRI
LP with CSF analysis
EMG
Edrophonium Chloride (Tensilon)
Toxin identification via ELISA or tissue culture in serum, blood, GI
contents, vomit or feces
Botulinum Symptoms
40 x 10-12g/mL of type A botulinum toxin in serum
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Patient at rest
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Patient smiling
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Bilateral mild ptosis,
mydriasis, disconjugate
gaze, & symmetric facial
muscles
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Absent periorbital smile
creases, ptosis,
mydriasis, disconjugate
gaze, & asymmetric smile
Botulism Evaluation
Botulism Treatment
• Supportive, including mechanical
ventilation
• If detected early, passive immunity
can be induced via a horse-serum
derived antitoxin
• Botulinum Antitoxins:
– Trivalent (A,B,E) derived from equine
sources utilizing Fab & Fc
antibodies
– Heptavalent (A,B,C,D,E,F,G) derived
from "despeciated" equine IgG
antibodies which have had the Fc
portion cleaved off leaving the F(ab')
portions
Anthrax: Bacillus anthracis
• Long-lived endospore (centuries) that when inhaled, ingested, or
in direct contact with skin reactivates & rapidly multiplies
• Can be grown in vitro
• Does not spread directly from one infected animal or person to
another, but spores can be transported by clothing, shoes, or a
dead body
• Pasteur developed the first effective vaccine for anthrax in 1881,
followed by a century of animal vaccination programs,
sterilization of raw animal waste materials & world-wide anthrax
eradication programs
– 5 US confirmed fatalities in 2006
• Fact: Thought to be the 6th Biblical Plague (shkhin ‫)ש ִחין‬
ְׁ or “boils”
Bacillus Anthracis
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Rod-shaped bacterium 1 by 9 um in size,
discovered by R. Koch in 1877, currently
with 89 strains
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Once ingested, absorbed or inhaled the
bacterium begins multiplying, killing the
animal within days to months via an exotoxin
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Most anthrax bacteria inside the body are
destroyed by “normal” anaerobic bacteria
The greater danger lies in the bodily fluids
that spill from the body into the soil where
the anthrax bacteria turn into a dormant
protective spore form
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The virulence of a strain of anthrax primarily
dependant upon the poly-D-glutamic acid
capsule that protects the bacterium from
phagocytosis by host neutrophils & its
toxins: “edema” toxin & “lethal” toxin
Anthrax Types
• Pneumonic / “Woolsorter’s Disease”
– Presents with cold or flu-like symptoms for several days, followed
by severe & often fatal respiratory collapse (mortality is near
100%)
– This mode of infection is used as a bioweapon
• Gastroenteric / Foodborn
– Hematemesis, gastrointestinal difficulty, severe diarrhea, acute GIT
inflammation & anorexia
– Spreads through the bloodstream with a fatality rate of 25% to
60%
• Cutaneous
– Boil-like skin lesion that eventually forms an ulcer with a large,
painless central eschar
– If untreated, 20% of all cutaneous skin infection cases progress to
toxemia & death
– 5% fatality rate with treatment
Anthrax: Widened Mediastinum
Anthrax Treatment & Prevention
• Direct person-to-person spread unlikely, but patient’s clothing
& body may be contaminated with anthrax spores
• Effective decontamination with simple soap & water
– Waste water should be treated with bleach
– Boil contaminated articles with disinfectants, chlorine or
simply burn in a contained area
• Early antibiotic treatment of anthrax essential with
fluoroquinolones (cipro), doxycycline, erythromycin,
vancomycin or penicillin
• Anyone working with anthrax in a suspected or confirmed
victim should wear a HEPA or P100 filter mask
Treatment & Prevention
• If death occurs from anthrax the body should be quarantined
– Burial does not kill anthrax spores
• The most effective form of prevention is vaccination against
infection but this must be done well in advance of exposure to
the bacillus, and does not protect indefinitely
• Components of black tea, such as polyphenols, have the ability
to inhibit the activity of anthrax considerably
– The addition of whole milk to a standard cup of tea completely
inhibits its antibacterial activity against anthrax
BioThrax
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FDA-licensed vaccine,
produced from a non-virulent
strain of the bacterium, is called
“BioThrax” or “Anthrax Vaccine
Adsorbed” (AVA)
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Administered in a six-dose
series at 0,2,4 weeks & 6,12,18
months
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Annual boosters required to
maintain immunity
– Painful, & causes significant
swelling
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Soviets developed a live spore
vaccine, known as STI, whose
serious side effects restrict use
to healthy adults
Anthrax Hemorrhagic Meningitis
Outbreak Features
• Rapid increase in incidence of a rare disease
– Or endemic disease rapidly & uncharacteristically emerging
• Rapid increase in those seeking care for URI / GI illnesses
– Systemic symptoms delayed >18 hours if limited dermal exposure
– Single location (building, city, stadium)
• Large number of rapidly fatal cases
– Respiratory Exposure: death in <15 minutes
– Skin bbsorption: death in 1 to 2 minutes
• Uncommon illness with bioterrorism potential
– “Sentinel Patients”, i.e. inhalational anthrax
HPI
• Often the first history is the only history available if
patients rapidly decompensate
• History of exposure to a nerve agent may be absent
• Always suspect the diagnosis when multiple patients
present with symptoms of cholinergic excess
• Occupational history can aid in making the
diagnosis in cases of accidental releases
– Farmers, military personnel, chemical demilitarization
laborers, & laboratory workers
Physical Exam & DDX
• Clinical signs and symptoms related to unopposed stimulation at
cholinergic, GABA & NMDA receptors as discussed previously
• Diagnosis is easier in the severely symptomatic patient
• Pathognomonic:
– Miosis, copious secretions, & generalized muscular fasciculations in
a gasping, cyanotic, seizing patient
• DDX:
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Epilepsy
Gastroenteritis
Upper Respiratory Infection
Heat-Related Illness
Stroke / Head Trauma
Drug overdose
Laboratory Studies:
RBC Cholinesterase Levels
• Labs do not aid in acute treatment; treat on clinical suspicion
– Never withhold treatment while awaiting results
• RBC & plasma cholinesterase (“pseudocholinesterase”) activity
can be assayed in blood
– Tissue cholinesterase activity cannot be directly measured
• RBC cholinesterase is a sensitive indicator of nerve agent toxicity
– Clinical symptoms correlate with 20-25% reduction enzyme activity
• Rising enzyme levels indicate no further absorption occurring
– RBC cholinesterase replaced fully every 120 days
Other Studies
• ABG:
Decreased PaO2, increased PCO2
• Lactate & CPK:
Elevated in seizures (hypoxia, fasciculations)
• Electrolytes:
Hypokalemia (G series agents)
• Special Tests:
M256A1 or CAM assay, M8, M9 papers
• ECG:
Bradycardia, AV blocks (muscarinic)
Tachycardia, PVC, VT, VF, (hypoxia)
PR interval & QT prolongation, torsades
• EEG:
Monitoring for paralyzed patients
Nicotinic effects of agents masks seizures
EEG Findings
• Greater-than-normal variations in potential
• Increased frequency with increased beta waves
• Irregularities in rhythm & intermittent appearance of abnormal
high-voltage, slow waves most prominent in the frontal leads
• EEG abnormalities often decreased or reversed by atropine
– EEG abnormalities of a subject poisoned with sarin showed slow
activity with bursts of high-voltage, 5-Hz waves in temporo-frontal
leads for 8 days on continuous atropine & benzodiazepine infusion
Imaging: CXR
• Any respiratory
distress, dyspnea, or
post intubation to
evaluate for noncardiogenic pulmonary
edema
ARDS Post Neurotoxin Inhalation
Initial Management
• Goals: rapid termination of exposure, treating life-threatening
emergencies, & administration of antidotes
– Safety of patients, EMS, rescuers & hospital workers depends on
early exposure recognition to avoid creating more victims
• Highest level of PPE required:
– Fully encapsulated, chemical-resistant, vapor-protective suit via SCBA &
full face shielding, & butyl rubber gloves
• ABCs
– Supplemental O2, oximetry & cardiac monitoring, IV access
– Early intubation & ventilatory support if severe toxicity
– Respiratory failure is leading cause of death
• Medications
– Mark I auto-injectors (atropine, pralidoxime chloride 2PAM)
Effective Decontamination
• In a “normal” MCI, priorities are: stabilize patient then
decontaminate; In a neurotoxin release priorities are:
decontaminate then stabilize patients
• Goal is to prevent further absorption of nerve agents & prevent
the spread of nerve agents to others
• Remove all clothing & jewelry
• Cleanse eyes, mucus membranes, wounds & entire skin
surface skin with soap & water or 0.5% hypochloride (1:9 ratio
of bleach:water)
– Breaks neurotoxin ionic bonds
• Clothing & used solution are “contaminated” evidence
– Requires double bagging & disposal in a closed container
Basic Decontamination Plan
Holding
Area
Cut
&
Strip
Shower
&
Rinse
Drying
Clean
Area Clothing
Hospital Decontamination
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Although prior to EMS transport from
a scene, patients undergo initial
decontamination, hospital staff must
be trained in self-protection, triage,
treatment, & decontamination
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In an MCI, patients often self-transport
without EMS treatment
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In the Tokyo subway sarin attack, 85%
of patients arrived via private car
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This emphasizes the importance of
hospital decontamination facilities &
training as many victims likely to
require initial triage &
decontamination at the ED
ED & Hospital Treatment: ABCs
• All personnel must wear PPE until adequate decontamination is
assured or the need for decontamination is eliminated
• Any symptomatic patient: O2, pulse ox, cardiac monitor, & IV
• Early ETI & ventilatory support is paramount if severe toxicity
– Avoid succinylcholine: metabolized by plasma cholinesterase
leading to markedly prolonged paralysis
– Suction is an important adjunct, as secretions may be profuse
• Early consultation with neurology, toxicology, internal
medicine, psychiatry, surgery & critical care is essential
• In an MCI, activate the hospital emergency plan (DisasterNet)
– DisasterNet automatically starts EOC notifications
• Regional poison center (1-800-222-1222)
NIMS, EOP, SNS Federal, State & Local Responses
• Rapid delivery of critical
medical assets to the site of
an emergency
• Coordinates agencies in the
event of a terrorist attack or
natural disaster
• SNS anaged by the CDC as a
national repository of:
– Antibiotics, antidotes,
antitoxins, life-support
meds, IV / airway supplies,
& other med-surg items
• “12-hour Push Package”
arrives <12 hours after the
federal decision to deploy
– 2nd phase arrives 24–36 hrs
Initial Patient Care
• Detailed health histories must be obtained as many patients &
families may not be aware of initial exposure
• The key to recognizing neurotoxin exposure is the appearance
of multiple patients with similar signs and symptoms
• The route of exposure & the dose of the nerve agent determine
the onset & severity of signs & symptoms
– Inhaled agents produce a rapid onset of symptoms, potentially
misinterpreted as a URI or allergy symptoms
– Patients with only ocular findings following vapor exposure can be
discharged home safely with rapid opthmology referral
• Admit patients with suspected liquid exposures for observation
after decontamination
– Onset of symptoms may be delayed 18 hours
Treatment if Completely
Asymptomatic
• For those patients that may have been exposed but
are not exhibiting any symptoms
• This may include malingerers or opportunists
– Legally prudent to observe
• Reassurance of the rarity of significant health effects
• Place under medical observation in a floor bed:
• Vapors:
• Liquids:
1 hour
18-24 hours
Inpatient Care
• Patients in respiratory distress may need ventilatory
assistance despite aggressive antidotal therapy
• If critically ill with complications such as anoxic
brain injury (prolonged seizures or respiratory
arrest) may require prolonged intensive care
• Follow RBC cholinesterase and electrolyte levels
• Acute management of & secondary medical or
surgical emergencies
– Cardiac Arrests
– COPD Exacerbations
– Blast Injuries
Chronic Neurological &
Neuropsychological Effects
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May persist for months if severe cholinergic effects
– If discharged without complications or a significant exposure from
the hospital generally no further acute care required
• Subtle behavioral & cognitive changes may persist for weeks
• Permanent neurological sequelae if anoxic brain injury present
• Educate patients on potential long-term complications (>3
years), including:
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Behavioral & cognitive changes difficult to distinguish from PTSD
Impaired memory, difficulty concentrating, anxiety, irritability, depression
Symmetric sensorimotor peripheral neuropathy
Night-time miosis
Postural imbalance
Fatigue
Nausea
Joint stiffness
Medical Errors - Initial
• Failure of EMS to secure scene, turning themselves into victims
• Failure to decontaminate victims of liquid nerve agent exposure
leads to contamination of rescuers & hospital personnel
• Failure to recognize symptoms of cholinergic excess as being
caused by nerve agent toxicity leading to delays in care
• Failure to recognize succinylcholine causes prolonged paralysis
• Disposing of evidence collected during triage or treatment
• Poor documentation leading to confusion at hospital
Medical Errors - Delayed
• Failure to recognize symptoms of cholinergic excess
may not appear for 18 hours in low-level exposures
• Solely using presence or absence of miosis to guide
atropine therapy
• Over-reliance on pseudocholinesterase levels to
guide treatment
• Failure to suspect occult seizures in paralyzed
patients & order EEG to prevent hypoxic brain injury
Antidotes
Atropine
Pralidoxime Chloride (2 PAM)
Antidotes
• Even with rapid administration respiratory failure
may occur due to bronchoconstriction, increased
airway secretions, & increased airway resistance
– Prepare to provide intubation & mechanical ventilation
• Supplemental oxygen, suctioning, & careful
monitoring of vital signs, electrolyte levels, & cardiac
rhythm are essential
• Symptoms often improve after antidote
administration, though the duration of the symptoms
depends on the route & degree of exposure to the
nerve agent
Antidotes Two-Tiered
Mechanisms of Action
• Atropine (Anticholinergic):
– Counteracts muscarinic effects resulting from excess ACh in the
absence of functional AChE
– Dries respiratory secretions; does not relieve diaphragm paralysis
– Continue dosing until symptoms improve (“atropinization”)
– Adverse effects include: flushing, warmth, tachycardia, urinary
hesitancy, blurred vision, & drowsiness
• 2-PAM (Oxime / Cholinesterase Reactivator)
– Removes organophosphate from AChE which then deactivates ACh
– Restores normal skeletal muscle function (including diaphragm)
– Adverse effects include malignant HTN, tachycardia, diplopia, N/V &
dizziness
Mark I Auto-Injectors
• 2mg atropine auto-injector
contains glycerin, phenol,
citrate buffer, & water
• 600mg 2-PAM auto-injector
contains benzyl alcohol,
glycine, & water
• Do not administer to patient
with hypersensitivity to any
component solution
Pyridostigmine (Mestinon, Regonol)
Chemoprophylaxis
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Temporarily binds to AChE theoretically blocking
binding of nerve agents to AChE
• Effective: GA, GD, GF
• Ineffective: GB, VX
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Orally available cholinesterase inhibitor
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Only effective in preventing peripheral effects
– Ionized form does not pass into CNS
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50% of the Gulf War military taking chemoprophylaxis experienced
flatus, diarrhea, & abdominal cramping
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5-30% had urinary frequency & urgency, headaches, rhinorrhea,
diaphoresis, & / or paresthesias
Common Treatment Problems
• Not adding benzodiazepine as adjuncts to antidote
treatment:
– Necessary for seizure prophylaxis & / or control
– Treat manifestations from fasciculation to paralysis
• Underdosage
– Administering too little antidote to relieve symptoms
– Failing to administer atropine when needed (late
recognition)
• Overdosage
– Administering antidote to un-exposed patients
Management Steps
US Army, Biologic Casualties Handbook, 2001
1. Maintain an index of suspicion
2. Protect thyself
3. Assess the patient
4. Decontaminate as appropriate
5. Establish a diagnosis
6. Render prompt therapy
7. Practice good infection control
8. Alert the proper authorities
9. Assist in the epidemiologic investigation
10. Maintain proficiency & spread the gospel
Summary
• Recognizing the various
presentations of neurotoxin
bioterrorism
• Review of the mechanism of
action of organophosphates
and antidotes
• Evaluation of prehospital,
emergency, and in-patient
patient management of the
patient with neurotoxicity
References
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BioChem 1st Responder ER
National Incident Management System (NIMS)
www.CNSForum.com
Ohio Emergency Operations Committee (OEOC)
Ohio Emergency Response Plan (OERC)
Ohio Outbreak Response & Bioterrorism Team (ORBIT)
Kentucky Emergency Response Plan (KERP)
DHS Chemical Stockpile Emergency Preparedness Program (CSEPP)
Centers for Disease Control (CDC)
Center for Infections Disease Research & Policy Bioterrorism Prepardness
Institutes of Medicine Committee on R&D Needs for Improving Civilian Medical
Response to Chemical & Biological Terrorism Incidents
Food and Drug Administration (FDA)
NC Statewide Program for Infection Control & Epidemiology Bioterrorism Agents
UAB at Birmingham Bioterrorism & Emerging Infections Education
www.cbwinfo.com