Between a Rock & a Hard Place: Response to Neurological Bioterrorism

1. Between a Rock & a Hard Place: Response to Neurological Bioterrorism Amy Gutman MD prehospitalmd@gmail.com

2. Overview • Epidemiology of Bioterrorism • Neurological Agents of Bioterrorism • Mechanisms of Action • Response to Bioterrorism • Prehospital • Emergency Department • In-Patient

3. A Thought 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

4. History of Bioterrorism

5. Consider Bioterrorism Sources In Ulster County

6. Likelihood of Agent Release Vapor / Aerosol Inhalation: Widespread morbidity & mortality Immediately effects in close proximity Large affected area due to weather conditions Liquid Release: Rapid symptom onset limits victims even in a large water source Direct contact or via ingestion

7. Exposure vs Contamination* *Credited to Dr Leonard Singer

8. Neurotoxin Mechanisms of Action • ACh released when impulse reaches presynaptic neuron • Ach travels in synaptic cleft to postsynaptic membrane, binding muscarinic or nicotinic receptor • ACh receptor activated, generating an action potential • ACh detaches from receptor & degraded by AChE which regenerates the receptor • Neurotoxins inhibit ACh: • Bind to 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

9. Pathophysiology: Irreversibly inactivate AChE causing toxic Ach accumulation at receptors & synapses • Muscarinic: Miosis, bronchoconstriction, N/V/D, bradycardia, glandular hypersecretion, urinary & fecal incontinence • Nicotinic Skin: Sweating • Nicotinic Muscle: Defasciculation then weakness & flaccid paralysis • CNS Cholinergic: Irritability, giddiness, fatigue, lethargy, amnesia, ataxia, seizures, coma, & respiratory depression • CNS Delayed: Anxiety, ataxia, insomnia, nightmares, depression, difficulty concentrating, slow recall, confusion, slurred speech • Adrenal Medulla: Tachycardia & HTN • GABA & NMDA: Neurotransmission antagonized mediating seizures & CNS neuropathology

10. Nerve Agent Pharmacologic Effects“DUMBELS” or “M T W Th F”* • Diarrhea • Urination • Miosis • Bronchorrhea / Bronchoconstriction • Emesis • Lacrimation • Salivation • “Days of The Week” • Mydriasis • Tachycardia • Weakness • Hypertension • Fasciculations *Common mnemonic "SLUDGE" does not include bronchorrhea or bronchoconstriction

11. Bioterrorism AgentsChemical Weapons Convention of 1997 banned production, stockpiling & use of chemical weapons, & provides for the monitoring of their destruction 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) Coxiellaburnetii(Q fever) Escherichia coli 0157:H7 Filoviruses(Ebola, Marburg) G Agents (Sarin, Soman) Francisellatularensis (tularemia) Hantavirus 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)

12. 40,000 Metric Ton Russian Chemical Stockpile

13. V Agents: VX • Developed by England in 1952 • Information traded with US for nuclear weapons technology • Oily, odorless, amber liquid, does not readily evaporate • Must be aerosolized into tiny droplets • Degraded products continue to have neurotoxic effects on ground for 2 - 6 days • Enters body via skin or inhaled as a vapor • V agents ~10X more poisonous than GB (sarin)

14. G “Deutsche Grun Drei” Agents Other 1st V agent; discovered by Nazis Released on Iranians, Kurds & Japanese 1967 Yom Kippur War

15. Botulism:Clostridium botulinum • Paralytic illness caused by an anaerobic, gram positive, spore-forming rod • Lethal dose: one microgram • ~110 cases in US annually • 72% infant • 3% wound • 25% food born due to home-canning • The heat-labile toxin blocks ACh release at nerve synapses

16. Symptoms & Diagnosis • 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: muscle weakness • DDX: • Guillain-Barré syndrome, CVA, Myasthenia gravis

17. Botulinum Symptoms40 x 10-12g/mL of type A botulinum toxin in serum • Patient at rest • Bilateral mild ptosis, mydriasis, disconjugate gaze, & symmetric facial muscles • Patient smiling • Absent periorbital smile creases, ptosis, mydriasis, disconjugate gaze, & asymmetric smile

18. Botulism Evaluation • Diagnostic Testing: • CT, MRI • LP • EMG • Edrophonium Chloride (Tensilon) • Toxin ID via ELISA or culture in body fluids

19. Botulism Treatment Supportive, including mechanical ventilation If detected early, passive immunity 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

20. 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 • No direct spread, but spores transported by clothing, shoes, or a dead body • Pasteur developed 1st effective vaccine in 1881, followed by a century of animal vaccination, sterilization of animal waste, & world-wide anthrax eradication programs • Fact: Thought to be the 6th Biblical Plague (shkhinשְׁחִין) or “boils”

21. Bacillus Anthracis Rod-shaped bacterium 1 by 9um in size, known to have 89 strains Once ingested, absorbed or inhaled, bacterium rapidly multiplies, killing animal within days to months via exotoxin Most anthrax inside body destroyed by “normal” anaerobic bacteria The greater danger lies in fluids that spill from body into soil where anthrax turns into a dormant protective spore The virulence of a strain dependent upon poly-D-glutamic acid capsule that protects bacterium from phagocytosis by host neutrophils & its toxins: “edema” toxin & “lethal” toxin

22. Anthrax Types • Pneumonic / “Woolsorter’s Disease” • Flu-like symptoms, followed by severe & often fatal respiratory collapse (mortality near 100%) • This mode of infection is used as a bioweapon • Gastroenteric / Foodborn • Hematemesis, gastrointestinal difficulty, severe diarrhea, acute GIT inflammation & anorexia • Spreads through bloodstream with fatality rate of 25-60% • Cutaneous • Boil-like lesion that forms an ulcer with a large, painless central eschar • If untreated, 20% progress to toxemia & death • 5% fatality rate with treatment

23. Anthrax Treatment & Prevention • Direct person-to-person spread unlikely, but clothing & body may be contaminated with anthrax spores • Effective decontamination with simple soap & water • Waste water treated with bleach • Boil articles with disinfectants, chlorine or burn in a contained area • Early antibiotic treatment with fluoroquinolones, doxycycline, erythromycin, vancomycin or penicillin • Anyone working with anthrax in a suspected or confirmed victim should wear a HEPA or P100 filter mask

24. Treatment & Prevention • If death occurs, quarantine body • Burial does not kill anthrax spores • The most effective form of prevention is vaccination but must be done well in advance of exposure, & 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

25. BioThrax Vaccine from non-virulent strain of bacterium, is “BioThrax” or “Anthrax Vaccine Adsorbed” (AVA) Administered in a six-dose series at 0,2,4 weeks & 6,12,18 months Annual boosters to maintain immunity Painful, & causes significant swelling Soviets developed a live spore vaccine, known as STI, whose serious side effects restrict use to healthy adults Anthrax Hemorrhagic Meningitis

26. 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 hrs if limited dermal exposure • Single location (building, city, stadium) • Large number of rapidly fatal cases • Respiratory Exposure: death in <15 minutes • Skin absorption: death in 1 to 2 minutes • Uncommon illness with bioterrorism potential • “Sentinel Patients”, i.e. inhalational anthrax

27. HPI • Often first history is only history available if rapidly decompensates • History of exposure to a nerve agent may be absent • Always suspect diagnosis when multiple patients present with symptoms of cholinergic excess • Occupational history aid in making diagnosis in accidental releases • Farmers, military, laboratory workers • Unfortunately…1st patient is often “Patient 0” ~ what does that mean for EMS, ED & Hospital staff?

28. Physical Exam & DDX • Signs & symptoms related to unopposed stimulation at cholinergic, GABA & NMDA receptors • Diagnosis easier in severely symptomatic patient • Pathognomonic: • Miosis, copious secretions, & generalized fasciculations in a gasping, cyanotic, seizing patient • DDX: • Epilepsy • Gastroenteritis • Heat-Related Illness • Stroke / Head Trauma • Drug overdose

29. Laboratory Studies: RBC Cholinesterase Levels • Labs don’t help acute treatment; treat on clinical suspicion • Never withhold treatment while awaiting results • RBC & plasma cholinesterase (“pseudocholinesterase”) activity can be assayed in blood & is a sensitive indicator of nerve agent toxicity • Clinical symptoms correlate with 20-25% reduction enzyme activity • Tissue cholinesterase activity cannot be directly measured • Rising enzyme levels indicate no further absorption • RBC cholinesterase replaced fully every 120 days

30. 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

31. 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

32. Imaging: CXR • Any respiratory distress, dyspnea, or post intubation to evaluate for non-cardiogenic pulmonary edema ARDS Post Neurotoxin Inhalation

33. Initial Management • Rapid termination of exposure, treat life-threatening emergencies, administration of antidotes • Safety of patients, EMS, rescuers & hospital workers depends on early exposure recognition • Highest level of PPE initiallu required: • Level A: Fully encapsulated, chemical-resistant, vapor-protective suit with SCBA & full face shielding, & butyl rubber gloves • ABCs • O2, co-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), atropine

34. Decontamination • In a normal MCI, priorities are stabilize then decontaminate; In a neurotoxin release: decontaminate then stabilize • Goal: prevent further absorption of agents & prevent spread • 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

35. Basic Decontamination Plan Shower & Rinse Drying Area Clean Clothing Cut & Strip Holding Area

37. Hospital Decontamination • Although prior to EMS transport from a scene, patients undergo initial decontamination, hospital staff must be trained in self-protection, triage, treatment, & decontamination • In an MCI, patients often self-transport without EMS treatment • In the Tokyo subway sarin attack, 85% of patients arrived via private car • This emphasizes the importance of hospital decontamination facilities & training as many victims likely to require initial triage & decontamination at the ED

38. ED & Hospital Treatment: ABCs • All personnel must wear PPE until decontamination assured or need for decontamination is eliminated • Any symptomatic patient: O2, pulse ox, cardiac monitor, & IV • Early ETI & ventilatory support paramount if severe toxicity • Avoid succinylcholine: metabolized by plasma cholinesterase leading to markedly prolonged paralysis • Suction is important as secretions may be profuse • Consults with neurology, toxicology, IM, psychiatry, surgery & critical care • In an MCI, activate the hospital emergency plan (i.e. DisasterNet) • Regional poison center (1-800-222-1222)

39. NIMS, EOP, SNS Federal, State & Local Responses • Rapid delivery of critical medical assets to emergency site • Coordinates agencies if terrorist attack or natural disaster • SNS enacted by the CDC as a national repository of: • ABX, antidotes, antitoxins, life-support meds, IV / airway supplies, & other med-surg items • “12-hour Push Package” arrives <12 hours after federal decision to deploy • 2nd phase arrives 24–36 hrs

40. Initial Patient Care • Detailed health histories important as potential patients & families may not be aware of initial exposure • The key to recognizing neurotoxin exposure is appearance of multiple patients with similar signs and symptoms • The route of exposure & 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

41. Treatment if Completely Asymptomatic • Patients who may have been exposed but asymptomatic • 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: 1 hour • Liquids: 18-24 hours

42. Inpatient Care • Patients in respiratory distress need ventilatory assistance despite aggressive antidotal therapy • If critically ill with complications such as anoxic brain injury (prolonged seizures or respiratory arrest), require prolonged intensive care • Follow RBC cholinesterase and electrolyte levels • Management of secondary medical or surgical emergencies • Cardiac Arrests • COPD Exacerbations • Blast Injuries

43. Chronic Neurological & Neuropsychological Effects • May persist for months if severe cholinergic effects • If discharged without complications or minimal exposure, 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): • 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

44. 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

45. 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

46. Antidotes Atropine Pralidoxime Chloride (2 PAM)

47. 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, & monitoring of vital signs, electrolyte levels, & cardiac rhythm are essential • Symptoms often improve after antidote administration, though duration of symptoms depends on route & degree of exposure to the nerve agent

48. Antidotes Two-Tiered Mechanisms of Action • Atropine (Anticholinergic): • Counteracts muscarinic effects resulting from excess ACh in 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 deactivates ACh • Restores normal skeletal muscle function (including diaphragm) • Adverse effects: malignant HTN, tachycardia, diplopia, N/V & dizziness

49. 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

50. Temporarily binds to AChE theoretically blocking binding of nerve agents to AChE Effective: GA, GD, GF Ineffective: GB, VX Orally available cholinesterase inhibitor only effective in preventing peripheral effects Ionized form does not pass into CNS 50% Gulf War military taking chemoprophylaxis experienced flatus, diarrhea, & abdominal cramping 5-30% had urinary frequency & urgency, headaches, rhinorrhea, diaphoresis, & / or paresthesias Pyridostigmine (Mestinon, Regonol) Chemoprophylaxis