Nerve Agents

Joshua Rotenberg MD MMS, Pediatric Joshua Rotenberg MD MMS, Pediatric NeurologyNeurology

3 ER Cases

Which patient has nerve agent poisoning? 9 year-old with miosis, agitation, copious secretions, uncontrolled urination. HR 120. RR 16/shallow. Sat 83%15 year-old with generalized seizure, tongue fasciculations, absent gag, absent reflexes2 year-old old with fussiness/diarrhea progressing to impaired consciousness, hypotonia


Nerve Agents in Children

Josh Rotenberg MD MMSFellow, Pediatric Neurology

Staff Pediatrician, WRAMC & NNMCAssistant Professor of Pediatrics, USUHS


Nerve Agents in Children

Background: Scope of the ProblemBackground: The agentsDiagnosisIsolation/DeconTreatmentPediatric Issues


Background: Scope of the Problem

CWA in US– the most important act of terrorism in which

CWA was attempted to use a was the World Trade Center bombing in 1993.

the explosive used by the terrorists contained sufficient cyanide to contaminate the entire structure. Fortunately, the cyanide was destroyed by the blast


Background: Scope of the Problem

Police foil terror plot to use sarin gas in London (Filed: 18/02/2001)

Bin Laden British cell planned gas attack on European Parliament (Filed: 16/09/2001)


Background: Scope of the

Problem

Iran-Iraq war (1984-1988) – UN confirmed that Iraq used Tabun and other

organophosphorous nerve agents

Sarin and Sulphur mustard used on Kurds in Northern Iraq

Iraq has weaponized VX - 4 tonsGulf-War: large, urban civil popualation threatened for first time since WW1


Sarin Attacks in Japan

Matsumoto Japan, June 19947 died, 58 admitted, 600 injured

Tokyo Subway March 1995

Sarin released at several points in the Tokyo subway

11 killed, 5,500 injured

secondary contamination of the house staff in more than 20%


Background: The agents

Nerve agents include:–Tabun (GA)–Sarin (GB)–Soman (GD), and –VX



Originally developed as insectisides more powerful than organophosphates

Tabun is easiest and cheapest to manufacture. – Described as a starter agent for CW

program. Some consider most likey to be used as terrorist agent.

Sarin has been used in terrorist attacksVX “only exists in military stockpiles”



Exist as a liquid or a gasLiquid is colorless (g-type) amber-colored (VX)Gas can be odorless, fruity (tabun) or slight camphor odor (soman) Vary in volatility – some more persistent than others– Sarin as volatile as water– VX very persistent



Toxic effects depend on the concentration of the agent inhaled and the time exposed to the agent.– LD50 - 100 mg/m3 for 1 minute is

equivalent to 50 mg/m3 for 2 minutes

Note the vapor density– Sarin 4.86– VX 9.2



When would you launch a sarin attack?


How do nerve agents work?

Irreversible phosphorylation of cholinesterase enzymes at acetycholine receptors– Nicotinic– Muscarinic– CNS– Adrenal


Nerve Agents-Mucosal Absorption

Nature and onset of signs and symptoms vary by route of absorption. – Gases may be absorbed through any part of the

respiratory tract: mucosa of the nose and mouth to the alveoli of the lungs.

Aerosol particles – > than 5 µm tend to remain in the upper respiratory tract– < than 1 µm tend to be breathed in and out again,

although some of these smaller particles may be retained.

They may also be directly absorbed by the eye/skin/GI tract


Nerve Agents - Absorption via Skin

Agents which penetrate the skin may form temporary reservoirs so that delayed absorption may occur (less so, that OPP). Even the vapor of some agents can penetrate the intact skin and intoxication may follow. Wounds/abrasions (even minor injuries caused by shaving ) present areas which are more permeable than intact skin. The penetration of agents through the GI tract or abrasions may not neccessarily be accompanied by irritation or damage to the surfaces concerned.


Neuromuscular Effects

Twitching Weakness Paralysis Respiratory failure


Autonomic Nervous System Effects

– Reduced Vision

– Small pupil size

– Drooling

– Sweating

– Diarrhea

– Nausea

– Abdominal pain

– Vomiting


Eyes -- Miosis

most common findingMatsumoto - 134/219 -2.5 mm or less

improved with atropineResolved in a month

– Impaired acuity in 124/219– Blurry vision

Visual DarknessOcular pain


Central Nervous System Effects

– Headache

– Convulsions

– Coma

– Respiratory arrest

– Confusion

– Slurred speech

– Depression

– Respiratory depression


Delayed (Chronic) CNS Effects

Giddiness, anxiety, jitteriness, restlessness, emotional lability, excessive dreaming, insomnia, nightmares, headaches, tremor, withdrawal and depression, drowsiness difficulty concentrating, slowness on recall, confusion, slurred speech, ataxia. bursts of slow waves of elevated voltage in EEG, especially on hyperventilation,


Cause of death In the absence of treatment– anoxia resulting from airway obstruction,

weakness of the muscles of respiration and central depression of respiration.

Airway obstruction – due to pharyngeal muscular collapse, – upper airway and bronchial secretions, – bronchial constriction and – occasionally laryngospasm and paralysis of the

respiratory muscles.


Cause of death

With adequate pulmonary support/toilet and atropine, the individual may survive several lethal doses of a nerve agent. However, if the exposure has been many times the lethal dose, death may occur despite treatment as a result of respiratory arrest and cardiac arrhythmia. When overwhelming doses of the agent are absorbed quickly, death occurs rapidly without orderly progression of symptoms.


Other symptoms

Headachecough sore throat

Can persist for weeks


Differential Diagnosis

Sudden Mass casualties - no sign of trauma Suspect airborne toxin

Hypoxemic, miosis, profuse secretions Anti -Cholinesterase agentUnconscious, non-hypoxemic Cyanide– venous blood gasses arterialized

Less acute causes of respiratory problems Bo-tox - paralysis, absent reflexes ARDS like picture-anthrax,plague,phosgene


Diagnosis: Treatment: institute rapidly based on clinical judgment Can measure RBC levels of acetycholinesterase– Assess treatment and recovery.

– Insensitive as a screen Matsumoto: ChE decreased in 43% of severely affectedTokyo: decreased in 74% of admiitted4% have genetic low levelsHave genetic high levels, lose 50%, still be nlOne call to lab, 3 send outs-time is critical

Clinical presentation is likely to vary in children.



Isolation/Decon

Decontamination is necessaryDogma– 0.05% bleach- people– 0.5% household bleach - equipment

Truth: Use what is available– Good results can be obtained with such

widely differing means as talcum powder, flour, soap and water, or special decontaminants.


Isolation/DeconIsolation and Decon are necessary in the field– Hot, Warm, Cold Zone - Triage in hot and cold zones

– Tokyo: Most casualties arrive in POVFirst responders may also be early casualties– Rotate health care workers in “hot zone”

23 % health care workers had some sort of physical disorder, though mild. – symptoms included ocular pain, headache, sore

throat, dyspnea, nausea, dizziness, and nose pain

– none was seriously affected


Triage: Tokyo Subway, St. Lukes

Mild severity– miosis, rhinorrhea, and mild headache

Moderate severity – victims were immobile or complained of

moderate degree dyspnea, vomiting, severe headache or with neurologic complication like fasciculation

Critical severity – victims had cardiac or respiratory arrest.


Treatment

Atropine, respiratory support (secretion management)Antidotes must be given quickly– But may still be effective if given late,

even in extremis


Treatment

Atropine-give liberally to dry secretions– average total dose in adult 50 mg

Pralidoxime 1 g over 5-10 minFasciculations, Seizures treated with benzodiazepinesIM not optimal but acceptable


Mark 1 - USA/USAF

Atropine - 2 mg (0.7 ml)2 PAM Cl autoinjector dispenses 600 mg/2 ml


Prophylaxis

PyridostigmineMilitary use only


Supportive therapy for CWA exposure include

Pulmonary treatment/toilet– supplementary oxygen – bronchodilators

Fluids, elctrolytes, nutritionHypothermiaEye care Attention to skin lesions, Treatment of complicating infections


Pediatric considerations/guidanceAntidotes - DosagesOrgan System SpecificTokyo Subway, 1995– 16 children– 5 pregnant women

Matsumoto, 1994– age 3-89

– mean 33 y.o.


Treatments: Pediatric Dosage

Atropine - ACLS protocol – 0.02 to 0.05 mg/kg to a maximum of 2 mg.

May repeat q 10 minutes to reverse cholinergic symptoms.

Min dose – 0.1 mgMax dose - 0.5 mg child; 1 mg adolescent

Should we be liberalwith atropine?

ACLS dosing may not be sufficient


Atropine Poisoning in Israeli Children

– n=268, 92% of pediatric ER’s– Most cases accidental; 7.5% intentional

by parents expecting exposure– doses of 0.01 to 0.17 mg/kg– no fatalities,seizures– 0.045 to 0.17 mg/kg - mild effects



Pralidoxime (US) 2-PAM, Protopam– 20-50 mg/kg x 1 im/iv/sc. May repeat in 1

hour to relieve muscle weakness (nicotinic)

– Watch for muscle rigidity, laryngospasm, tachycardia

– n.b. others used in Europe and Israel– Some studies suggest continuous infusion

may be betterno data in kids



Diazepam – For severe seizures/status epilepticus30d to 5 y – 0.05 to 0.3 mg/kg IV to a max of 5mg/dose. May repeat q15-30 minutes5 y.o. – 0.05 to 0.3 mg/kg IV to a max of 10 mg/dose.


CNSCarbamate and Organophosphate poisoning in young children -- Pediatric Emerg Care, April 1999

– age 2-8, Median 2.8

Stupor/Coma 100%Hypotonia 100%Miosis 56%Diarrhea,, Bradycardia, Salivation 25-37%Pulmonary edema 37%

Predominance of CNS findings in children?– Immaturity of blood brain vs. developmental effect

on CNS cholinesterase


Pulmonary

Increased minute volume and vapor density increases dose of vapor to childrenSmaller airway will be more easily obstructed– bronchoconstriction and secretions


Dermatologic

Skin absorption of liquid may be significant consideration in infants. Large surface to volume ratio in children compared to adultsFat soluble agents (less than OPP)Breaks in skin may permit easier penetration of agent. – Incidence of atopy is approx 4%.


Dermatologic

Decontamination - Bleach is a mild to moderate mucosal irritant. 0.5% bleach may cause contact dermatittisIn children can present like “prickly heat”, erythema, edema, blistering.


Environmental Exposure/ Temperature Regulation:

Hypothermia - Patients will be fully disrobed before decontamination– cold water/bleach solution.

Adequate cover, clothing, diapers should be available for parents and children.Watch for delayed effects with warming


Feeding

No information is available regarding breast feeding. – However, nerve agents are less lipid

soluble than OPP.

Breast feeding mothers should be encouraged to pump and discard.– Until when? No research done

Institutions should be ready to support infant feedings


Developmental-Triage and care

Mild and early symptoms may be missed due to a child’s inability to communicate symptoms of pain and pressure. Alternatively, a physician might dismiss signs symptoms such as sleepiness, hypotonia, cramps, rhinnorhea as typical of other childhood illnesses and behavior.What will we do with the mother/infant pairs in decon?Unescorted children?


Long-Term Effects:

CNS: Organophospate poisoning literature suggests chronic CNS (neurocognitive/cerebellar) and PNS impairmentCarcinogenicity: Limited data in animals suggests no effect. One study suggests genotoxicity in human lymphocytesReproductive Effects: Limited data in animals suggests no effect. – Tokyo - well babies


Take Home Goodies

Mass cas + no trauma=Inhalant

Presentation varies with: agent, state, absorption, temperature

Autonomic, CNS, muscular symptoms

Start treatment based on suspicion– atropine, respiratory support– Consider diazepam, pralidoxime

Pediatric Issues: acute and chronic


AAP Guidelines

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Nerve Agents

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