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 reflexes 2 year-old old with fussiness/diarrhea progressing to impaired consciousness, hypotonia
Joshua Rotenberg MD MMS, Pediatric Neurology

Nerve Agents in Children

Josh Rotenberg MD MMS
Fellow, Pediatric Neurology Staff Pediatrician, WRAMC & NNMC Assistant Professor of Pediatrics, USUHS

Joshua Rotenberg MD MMS, Pediatric Neurology

Nerve Agents in Children

Background: Scope of the Problem Background: The agents Diagnosis Isolation/Decon Treatment Pediatric Issues

Joshua Rotenberg MD MMS, Pediatric Neurology

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
Joshua Rotenberg MD MMS, Pediatric Neurology

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)

Joshua Rotenberg MD MMS, Pediatric Neurology

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 tons Gulf-War: large, urban civil popualation threatened for first time since WW1
Joshua Rotenberg MD MMS, Pediatric Neurology

Sarin Attacks in Japan

Matsumoto Japan, June 1994
7 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%
Joshua Rotenberg MD MMS, Pediatric Neurology

Background: The agents

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

Joshua Rotenberg MD MMS, Pediatric Neurology

Background: The agents

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 attacks VX only exists in military stockpiles
Joshua Rotenberg MD MMS, Pediatric Neurology

Background: The agents

Exist as a liquid or a gas Liquid is colorless (g-type) ambercolored (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 MD MMS, Pediatric Joshua Rotenberg
Neurology

Background: The agents

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

Joshua Rotenberg MD MMS, Pediatric Neurology

Joshua Rotenberg MD MMS, Pediatric Neurology

When would you launch a sarin attack?

Joshua Rotenberg MD MMS, Pediatric Neurology

How do nerve agents work?

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

Joshua Rotenberg MD MMS, Pediatric Neurology

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 m tend to remain in the upper respiratory tract < than 1 m 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 Rotenberg MD MMS, Pediatric Joshua
Neurology

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.
Joshua Rotenberg MD MMS, Pediatric Neurology

Neuromuscular Effects
Twitching Weakness Paralysis Respiratory failure

Joshua Rotenberg MD MMS, Pediatric Neurology

Autonomic Nervous System Effects

Reduced Vision Small pupil size Drooling Sweating Diarrhea Nausea

Abdominal pain
Vomiting
Joshua Rotenberg MD MMS, Pediatric Neurology

Eyes -- Miosis
most common finding Matsumoto - 134/219 -2.5 mm or less
improved with atropine Resolved in a month

Impaired acuity in 124/219 Blurry vision

Visual Darkness Ocular pain

Joshua Rotenberg MD MMS, Pediatric Neurology

Central Nervous System Effects

Headache Convulsions Coma Respiratory arrest Confusion Slurred speech

Depression
Respiratory depression
Joshua Rotenberg MD MMS, Pediatric Neurology

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,
Joshua Rotenberg MD MMS, Pediatric Neurology

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.
Joshua Rotenberg MD MMS, Pediatric Neurology

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.
Joshua Rotenberg MD MMS, Pediatric Neurology

Other symptoms
Headache cough sore throat

Can persist for weeks

Joshua Rotenberg MD MMS, Pediatric Neurology

Differential Diagnosis
Sudden Mass casualties - no sign of trauma Suspect airborne toxin Hypoxemic, miosis, profuse secretions Anti -Cholinesterase agent Unconscious, non-hypoxemic Cyanide
venous blood gasses arterialized

Less acute causes of respiratory problems

Bo-tox - paralysis, absent reflexes ARDS like picture-anthrax,plague,phosgene
Joshua Rotenberg MD MMS, Pediatric Neurology

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 affected Tokyo: decreased in 74% of admiitted 4% have genetic low levels Have genetic high levels, lose 50%, still be nl One call to lab, 3 send outs-time is critical

Diagnosis:

Clinical presentation is likely to vary in children.

Joshua Rotenberg MD MMS, Pediatric Neurology

Joshua Rotenberg MD MMS, Pediatric Neurology

Isolation/Decon
Decontamination is necessary Dogma
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.
Joshua Rotenberg MD MMS, Pediatric Neurology

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

Tokyo: Most casualties arrive in POV First responders may also be early casualties 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
Joshua Rotenberg MD MMS, Pediatric Neurology

Rotate health care workers in hot zone

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.
Joshua Rotenberg MD MMS, Pediatric Neurology

Treatment
Atropine, respiratory support (secretion management) Antidotes must be given quickly
But may still be effective if given late, even in extremis

Joshua Rotenberg MD MMS, Pediatric Neurology

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

Pralidoxime 1 g over 5-10 min Fasciculations, Seizures treated with benzodiazepines IM not optimal but acceptable

Joshua Rotenberg MD MMS, Pediatric Neurology

Mark 1 - USA/USAF
Atropine - 2 mg (0.7 ml) 2 PAM Cl autoinjector dispenses 600 mg/2 ml

Joshua Rotenberg MD MMS, Pediatric Neurology

Prophylaxis
Pyridostigmine Military use only

Joshua Rotenberg MD MMS, Pediatric Neurology

Supportive therapy for CWA exposure include

Pulmonary treatment/toilet
supplementary oxygen bronchodilators

Fluids, elctrolytes, nutrition Hypothermia Eye care Attention to skin lesions, Treatment of complicating infections
Joshua Rotenberg MD MMS, Pediatric Neurology

Pediatric considerations/guidance
Antidotes - Dosages Organ System Specific Tokyo Subway, 1995
16 children 5 pregnant women

Matsumoto, 1994
age 3-89 mean 33 y.o.
Joshua Rotenberg MD MMS, Pediatric Neurology

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 mg Max dose - 0.5 mg child; 1 mg adolescent

Should we be liberal with atropine? ACLS dosing may not be sufficient

Joshua Rotenberg MD MMS, Pediatric Neurology

Atropine Poisoning in Israeli Children

n=268, 92% of pediatric ERs 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

Joshua Rotenberg MD MMS, Pediatric Neurology

Treatments: Pediatric Dosage

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 better
no data in kids
Joshua Rotenberg MD MMS, Pediatric Neurology

Treatments: Pediatric Dosage

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

Joshua Rotenberg MD MMS, Pediatric Neurology

Carbamate and Organophosphate poisoning in young children -- Pediatric Emerg Care, April 1999
age 2-8, Median 2.8

CNS

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
Joshua Rotenberg MD MMS, Pediatric Neurology

Pulmonary
Increased minute volume and vapor density increases dose of vapor to children Smaller airway will be more easily obstructed
bronchoconstriction and secretions

Joshua Rotenberg MD MMS, Pediatric Neurology

Dermatologic
Skin absorption of liquid may be significant consideration in infants. Large surface to volume ratio in children compared to adults Fat soluble agents (less than OPP) Breaks in skin may permit easier penetration of agent.
Incidence of atopy is approx 4%.
Joshua Rotenberg MD MMS, Pediatric Neurology

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

Joshua Rotenberg MD MMS, Pediatric Neurology

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

Joshua Rotenberg MD MMS, Pediatric Neurology

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

Joshua Rotenberg MD MMS, Pediatric Neurology

Developmental-Triage and care

Mild and early symptoms may be missed due to a childs 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? Joshua Rotenberg MD MMS, Pediatric
Neurology

Long-Term Effects:
CNS: Organophospate poisoning literature suggests chronic CNS (neurocognitive/cerebellar) and PNS impairment Carcinogenicity: Limited data in animals suggests no effect. One study suggests genotoxicity in human lymphocytes Reproductive Effects: Limited data in animals suggests no effect.
Tokyo - well babies
Joshua Rotenberg MD MMS, Pediatric Neurology

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

Joshua Rotenberg MD MMS, Pediatric Neurology

AAP Guidelines

Joshua Rotenberg MD MMS, Pediatric Neurology