chemical terrorism attacks - update on antidotes - handout

Adapted from Lawrence DT and Kirk MA, Chemical Terrorism Attacks: Update on Antidotes. Emerg Med Clin N Am 25 (2007) 567–595

Chemical Terrorism Attacks: Update on Antidotes

Nerve agents

Vapour exposures immediate symptoms (seconds to minutes)

Dermal exposures delayed (minutes to 18 hours)

Farooq Khan MDCM PGY3 FRCP-EM

McGill University November 14

th 2011


Mark-1 Kit

Atropine Mechanism Atropine acts at muscarinic cholinergic receptors as a competitive antagonist. It is used to counter

muscarinic effects, and administration will result in drying of secretions, alleviating bronchospasm, and reversing central

apnea. Given within the first 5 minutes, it can prevent organophosphate-induced seizures

Delivery autoinjector is more effective than IM injections using a conventional syringe, can go through clothing or

protective garments. Additional atropine doses should be administered IV once access is obtained

Dosing

Field treatment for severe poisoning is three autoinjectors or 6 mg initially with retreatment q 5-10 min

The initial intravenous dose should be 2 mg for adults or 0.02 mg/kg for children

Atropine doses should be repeated q 5 min until the therapeutic endpoint is reached (ie, until pulmonary

secretions are dried [reflected by improved oxygenation] and ease of breathing [or ease of ventilation])

Typical total dose required after nerve agent poisoning has ranged from 5 to 20 mg (up to 200mg in cases)

Precautions. Excessive doses of atropine can result in deleterious effects including delirium, agitation, and tachycardia

and hypertension. Atropine will likely not improve miosis or skeletal muscle paralysis; therefore, reversal of these effects

is not a therapeutic endpoint.

Benzodiazepines Indications

Any patient who has significant symptoms from nerve agent exposure to prevent seizure and neuronal damage

Infused rapidly to unresponsive patients who may have nonconvulsive seizures due to the onset of paralysis

Alleviate extreme anxiety


Dose/delivery

Diazepam 10 mg IM auto-injector in the field, Midazolam IM/IV in hospital

2-PAM Neither atropine nor benzodiazepines will alleviate symptoms affecting the nicotinic system.

Over time, nerve agents will form an irreversible covalent bond with AChE in a process termed aging.

Once aging occurs, the patient will not regain vital functions, such as muscle strength or respiratory drive, until

new enzyme is synthesized (may take weeks to months)

Oxime reactivates AChE if administered before aging

Indications. 2-PAM should be given to any patient exposed to an organophosphate nerve agent who is showing any

systemic toxicity. This is particularly true if there are fasciculations or weakness.

Dose/Delivery

Mark 1 auto-injector 600mg IM per dose for the field (max

3 injections). IV preferred in hospital.

Initial dose is 1- 2 g diluted in 100mL normal saline

and given over 15-30 min

Initial pediatric dose is 20 to 50 mg/kg up to 2 g

WHO recommendation >30mg/kg bolus then

>8mg/kg/hour infusion to maintain therapeutic levels

due to short t½ (90 min)

For severely poisoned patients: 2 g IM or slow IV

infusion over 15-30 minutes then 500mg/h infusion.

Precautions. Rapid delivery can cause laryngospasm,

rigidity, and self-limited hypertension responding to

phentolamine 5 mg IV

Pediatrics ↑minute ventilation/kg → ↑ risk with exposure

Small airways with bronchospasm and ↑secretions→ ↑rates of respiratory distress/failure

↑prone to seizures

The dose for atropine can be up to 0.05 - 0.1 mg/kg either IV/IO/IM. 40 kg can be administered an adult (2 mg) autoinjector 20 kg can receive a 1-mg autoinjector 10 kg can receive a 0.5-mg autoinjector

The dose for 2-PAM is 25 to 50 mg/kg, up to a total of 2 g. 12 kg will be able to tolerate the dose of one 600-mg 2-PAM autoinjector

Diazepam should be dosed at 0.05 to 0.3 mg/kg IV,

> 30 kg can receive an adult autoinjector Autoinjector needle is 1 inch, so choose site carefully

Stockpile antidotes if stocks run out, glycopyrrolate (no central effects), scopolamine (more potent central effects), diphenhydramine, and jimsonweed extract can be used as alternatives


Cyanide Found in smoke inhalation, industrial accidents, suicide attempts, criminal poisonings and can be potent chemical

weapon.

Primary toxic action is inducing cellular hypoxia through inhibition of cytochrome oxidase, blocking oxidative phosphorylation → shift from aerobic to anaerobic metabolism causes a depletion of cellular ATP and ↑lactic acid Effects depend on dose/route/timing

o CNS and cardiac toxicity because these are the most O2-sensitive systems

o Concentrated exposure→ death within minutes (i.e. no time for medical intervention)

o Lesser exposure→ nonspecific symptoms including shortness of breath, hyperventilation, headache,

weakness, and dizziness, which can be attributed to anxiety or other exposures

o Progression to confusion, lethargy, seizures, and coma.

o Neurally mediated tachypnea along with an initial ↑BP

o Can progress to cardiac arrest heralded by bradycardia and hypotension

o Cherry red color and ↑O2 Sat

Cyanide antidote kit

Amyl nitrite, sodium nitrite, and sodium thiosulfate


Mechanism

o Nitrites (amyl and sodium) induce methemoglobinemia

o Cyanide has a ↑affinity for methemoglobin and will leave the mitochondria to bind to it and allow the

mitochondria to resume oxidatitive phosphorylation.

o Sodium thiosulfate acts as a sulfhydryl donor for the enzyme for the enzyme rhodanese that converts cyanide to

the less-toxic renally excreted thiocyanate

Indications to initiate therapy

High index of suspicion

o clusters of patients, structural fire victim, high risk activity (e.g. jeweller, lab worker)

Clinical presentations

o sudden LOC, seizures, HD instability without probable cause

Surrogate markers

o lactate, metabolic acidoses, narrow arteriovenous O2 Sat gap

Dose/delivery

Crush amyl nitrite glass pearls and inhale or administer via BMV until IV line (goal to induce 3-5% MetHb)

Then switch to sodium nitrite IV 300mg (10ml of 3% sol’n) over 2-4min,

Peds: 10mg/kg with normal Hb, 6mg/kg in anemic or unknown Hb child

Sodium thiosulfate 12.5g IV (50ml of 25% sol’n) over 10 min, peds 1.65ml/kg of 25% sol’n

Give with high-level O2 , charcoal for oral exposures

Precautions

Vasodilation, tachycardia, hypotension with high doses of nitrite

↓ O2 carrying capacity with MetHb, avoid in anemic, CO poisoned

Thiosulfate can cause hemolysis in G6PD deficiency

Thiocyanate can be toxic in renal failure (abdo pain, rash, vomiting, CNS dysfunction)

Hydroxycobalamin Combines with CN to cyanocobalamin a.k.a. Vitamin B12 (safe and renally excreted)

Low threshold of administration given safety profile

Dose

o 70mg/kg, max 5g(adult dose) IV over 15 min

o Each vial of 250ml contains 2.5g, which needs to be diluted in 100ml of NS to bind 250mg of CN

o Repeat dosing in severe toxicity

Combine with sodium thiosulfate but either sequentially or in a different line (inactivated if in the same line)

scavenges NO and prevents hypotension

transient red discoloration of skin and mucus membranes, interferes with lab assays of bili, creat, mg, fe

otherwise safe and preferred over nitrites

Mass exposure Most patients will not have significant exposures

Patients presenting in cardiac arrest will have low survival

Reserve antidotes for those most likely to survive

Can use thiosulfate alone


Botulism Clostridial toxins A, B, E, and F

Highly potent (LD 50 of 1μg/kg)

Food water (onset 2h-5 days), aerosolized (onset 3 days), injection

Prevents fusion of synaptic vesicles with presynaptic membrane in PNS (cannot cross BBB) prevents

neurotransmission

Descending weakness, EOMs and bulbar cranial nerves (diplopia/dysarthria/dysphagia) then motor function of

UE then LE. Can affect intercostals and diaphragm needing mechanical ventilation. Spared sensory and

mentation.

Anti-muscarinic effects and nausea vomiting precede neurologic symptoms

Paralysis is irreversible until cleaved protein is regenerated which can last months

Antitoxin

halts progression of paralysis

binds and neutralizes free botulinum toxin

indicated on clinical suspicion (clusters of patients with similar geography etc)

dose 1 vial of Ig IV over 30-60 min diluted 1:10 in NS

1% allergic reaction to horse serum based Ig

Baby-BIG is human derived and recommended in infants

Thallium Less well known toxic heavy metal odourless and colorless dissolved in water (used in myocardial scintigraphy)

Minimum lethal dose of 12mg/kg

Absorbed from GI tract, causes green discoloration of urine in 1h

Unclear if Interferes with Krebs cycle, glycolysis, and oxidative phosphorylation, or forms stable complexes with

the active sulfhydryl sites on enzymes

Nonspecific symptoms (early GI, mostly neuro)

Reliable early clue for thallium toxicity is an ascending, rapidly progressive painful sensory peripheral

neuropathy (feet)

Delayed alopecia (weeks)

Prussian Blue Enhances elimination by blocking enteroenteric and enterohepatic recirculation of thallium

Indicated for any patient with toxicity or known exposure

150-250 mg/kg/day divided tid until urinary thallium excretion is <0.5mg/day

No side effects except blue tears and constipation (Dissolve in 50ml of 15% mannitol as cathartic)

Can use activated charcoal as alternative if in low supply of Prussian blue


Radiation

Potassium iodide (KI)

Prevents thyroid cancer in patients exposed to radioactive iodine

Subtotal protection

Must be administered within hours

Indications

o Children, pregnant or lactating women with >0.05 Gy exposure

o Adults over 40 with dose >5 Gy

Dose

o Newborn – 1 month: 16 mg po qd

o Infants and children <3 : 32 mg po qd

o Children 3-18: 65 mg po qd

o Adults: 130 mg po qd

Prussian blue For cesium-137 (used in radiotherapy and medical devices, could be used in dirty bomb), behaves like

potassium. Physiological t½ of 50-150 days, renally excreted in 4:1 ratio with fecal excretion

↓urine/feces excretion ratio to 1:4 and ↓t ½ by 43%

Dose 3-10g/day

FDA recommendation : 3g bid for adults, 1g tid for children 2-12 ×30days

Mostly non toxic and not absorbed, although not studied in ARS GI syndrome where there is severe

inflammation of mucosa.

chemical terrorism attacks - update on antidotes - handout

Health & Medicine