Background

Nerve agents, or acetylcholinesterase inhibitors, are some of the most lethal substances ever to be weaponized. These agents exist in multiple forms from thick viscous liquids to highly dissolvable gases. They are chemically similar to organophosphates used for pesticides, and the syndromes they cause are much more common in farming communities than they are on the battlefield. The most lethal forms only require 1/1000th of an ounce to obtain a lethal dose in 50% of exposed population (LD50).

Nerve agents consist of mainly two classes, V agents and G agents. V agents are viscous in nature and can be spread in numerous ways. They are extremely dangerous if touched or ingested but can also pose a vapor hazard in close proximity. G agents are liquids at room temperature and are extremely effective as chemical weapons due to the ability to quickly expose a large number of people to lethal inhaled doses by vapor exposure.

Physiologically, these agents bind to acetylcholinesterase, thus inhibiting breakdown of acetylcholine. The two main types of cholinergic receptors where nerve agents interact are muscarinic and nicotinic. Muscarinic receptors are located in the smooth muscles and the glands. Symptoms caused by over-stimulation of muscarinic receptors can be recalled using the DUMBBELS mnemonic (Diarrhea, Urination, Miosis, Bronchorrhea/Bronchoconstriction, Bradycardia, Emesis, Lacrimation, Salivation). These symptoms can be countered by atropine (discussed later in the treatment section). Nicotinic receptors located in skeletal muscle and nerve ganglia are also affected by nerve agents. Symptoms caused by over-stimulation of nicotinic receptors can be remembered by using the first letter of the days of the week as a memory assist (Mydriasis, Tachycardia, Weakness, Hypertension, Fasciculations).  Administration of pralidoxime (2PAM) restores cholinesterase activity which typically results in improvement of the nicotinic symptoms.

Signs and Symptoms

Nerve agent poisoning can range from mild to severe; a severe exposure may quickly lead to death if not reversed. Rapid antidote treatment is extremely important since some nerve agents can irreversibly bind to acetylcholinesterase (for example, the half-life for irreversible binding, termed aging half-life, for soman/GD is two minutes).

For mildly affected individuals not wearing eye protection, miosis is commonly seen.  Other obvious muscarinic effects include severe lacrimation and profuse sweating, followed by nausea and vomiting, along with dyspnea and shortness of breath due to bronchorrhea and bronchoconstriction. More severely affected patients will have all of these signs and symptoms as well as profound weakness, fasciculations, seizures, loss of consciousness, apnea and death.

The speed of symptom onset depends on the route of exposure and dose of the agent. Inhalational exposure tends to result in faster onset of symptoms and can quickly cause death due to rapid systemic distribution. Dermal exposures, such as exposures with V agents, can cause delayed onset of symptoms.

Decontamination

As with most chemicals, removing the exposed patient from the contaminated area to prevent further exposure and damage is the most important step. In vapor exposures, this means removing the casualty from the area and quickly removing any article of clothing or piece of equipment with possible agent contamination.

Reactive skin decontamination lotion (RSDL) is largely accepted as the most effective decontaminate for nerve agent dermal exposure. Covering all exposed skin with RSDL as quickly as possible can be a life-saving measure. If RSDL is not available, 0.5% hypochlorite solution or soap and water are alternatives.  Decontamination should not be delayed if RSDL is not available.  For casualties exhibiting moderate to severe symptoms (respiratory distress, seizures, altered consciousness), antidotes should be administered immediately while initiating decontamination.

Nerve Agent Diagnostics

Diagnosis of nerve agent exposure is based on rapid identification of the clinical symptoms and identification of the agent through detection methods. Laboratory measurement of serum acetylcholinesterase levels is not useful for nerve agent exposure since the value does not correlate with signs and symptoms or prognosis. There is no utility in baseline ACHE levels due to intra-individual variability.

Nerve Agent Treatment

Nerve agent antidotes include 2PAM, atropine, and benzodiazepines. Autoinjectors to treat nerve agent toxicity are available as Autoinjector Nerve Agent Antidote (ATNAA) which contains atropine and 2PAM, and Convulsant Antidote Nerve Agent (CANA) which contains the benzodiazepine diazepam.

2PAM

Pralidoxime (ATNAA autoinjector or IV/IO) reverses the bond between the acetylcholinesterase and the nerve agent and thus prevents irreversible binding to acetylcholinesterase, termed aging.  2PAM is available both in autoinjector form as well as in an IV form. 2PAM is known to work synergistically with atropine (some 30x greater).  The are other oximes with varying effects depending on the agent, but pralidoxime is the available agent in DoD inventory.

Atropine

Atropine (ATNAA autoinjector or IV/IO) is used to treat the muscarinic effects. Atropine will help dry secretions (bronchorrhea) and counter the effects of the bronchoconstriction caused by the nerve agent. The amount of nerve agent and the degree of symptoms a patient is experiencing will determine the amount of atropine required to control symptoms. Large doses of atropine may be required to counter the effects of some nerve agent exposures, in particular organophosphates. Tachycardia is NOT a contraindication for atropine administration, as tachycardia may be secondary to respiratory distress.  Therefore, atropine treatment should be titrated to achieve reversal of life-threatening bronchorrhea and bronchoconstriction even in the setting of tachycardia.

Benzodiazepines

Benzodiazepines, such as diazepam (CANA) or midazolam are the mainstay of seizure treatment. Benzodiazepines may also help counter nicotinic effects, particularly muscle fasciculations. Current literature recognizes midazolam as the most effective seizure reversal agent, based on animal studies.  Midazolam has the fastest bioavailability when given intramuscularly (IM).  Diazepam is the benzodiazepine in autoinjectors and is efficacious, but it is entirely appropriate to use another benzodiazepine when IV access has been established or when autoinjectors have been depleted. 

Nerve agent antidotes may be dosed based on the severity of symptoms. However, in a field environment when the amount and type of nerve agent exposure are unknown, give 3 ATNAAs and 1 CANA for any symptomatic patient (other than isolated miosis) with suspected nerve agent exposure. If symptoms persist beyond this treatment, consider an atropine drip (see atropine/scopolamine protocol in Appendix A). For severe poisoning, additional 2PAM can be given after delivering 3 ATNAAs. There is a paucity of literature to guide dosing but current subject matter expert consensus is to dose an additional 500mg IV/IO over 5 minutes and then an infusion of 10mg/kg/hr until clinical improvement is stable which may require infusion for more than 24 hours. (See Appendix B.)

Prophylaxis

The planning considerations and the risk:benefit analysis in the decision to use pyridostigmine bromide (PB) prophylaxis is outside the scope of this CPG.  However, it is important for providers to understand the clinical effects experienced by those on pyridostigmine prophylaxis and how pre-treatment can affect clinical presentation and response to treatment. Pyridostigmine (30mg tablet) is approved by the FDA for use as a pretreatment to exposure to soman, based on efficacy in reducing soman lethality when used in conjunction with 2PAM and atropine treatment in animals. (See FDA Pyridostigmine Bromide Package Insert.)¹⁸ There are no human studies.

Pyridostigmine acts by inhibiting a portion (20-40%) of peripheral acetylcholinesterase.  It does not readily cross the blood brain barrier so it does not cause central inhibition.  Thus side effects of pyridostigmine prophylaxis are typically mild cholinergic or nicotinic symptoms (diarrhea, abdominal pain, and dysmenorrhea were the most common side effects in volunteers). Pyridostigmine and mefloquine (for malaria prophylaxis) taken together may have an additive effect on the gastrointestinal tract with increased diarrhea.  Opioid-associated bradycardia may be worsened when pyridostigmine is combined with opioids. Pyridostigmine may enhance the activity of depolarizing neuromuscular blocking agents (succinylcholine) but may require a higher dose of non-depolarizing neuromuscular blockers. Treatment for nerve agent toxicity is the same for patients on pyridostigmine prophylaxis.