Chemical Terrorism Update: Nerve Agents

The author describes how the organophosphates commonly known as nerve gas induce cholinergic crisis and what must be done to rescue and treat victims.

By Coleman O. Martin, MD

Dr. Martin is a faculty member in the department of neurology at the University of Iowa Hospitals and Clinics in Iowa City.

 

An understanding of the enzyme acetylcholine esterase (AChE) has led to the development of drugs for the treatment of myasthenia gravis and Alzheimer's disease. Regrettably, exploitation of this enzyme in a very different direction has also occurred. In 1936, German chemists recognized that minute amounts of certain organophosphate molecules could induce a cholinergic crisis. This spurred development of these molecules for use as chemical weapons. More recently, Iraq used the nerve agents tabun and sarin on Iranian troops in the 1980s, and the Japanese cult Aum Shinrikyo used sarin in the Tokyo subway attack of 1995.

This article will review the physical characteristics of the most common nerve agents, the pathophysiology of these toxins, and the treatment of organophosphate toxicity and its long-term sequelae.
 

What are the organophosphate poisons?

Organophosphates are well established as agricultural insecticides. Malathion, for example, is commercially available in the United States. Because it is inactivated slowly by insect metabolism, malathion's effect on humans is comparatively minimal. However, the organophosphates developed for military use are approximately 100,000 times more potent. While they are commonly referred to as nerve gas, "nerve agents" is the preferred term for these poisons, which are dispersed as aerosol and form vapor under normal atmospheric conditions.

The four nerve agents that have received the greatest military attention are tabun, sarin, and soman (among the so-called G agents), and VX. The two clinically significant characteristics that distinguish the nerve agents from one another are the primary mode of absorption and the pharmacokinetics involved in the interaction between the agents and AChE. The table on page 46 summarizes the properties of these four agents.
 

How are nerve agents absorbed?

Although all nerve agents penetrate clothing and skin, the high volatility of the G agents makes them primarily an inhalation hazard. These agents evaporate quickly and are considered nonpersistent in the environment. In contrast, VX persists in the environment for weeks. On initial release, VX is also an inhalation hazard. Moreover, because this agent penetrates skin more easily than the G agents, it is considered a contact hazard. Based on animal studies, rapid respiratory absorption of 1 mg of any of these agents is lethal to humans.
 

What does the term "aging" refer to?

When a nerve agent initially binds with AChE, the interaction is reversible; the undocking of the poison will restore normal function to the enzyme. With time, however, these agents lose an alkyl group, which changes the kinetics of the enzyme-poison complex, permanently deactivating the enzyme. This process, termed aging, occurs at different rates. Aging of the soman-enzyme complex is the fastest; it is 50% complete in as little as two minutes. VX and organophosphate insecticides age slowly over several days.
 

What are the clinical effects of the nerve agents?

The reduction of AChE activity leads to the accumulation of the excitatory neurotransmitter acetylcholine in both the peripheral nervous system and the central nervous system (CNS). Peripherally, stimulation of muscarinic receptors increases parasympathetic tone, which manifests clinically as fecal and urinary incontinence and increased secretions. In addition to the signs represented by the acronym SLUD (salivation, lacrimation, urination, and defecation), other signs that may occur include sweating, pupillary constriction, bradycardia, and increased bronchial secretions. Stimulation of nicotinic receptors at the neuromuscular junction causes muscle fiber depolarization and fasciculations. Prolonged nicotinic stimulation induces muscle weakness and paralysis. In terms of CNS effects, penetration of the blood-brain barrier by nerve agents produces a decreased level of consciousness, convulsions, and depressed respiratory drive.
 

What is the time course of intoxication?

The time course of nerve agent toxicity is largely determined by the mode of exposure and dose. The organ system first affected provides a clue to the mode of exposure. Initial symptoms of chest tightness and bronchial secretions suggest a respiratory exposure. At a high dose, this may progress within minutes to generalized weakness and CNS depression or seizures. Symptoms starting with localized fasciculations, on the other hand, suggest a dermal exposure. In such cases, a slower progression would be expected because it would take longer for the agent to be absorbed and distributed. However, one account in the literature describes two patients with dermal nerve agent exposure who, after immediate decontamination, appeared well for 20 minutes, then precipitously decompensated with a generalized cholinergic crisis.
 

What is the differential diagnosis in nerve agent exposure?

Nerve agent exposure presents a diagnostic challenge. Lacrimation, conjunctival injection, bronchial secretions, and bronchial constriction can result from exposure to many chemical irritants. Cyanogen chloride deserves special mention; besides being a powerful conjunctival and mucosal irritant, it can lead to a rapid CNS deterioration due to cyanide toxicity. The cholinergic signs of miosis and salivation differentiate nerve agent exposure from other chemical intoxications. Several drugs can induce a cholinergic crisis such as pyridostigmine and bethanechol, which are used for the treatment of myasthenia gravis and urinary retention, respectively.
 

What laboratory tests are useful in diagnosing and managing nerve agent intoxication?

Red blood cell AChE activity decreases after exposure to nerve agents. Unfortunately, this test is usually not quickly available. Tests that may aid in detecting organ system dysfunction include spirometry and arterial blood gas analysis to assess ventilation, continuous cardiac telemetry to detect arrhythmias, and electroencephalography in unresponsive patients to assess for nonconvulsive status epilepticus.
 

Is patient decontamination necessary?

Decontamination can limit further absorption of the agent and protect members of the health care team from becoming intoxicated. As with cyanide and radiologic exposures, decontamination should be performed in a HAZMAT room by medical personnel wearing protective clothing and breathing from a separate air supply. Removal of the patient's clothing is indicated because vapors may be trapped in layers of clothing. Clothing should be bagged, sealed, and retained as possible legal evidence. If there is any suspicion that the patient has come into contact with nerve agent droplets or liquid, skin decontamination is also advised. Skin and hair can be successfully decontaminated with a dilute solution of hypochlorite bleach or alkaline soap and water.
 

How are nerve agent intoxications treated?

Patients presenting with ocular symptoms or increased respiratory secretions without evidence of respiratory compromise, weakness, or CNS depression should be considered for decontamination. These patients should be monitored for several hours before being discharged.

More severe intoxications require close attention to respiratory, cardiac, and CNS status. Respiratory compromise can occur for any of the following reasons: the hypersecretory state induced by nerve agents, which can lead to mucus plugging of airways; bronchiolar constriction in response to parasympathetic hyperactivity; impaired respiratory effort because of diaphragmatic weakness; pharyngeal weakness, leading to aspiration; and CNS depression, which reduces respiratory drive. Because of these compounding problems, patients should be considered for intubation if they have diminished mental status, a vital capacity below 15 ml/kg, or a negative inspiratory force of less than 20 cm of water.

As with botulinum toxin exposure, arterial blood gas analysis and pulse oximetry are less sensitive than spirometry to impending respiratory failure. If intubation is necessary, paralytic agents should be avoided because they can mask the motor manifestations of seizures.
 

What are the mechanisms of action of atropine and pralidoxime chloride (2-PAM) in treating nerve agent toxicity?

Atropine blocks the effects of acetylcholine at muscarinic receptors, which has the beneficial effect of reducing parasympathetic response. In addition to diminishing or halting the hypersecretory state, atropine greatly enhances ventilation by relaxing bronchioles. The usual adult dose of 2 to 4 mg can be repeated every 5 to 10 minutes until secretions stop and airway resistance falls to acceptable levels. A cumulative dose of 10 to 20 mg during the first three hours of therapy is not uncommon. Patients receiving high-dose atropine should be monitored for signs of atropine toxicity, such as delirium, increased fasciculations, urinary retention, and hyperthermia.

In moderate to severe intoxications, the oxime 2-PAM is given with atropine. This drug binds with AChE, displacing and hydrolyzing the organophosphate toxin. However, the efficacy of 2-PAM depends on the bond between the organophosphate and the enzyme being reversible. After aging occurs, 2-PAM is of little benefit. The adult dose of 2-PAM is 1 to 2 grams, administered with 100 ml of normal saline intravenously over 15 to 30 minutes. If paralysis is still present after an hour, the dose may be repeated. In critically ill patients with organophosphate pesticide toxicity, a 2-gram bolus followed by a maintenance infusion of 7.5 mg/kg/hour has been reported to be safe. Such an approach may be considered in severe nerve agent intoxications, particularly in the presence of large dermal exposures in which redistribution of the organophosphate may last beyond the 1.2-hour half-life of the drug.
 

How are seizures induced by nerve agent intoxication managed?

Seizures can occur as a direct effect of a nerve agent acting on the brain or as a secondary effect of hypoxia. Patients should be treated with 2-PAM and standard doses of benzodiazepines (for example, lorazepam 2 mg every three minutes until the seizures stop or a total dose of 0.1 mg/kg is reached). If the seizures continue after administration of lorazepam, patients should receive an intravenous loading dose of fosphenytoin (20 mg/kg), which is preferred over phenytoin because a phenytoin infusion and nerve agents can both lead to bradycardia and other arrhythmias. Continued uncontrolled seizures should be treated with barbiturate-induced coma with electroencephalographic monitoring.
 

What are the sequelae of nerve agent intoxication?

Patients with moderate to severe intoxication occasionally experience a relapse of weakness between days 1 and 4. This relapse has been termed the "intermediate syndrome." It is treated with supportive care and typically resolves within 5 to 18 days. Because of this tendency of patients to relapse, it is prudent to keep patients in the hospital for up to four days after exposure. Patients with organophosphate pesticide toxicity may develop a severe polyneuropathy one to three weeks after exposure. It is believed, however, that the militarized nerve agents do not cause this sequela. Long-term cognitive sequelae, such as depression, psychomotor slowing, and memory impairment, have been described after nerve agent intoxication.

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Emerg Med 34(11):44, 2002

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