Molecular models: A, Tabun (GA). B, Sarin (GB). C, Soman (GD). D, VX. Courtesy of Offie E. Clark, MS, US Army Medical Research Institute of Chemical Defense. C indicates carbon; F, fluorine; N, nitrogen, O, oxygen, P, phosphorus; and S, sulfur.
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Newmark J. Therapy for Nerve Agent Poisoning. Arch Neurol. 2004;61(5):649–652. doi:10.1001/archneur.61.5.649
Neurologists need to familiarize themselves with nerve agents, the most toxic of the chemical warfare agents. Their mode of action lies within the nervous system, and nonneurologists will look to neurologists for expert advice on therapy. These agents cause rapid-onset cholinergic crisis amenable to prompt treatment with specific antidotes. Experience on the battlefield and in terrorist attacks demonstrates that therapy saves lives.
You are walking through a crowded shopping mall, when you hear a soft "pop" and see smoke coming from the other end of the mall. You immediately notice dim vision, and your nose begins to run severely. Less than 1 minute later, you notice shoppers collapsing to the floor, breathing heavily, some of them losing consciousness and developing generalized seizure activity. You notice that their pupils are constricted. You immediately grab 2 small children near you, cover your nose and mouth with your jacket, and run out of the mall.
Nerve agents are the most toxic of the chemical warfare agents. Originally developed in the 1930s, they were weaponized and stockpiled, but not used, by Nazi Germany. Only Iraq has used them on the battlefield, against Iran, from 1984 to 1987. The United States has destroyed much of its old stockpile of nerve agent munitions in accord with the Chemical Warfare Convention.
The classic nerve agents are tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX (no common name) (Table 1 and Figure 1). All are liquids at standard temperature and pressure and all spontaneously evaporate, causing vapor and liquid hazards. Therefore, the term "nerve gas" is a dangerous misnomer. All except VX evaporate sufficiently quickly that they will be gone after being released and deposited outdoors within 24 hours, or about as rapidly as water. VX is oily, rather than watery, and evaporates so slowly that it remains an environmental hazard longer than 24 hours. Therefore, VX is described as "persistent," the others as "nonpersistent."
VX is the most toxic substance known in neurobiology, except for the biological toxins. A drop of VX liquid large enough to kill half of an exposed population (LD50 of liquid VX) would just cover the space between 2 adjacent columns of the Lincoln Memorial on the back of a US penny.
Clinical experience with nerve agent poisoning is limited to a few industrial accidents in the countries with weapons programs over the years, including a small number in the United States; 45 000 to 100 000 nerve agent casualties in the Iran-Iraq war, about whom Iranian physicians have recently published their clinical experiences1; and the roughly 5500 people who presented for clinical evaluation after the 2 terrorist attacks in Japan in 1994 and 1995.2 To my knowledge, the last neurologic review appeared in 1992.3
Nerve agents are especially toxic relatives of the commonly used organophosphate insecticides. Although they are more toxic per unit weight and have a shorter duration of effect (because they are much less fat soluble than organophosphate pesticides), their major mode of action is the same, namely, inhibition of synaptic acetylcholinesterase (AChE). By inhibiting this enzyme, which turns off cholinergic transmission, nerve agents produce hyperactivity in cholinergically innervated end organs and induce an acute, life-threatening cholinergic crisis. Animal data4 and clinical experience5 with antidotes designed to counteract cholinergic crisis demonstrate that this is the major life-threatening action of nerve agents.
Most exposures in battlefield and terrorist scenarios occur via the vapor route. Nerve agent vapor produces its effects in seconds to minutes. Initially, vapor directly inhibits AChE in pupillary muscle, producing miosis, and in upper respiratory glands, producing rhinorrhea and salivation. With inhalation, agent vapor will trigger hypersecretion of respiratory glands in bronchioles, causing clinical bronchorrhea, and hypercontraction of smooth respiratory muscle, causing bronchospasm. Nerve agent vapor is well absorbed through alveolar-capillary membranes, whose function is unaffected, and distributed systemically by the blood, incidentally inhibiting circulating cholinesterases, which (although not important symptomatically) provide useful laboratory evidence of exposure. The "gold standard" is erythrocyte AChE, although most clinical laboratories are not equipped to measure levels of this substance.
Circulating nerve agent first affects the gastrointestinal tract, causing cramping, abdominal pain, nausea, vomiting, and defecation. The heart will be affected, although clinical experience indicates that the effects will vary considerably, because each patient has a unique ratio of sympathetic to parasympathetic (vagal) input. Cholinesterase inhibitors will cause hyperstimulation of both, with an unpredictable effect on blood pressure and pulse rate. Nerve agents cause massive overstimulation of peripheral neuromuscular synapses, with a clinical progression from fasciculation to twitching, often misinterpreted by observers as seizure activity. Eventually, flaccid paralysis will result, but this will only occur when adenosine triphosphate is depleted and will never be the first clinical neuromuscular sign. Involvement of the diaphragm and intercostal muscles will further impair respiration. Finally, nerve agent delivered to the brain will stimulate all cholinergic synapses essentially simultaneously. Because acetylcholine is the most widely distributed neurotransmitter in the brain, a large nerve agent challenge will cause a rapid loss of consciousness, seizures, and inhibition of the medullary respiratory center, with central apnea. Death from nerve agent poisoning is usually caused by respiratory failure, mediated by bronchospasm, bronchorrhea, inadequate functioning of respiratory muscles, and lack of central respiratory input.
Nerve agent liquid exposure differs from vapor exposure because it has a generally slower onset. If the liquid route is suspected, through intact skin or through a wound, the patient must be monitored more closely for a longer period, because clinical decompensation is much more likely with this route than with uncomplicated vapor exposure. Skin decontamination may not suffice if not done immediately, because absorbed nerve agent may be trapped subcutaneously, penetrate systemically after a variable time course, and cause more symptoms.
A few patients who have survived mild exposures to nerve agents have reported neurobehavioral syndromes lasting weeks or months after exposure that persist when all other signs and symptoms, including miosis, have resolved. Symptoms have varied from a new-onset headache disorder to personality change and depression to higher-order difficulties in memory and reading. In some patients, this syndrome may be identical to posttraumatic stress disorder, based on the results of formal neurobehavioral batteries.6,7 In others, it may overlap with mild hypoxic encephalopathy. However, it is unexplained in some, and it is generally not highly correlated with dose.
Chronic effects of one-time exposure to nerve agents are few. By contrast to organophosphate insecticide exposures, an intermediate syndrome has not been reported. Only 1 case of delayed peripheral neuropathy has been reported in a survivor of the 1995 Tokyo subway attack.8 In a few cases, apparently permanent vestibular symptoms have been reported.9
In nerve agent poisoning, ventilatory support is crucial. Japanese experience in 1995 shows that even a patient in full cardiopulmonary arrest can sometimes be saved by resuscitation and ventilatory support if antidotal therapy is also administered.2
Principles of antidotal therapy of nerve agent poisoning have not changed since the British established them in 1945. All countries worldwide use the same 3 strategies: an anticholinergic drug to counteract acute cholinergic crisis, an oxime to reactivate inhibited AChE, and a specialized anticonvulsant to treat or prevent seizures and resultant neuronal damage.10,11
Every country uses atropine sulfate in the field for acute anticholinergic therapy of nerve agent poisoning. In the United States, this is packaged in 2-mg autoinjectors for intramuscular (IM) field use. In 2003, pediatric autoinjectors containing 0.5-mg and 1-mg doses were also approved by the Food and Drug Administration (FDA). According to military doctrine, initial therapy is 2, 4, or 6 mg, with retreatment every 5 to 10 minutes as needed. Once the patient reaches the hospital, intravenous atropine may be administered. Atropine reverses cholinergic crisis at muscarinic synapses, with excellent IM uptake. It binds to muscarinic postsynaptic receptors, preventing acetylcholine from stimulating the synapse. Because atropine does not bind to nicotinic receptors, neuromuscular symptoms such as twitching and discoordination will continue. The most life-threatening problems caused by nerve agent exposure are muscarinically mediated. The clinical end point for atropine administration is ease of breathing, without secretions. Iranian experience proves that atropine alone can save lives.1
In the United States, the fielded oxime for nerve agent poisoning is 2-pralidoxime chloride. The IM dose is 600 mg per autoinjector. Although there is no upper bound to atropine therapy, 2-pralidoxime chloride should not be given in doses greater than 2000 mg/h because of the risk of sudden elevation of blood pressure, whether via IM injection in the field or intravenously in the hospital.10 Oximes reactivate catalytic cholinesterase and simultaneously split nerve agent or organophosphate insecticides into harmless, rapidly metabolized fragments. After nerve agent binds to AChE, the resultant complex spontaneously loses a side chain, a reaction called "aging," rendering the remaining enzyme-inhibitor complex unable to be reactivated by oxime. Most nerve agents age slowly enough that this reaction can be ignored; sarin ages over hours and VX over days to weeks. Soman ages rapidly, with a half-time (t½) for the aging reaction of about 2 minutes. Once nerve agent–AChE complex has aged, oximes are therapeutically useless, although they will not hurt the patient.
The MARK 1 set (Meridian Medical Technologies, Columbia, Md) containing a 2-mg atropine and a 600-mg 2-pralidoxime chloride autoinjector, although developed for the US military, is approved by the FDA for general use. Most first-responder agencies in the United States have stockpiled this product. Hospital physicians will likely see a nerve agent casualty who has already been treated with this in the field.
Because of the high chance of seizures, the third leg of therapy for acute poisoning has always been an anticonvulsant. Exposure to nerve agents induces initially multicentric, cholinergically mediated seizures, but after an interval (20 minutes in guinea pigs), other neurotransmitter systems become involved. Probably for this reason, standard drugs used to treat status epilepticus or epileptic seizures do not stop seizures or status epilepticus induced by nerve agents.12 Of approved anticonvulsant drugs, only the benzodiazepines are effective. Because it is the only benzodiazepine approved by the FDA for use in seizures, the US military fields diazepam for this purpose, in 10-mg IM autoinjectors. Once the patient has reached a hospital, intravenous administration is preferred because of unpredictable IM uptake. Civilian physicians may choose any benzodiazepine for off-label use for this purpose. Recent animal experimentation has demonstrated that the most effective drug in this class, in terms of its speed of action, low dose required, and broad spectrum against all nerve agents, is midazolam hydrochloride.13 Israel has recently switched to midazolam for anticonvulsant therapy in the field. In the United States, this is not yet possible for military or first-responder field use, because midazolam is not FDA-approved therapy for seizures, but it is legal for physicians to use it in hospital settings in an emergency.
Although seizures supervene in a percentage of previously normal patients exposed to large doses of nerve agents, epilepsy does not appear to develop to any greater degree in these patients than in the general population. Electroencephalographic abnormalities usually resolve within weeks to months after a one-time exposure. The use of chronic anticonvulsant therapy is not advised. Pediatric adaptations of therapy have recently been reviewed.14
The US military is concerned about soldiers who might be poisoned by a rapid aging nerve agent and unable to obtain treatment until such time as oximes have become therapeutically useless. This was the rationale for fielding pyridostigmine bromide, familiar as a treatment for myasthenia, as a pretreatment for nerve agent poisoning in the 1990-1991 Gulf War.15 Given that troops have a huge excess of AChE (the logic went), if they face a rapid aging nerve agent that irreversibly removes large amounts of AChE from function, it would make sense before exposure to administer a small amount of this reversible acetylcholine inhibitor, so as to sequester a percentage of the patient's excess AChE and render it unavailable to be irreversibly inhibited by nerve agent. The result is that what would have been a lethal dose of nerve agent becomes survivable with antidotes. More than 100 000 US and allied troops were ordered to take pyridostigmine bromide during the Gulf War, with the normal informed consent rules waived by the FDA for the occasion. In 1992, the FDA withdrew the waiver of informed consent. In February 2003, just before the invasion of Iraq, the FDA approved pyridostigmine as a pretreatment for troops facing an attack using the rapid aging nerve agent soman. Therefore, at the time of writing, use of pyridostigmine is part of US and North Atlantic Treaty Organization military doctrine if intelligence determines that an attack by a rapid aging nerve agent is likely. Pyridostigmine was not used during the 2003 Iraq War, however, as no chemical attacks occurred.
In the military, we teach that in acute nerve agent poisoning the caregiver will win or lose the battle for the patient's life early on and at his or her echelon of care, not relying on evacuation to a more capable facility. In the civilian sector, this implies that the acute therapy of victims will usually be the responsibility of the emergency medical services system, rather than the neurologist or other hospital-based specialist. The community neurologist must be a key resource to teach others to render this emergency care.
All of the major military and many of the major civilian references may be downloaded free of charge from the Chemical Casualty Care Division Web site.16 Telephone consultation is also available around the clock at the US Army Medical Research Institute of Chemical Defense at (410) 436-3276.
Corresponding author and reprints: COL Jonathan Newmark, MC, USAR, Chemical Care Division, US Army Medical Research Institute of Chemical Defense, Attn: MCMR-UV—ZM (COL Newmark), 3100 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010-5400 (e-mail: firstname.lastname@example.org).
Accepted for publication December 2, 2003.
The opinions expressed herein are solely those of the author and not necessarily those of the Department of the Army or of the Department of Defense.
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