The organophosphorus nerve agents are the deadliest of the CWAs. They work by inhibition of tissue synaptic acetylcholinesterase, creating an acute cholinergic crisis. Death ensues because of respiratory depression and can occur within seconds to minutes.
The nerve agents tabun and sarin were first used on the battlefield by Iraq against Iran during the first Persian Gulf War (1984–1987). Estimates of casualties from these agents range from 20,000 to 100,000. In 1994 and 1995, the Japanese cult Aum Shinrikyo used sarin in two terrorist attacks in Matsumoto and Tokyo. Two U.S. soldiers were exposed to sarin while rendering safe an improvised explosive device in Iraq in 2004. Estimates by the U.S. government and various relief agencies suggest there were from several hundred to 1450 sarin casualties in Ghouta, Syria, in 2013.
The “classic” nerve agents include tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX; VR, similar to VX, was manufactured in the former Soviet Union (Table S3-1). All the nerve agents are organophosphorus compounds, which are liquid at standard temperature and pressure. The “G” agents evaporate at about the rate of water and thus probably will have evaporated within 24 h after deposition on the ground. Their high volatility thus makes a spill of any amount a serious vapor hazard. In the Tokyo subway attack in which sarin was used, 100% of the symptomatic patients inhaled sarin vapor that spilled out on the floor of the subway cars. The low vapor pressure of VX, an oily liquid, makes it much less of a vapor hazard but potentially a greater environmental hazard because it persists in the environment far longer.
Acetylcholinesterase inhibition accounts for the major life-threatening effects of nerve agent poisoning. The efficacy of antidotal therapy in the reversal of this inhibition proves that this is the primary toxic action of these poisons. At cholinergic synapses, acetylcholinesterase, bound to the postsynaptic membrane, functions as a turn-off switch to regulate cholinergic transmission. Inhibition of acetylcholinesterases causes the released neurotransmitter, acetylcholine, to accumulate abnormally. End-organ overstimulation, recognized by clinicians as a cholinergic crisis, ensues (Fig. S3-4).
Schematic diagram of the pathophysiology of nerve agent exposure. Nerve agent (
) binds to the active site of acetylcholinesterase (AChE), which is shown as floating free in space but is in reality a postsynaptic membrane-bound enzyme. As a result, acetylcholine
), which normally is released from presynaptic membrane but then is degraded, accumulates, and this leads to organ overstimulation and cholinergic crisis.
Clinical effects of nerve agent exposure are identical for vapor and liquid exposure routes if the dose is sufficiently large. The speed and order of symptom onset will differ (Table S3-2).
Exposure of a patient to nerve agent vapor will cause cholinergic symptoms in the order in which the toxin encounters cholinergic synapses. The most exposed synapses on the human integument are in the pupillary muscles. Nerve agent vapor easily crosses the cornea, interacts with these synapses, and produces miosis, described by Tokyo subway victims as “the world going black.” Rarely, this vapor also can cause eye pain and nausea. Exocrine glands in the nose, mouth, and pharynx are next exposed to the vapor, and cholinergic overload here causes increased secretions, rhinorrhea, excess salivation, and drooling. Toxin then interacts with exocrine glands in the upper airway, causing bronchorrhea, and with bronchial smooth muscle, causing bronchospasm. This combination of events can result in hypoxia.
Once the victim has inhaled, vapor can passively cross the alveolar-capillary membrane, enter the bloodstream, and incidentally and asymptomatically inhibit circulating cholinesterases, particularly free butyrylcholinesterase and erythrocyte acetylcholinesterase, both of which can be assayed. Unfortunately, the results of this assay may not be easily interpretable without a baseline, since cholinesterase levels vary enormously between individuals and over time in a healthy patient.
Usually the first organ system to become symptomatic from bloodborne nerve agent exposure is the gastrointestinal tract, where cholinergic overload causes abdominal cramping and pain, nausea, vomiting, and diarrhea. After the gastrointestinal tract becomes involved, nerve agents will affect the heart, distant exocrine glands, muscles, and brain. Because there are cholinergic synapses on both the vagal (parasympathetic) and sympathetic sides of the autonomic input to the heart, one cannot predict how heart rate and blood pressure will change once intoxication has occurred. Remote exocrine activity will include oversecretion in the salivary, nasal, respiratory, and sweat glands—the patient will be “wet all over.” Bloodborne nerve agents will overstimulate neuromuscular junctions in skeletal muscles, causing fasciculations followed by frank twitching. If the process goes on long enough, ATP in muscles will eventually be depleted and flaccid paralysis will ensue.
In the brain, since the cholinergic system is so widely distributed, bloodborne nerve agents will, in sufficient doses, cause rapid loss of consciousness, seizures, and central apnea leading to death within minutes. If respiration is supported, status epilepticus that does not respond to usual anticonvulsants may ensue (Chap. 418). If status epilepticus persists, neuronal death and permanent brain dysfunction may occur. Even in mild nerve-agent intoxication, patients may recover but may experience weeks of irritability, sleep disturbance, and nonspecific neurobehavioral manifestations.
The time from exposure to development of the full-blown cholinergic crisis after nerve agent vapor inhalation can be minutes or even seconds, yet there is no depot effect. Since nerve agents have a short circulating half-life, if the patient is supported and, ideally, treated with antidotes, improvement should be rapid, without subsequent deterioration.
Liquid exposure to nerve agents results in different speeds and orders of symptom onset. A nerve agent on intact skin will partially evaporate and partially begin to travel through the skin, causing localized sweating and then, when it encounters neuromuscular junctions, localized fasciculations. Once in muscle, the agent will cross into the circulation and cause gastrointestinal discomfort, respiratory distress, heart rate changes, generalized fasciculations and twitching, loss of consciousness, seizures, and central apnea. The time course will be much longer than with vapor inhalation; even a large, lethal droplet can take up to 30 min to exert an effect, and a small, sublethal dose could progressively take effect over 18 h. Clinical worsening that occurs hours after treatment has started is far more likely with liquid than with vapor exposure. In addition, miosis, which is practically unavoidable with vapor exposure, is not always present with low-level liquid exposure and may be the last manifestation to develop in this situation; such a delay is due to the relative insulation of the pupillary muscle from the systemic circulation.
Unless the cholinesterase is reactivated by specific therapy (oximes), its binding to the enzyme is essentially irreversible. Erythrocyte acetylcholinesterase activity recovers at ~1% per day. Plasma butyrylcholinesterase recovers more quickly and is a better guide to recovery of tissue enzyme activity.
TREATMENT Nerve Agent Intoxication
Acute nerve agent poisoning is treated by decontamination, respiratory support, and three antidotes: an anticholinergic, an oxime, and an anticonvulsant (Table S3-3). In acute cases, all these forms of therapy may be given simultaneously. DECONTAMINATION
Decontamination of a vapor is formally unnecessary; however, in the Tokyo subway attack, sarin vapor trapped in patients’ clothing caused miosis in 10% of emergency personnel. Removal of clothing would have prevented most of these instances. Examination of Table S3-2 reveals that expedient decontamination methods for liquid CWAs are available. For soap and water decontamination, the skin surface and hair are washed in warm or tepid water at least three times, or the exposed individual showers for 2 min, washing with soap and rinsing. The rapid physical removal of a chemical agent is essential. Scrubbing of exposed skin with a stiff brush or bristles is discouraged, because skin damage may occur and may increase absorption of agent. “Gentle” liquid dish soap and copious amounts of water should be used, with mild to moderate friction applied with a single-use sponge or washcloth in the first and second washes. The third wash should be a rinse with copious amounts of warm or tepid water. Shampoo can be used to wash the hair. Recent data from U.S. government funded research suggest that disrobing followed by soap and water decontamination efforts can reduce CWA concentrations by up to >99%. If only cold water is available, it should be used; decontamination should not be delayed while warm water is sought. Spot (local) decontamination with reactive skin decontamination lotion (RSDL), followed by a soap and water wash/shower, is the method preferred by the Department of Defense. RSDL is available for purchase by civilians and has been shown to be superior across a broad spectrum of nerve agents as well as sulfur mustard. RSDL is the only product approved by the U.S. Food and Drug Administration (FDA) for initial spot decontamination. An important caveat is that RSDL and 0.5% sodium hypochlorite (dilute bleach military field expedient) should not be used concurrently because of a potential exothermic reaction. In any event, decontamination must be accomplished before the patient enters the medical facility to avoid contaminating the facility and its staff. In patients with contaminated wounds, potentially contaminated clothing and other foreign material that may serve as a depot for the liquid agent should be extracted. RESPIRATORY SUPPORT
Death from nerve agent poisoning is almost always attributable to respiratory causes. Ventilation will be complicated by increased resistance and secretions. Atropine should be given before ventilation or as it begins, since it will make ventilation far easier. ANTIDOTAL THERAPY Atropine
In theory, any anticholinergic agent could be used to treat nerve agent poisoning. Worldwide, however, the choice is invariably atropine because of its wide temperature stability and rapid effectiveness when administered either IM or IV and because inadvertent administration of this drug usually causes little CNS dysfunction (Table S3-3). Atropine rapidly reverses cholinergic overload at muscarinic synapses but has little effect at nicotinic synapses. The practical implication is that atropine can quickly treat the life-threatening respiratory effects of nerve agents but probably will not help with neuromuscular (and possibly sympathetic) effects. In the field, military personnel are given a combined autoinjector containing both 2.1 mg of atropine and oxime (2-pralidoxime chloride [2-PAM Cl])—a product licensed by the FDA under the trade name Duodote. Its military designation is the Antidote Treatment Nerve Agent Autoinjector (ATNAA) (Fig. S3-5). Only full—and not divided—autoinjector doses can be administered. The field loading dose is 2, 4, or 6 mg, with re-treatment every 5–10 min until the patient’s breathing improves and secretions diminish. The Iranian military initially used larger doses during the Iran–Iraq war, in which oximes were in short supply. When the patient reaches a level of medical care at which drugs can be given IV, this is the preferred route. In small children, the IV route may be the initial avenue for atropine therapy; however, pediatric autoinjectors of 0.5 mg and 1 mg are manufactured. There is no upper limit to atropine therapy (whether IM or IV), but the total average dose for a severely afflicted adult is usually 20–30 mg.
In a mildly afflicted patient with miosis and no other systemic symptoms, atropine or homatropine eyedrops may suffice for therapy. This treatment will result in ~24 h of mydriasis. Frank miosis or imperfect accommodation may persist for weeks or even months after all other signs and symptoms have resolved. Oximes
Oximes are nucleophiles that reactivate the cholinesterase whose active site has been occupied and bound to nerve agent (Table S3-3). Therapy with oximes therefore restores normal enzyme function. Oxime therapy is limited by a second side reaction, called “aging,” in which a side chain on nerve agents falls off the complex at a characteristic rate. “Aged” complexes are negatively charged, and oximes cannot reactivate negatively charged complexes. The practical effect of this limitation differs from one nerve agent to another since each ages at a characteristic rate. For example, sarin ages in 3–5 h, tabun ages over a longer period (12–13 h), and VX ages much less rapidly (>48 h). All these intervals are so much longer than the patient’s expected life span and expected treatment time after acute nerve-agent toxicity that they are irrelevant. Soman, in contrast, ages in 2 min; thus, only a few minutes after exposure, oximes become useless in treating soman poisoning. The oxime used varies by country; the United States has approved and fielded 2-PAM Cl. ATNAAs and Duodotes (Fig. S3-5A) both contain autoinjectors holding 600 mg of 2-PAM Cl. Initial field loading doses are 600, 1200, and 1800 mg. Since blood pressure may become elevated after administration of 45 mg/kg in adults, field use of 2-PAM Cl is restricted to 1800 mg/h IM. During the time when more oxime cannot be given, atropine alone is recommended. In the hospital setting, 2.5–25 mg/kg of 2-PAM Cl by the IV route has been found to reactivate 50% of inhibited cholinesterase. The usual recommendation is 1000 mg by slow IV drip over 20–30 min, with ≤2500 mg over a period of 1–1.5 h. Active research aims to field a more effective and broader-spectrum oxime than 2-PAM Cl. Anticonvulsants
Nerve agent–induced seizures do not respond to the usual anticonvulsants used for status epilepticus, including phenytoin, phenobarbital, carbamazepine, valproic acid, and lamotrigine (Chap. 418). The only anticonvulsants that have been shown to stop this form of status are the benzodiazepines. Diazepam is the only benzodiazepine approved for seizures in humans, although other FDA-approved benzodiazepines (notably midazolam) work well against nerve agent–induced seizures in animal models. Diazepam therefore is manufactured in 10-mg injectors for IM use and given to U.S. forces for this purpose (Fig. S3-5B). Civilian agencies are stockpiling this field product (convulsive antidote for nerve agent [CANA]), which generally has not been used in hospital practice. Extrapolation from animal studies indicates that adults will probably require 30–40 mg of diazepam given IM to stop nerve agent–induced status epilepticus. In the hospital or in a small child unable to receive the autoinjector, IV diazepam may be used at similar doses. The clinician may confuse seizures with the neuromuscular signs of nerve agent poisoning. In the hospital, early electroencephalography is advised to distinguish among nonconvulsive status epilepticus, actual seizures, and postictal paralysis. Animal studies have shown that the most effective benzodiazepine in this situation is midazolam, which is not FDA-approved for seizures. At the time of this writing, a new drug application for use of midazolam against seizures has been submitted to the FDA. The superiority of IM midazolam to IV lorazepam in a large community trial of status epilepticus suggests that emergency personnel will soon incorporate autoinjectors into routine clinical practice and that these field products will thus become integrated into clinical medicine.
Peripheral neuropathy and the so-called intermediate syndrome, prominent long-term effects of insecticide poisoning, are not described in nerve agent survivors.
++ Table Graphic Jump Location TABLE S3-3Antidote Recommendations after Exposure to Nerve Agents ||Download (.pdf) TABLE S3-3 Antidote Recommendations after Exposure to Nerve Agents
|Patient’s Age ||Mild/Moderate Effectsa ||Severe Effectsb ||Other Treatment |
|Infants (0–2 years) ||Atropine (0.05 mg/kg IM or 0.02 mg/kg IV) and 2-PAM Cl (15 mg/kg IM or IV slowly) ||Atropine (0.1 mg/kg IM or 0.02 mg/kg IV) and 2-PAM chloride (25 mg/kg IM or 15 mg/kg IV slowly) ||Assisted ventilation after antidotes for severe exposure |
|Child (2–10 years) ||Atropine (1 mg IM or 0.02 mg/kg IV) and 2-PAM Clc (15 mg/kg IM or IV slowly) ||Atropine (2 mg IM or 0.02 mg/kg IV) and 2-PAM chloridec (25 mg/kg IM or 15 mg/kg IV slowly) ||Repeat atropine (2 mg IM, or 1 mg IM for infants) at 5- to 10-min intervals until secretions have diminished and breathing is comfortable or airway resistance has returned to nearly normal. This treatment is also valid for adolescent, adult, and elderly populations. |
|Adolescent (>10 years) ||Atropine (2 mg IM or 0.02 mg/kg IV) and 2-PAM Clc (15 mg/kg IM or IV slowly) ||Atropine (4 mg IM or 0.02 mg/kg IV) and 2-PAM Clc (25 mg/kg IM or 15 mg/kg IV slowly) || |
|Adult ||Atropine (2–4 mg IM or IV) and 2-PAM Cl (600 mg IM or 15 mg/kg IV slowly) ||Atropine (6 mg IM) and 2-PAM Cl (1800 mg IM or 15 mg/kg IV slowly) || |
Phentolamine for 2-PAM-induced hypertension (5 mg IV for adults; 1 mg IV for children)
Diazepam for convulsions (0.2–0.5 mg IV for infants <5 years; 1 mg IV for children >5 years; 5 mg IV for adults).
|Elderly, frail ||Atropine (1 mg IM) and 2-PAM Cl (10 mg/kg IM or 5–10 mg/kg IV slowly) ||Atropine (2–4 mg IM) and 2-PAM Cl (25 mg/kg IM or 5–10 mg/kg IV slowly) || |
Antidotes to nerve agents. A. The Antidote Treatment Nerve Agent Autoinjector (ATNAA) replaces the MARK I Kit. It is easier to self-administer and allows prompt distribution of the antidotes atropine and 2-pralidoxime chloride (2-PAM Cl). B. Diazepam 10-mg autoinjectors are carried by all U.S. military forces in a potential chemical battlefield and are being stockpiled by civilian first responders.