Disclosure
Because of the ongoing risk of chemical attack, emergency physicians must be able to care for victims of chemical weapon agents (CWAs). This article reviews the physical properties and general clinical effects of CWAs. It also describes the medical management of victims of CWAs, including the use of personal protective equipment (PPE), victim decontamination, provision of supportive care, and provision of specific antidotal therapy. To illustrate these principles with specific agents, the properties, clinical effects, and medical management of nerve agents and vesicant agents are reviewed briefly. For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education articles Chemical Warfare and Personal Protective Equipment. Risk of exposure to chemical warfare agents Injury from CWAs may result from industrial accident, military stockpiling, war, or terrorist attack. Industrial accidents continue to be a significant potential source of exposure to the agents used in chemical weapons. Chemicals such as phosgene, cyanide, anhydrous ammonia, and chlorine are used widely and frequently are transported by industry. The accidental release of a methylisocyanate cloud (composed of phosgene and isocyanate) was implicated in the Bhopal disaster in 1984. These accidents continue today, with nearly 9000 occurring in the United States in 2001 alone. CWAs first were used in 1915, when the German military released 168 tons of chlorine gas at Ypres, Belgium, killing an estimated 5000 Allied troops. Two years later, the same battlefields saw the first deployment of sulfur mustard. Sulfur mustard was the major cause of chemical casualties in World War I. CWAs have been used in at least 12 conflicts since, including the first Persian Gulf War (Iraq-Iran War). The Iraqi military also used chemical weapons against the Iraqi Kurds during the second Persian Gulf War. Civilians have also been exposed inadvertently to chemical weapons many years after weapon deployment during war. Approximately 50,000 tons of mustard shells were disposed of in the Baltic Sea following World War I. Since then, numerous fishermen have been burned accidentally while hauling leaking shells aboard boats. Leaking mustard shells also have injured collectors of military memorabilia and children playing in old battlefields. Although a number of international treaties have banned the development, production, and stockpiling of CWAs, these agents reportedly still are being produced or stockpiled in several countries. Within the last decade, terrorists deployed chemical weapons against civilian populations for the first time in history. The release of sarin in Matsumoto, Japan, in June 1994 by the extremist Aum Shinrikyo cult left 7 dead and 280 injured. The following year, in March 1995, the Aum Shinrikyo cult released sarin vapor in the Tokyo subway system during morning rush hour, leaving 12 dead and sending more than 5000 casualties to local hospitals. A derivative of fentanyl was also used against terrorists holding hostages in a Moscow theater in 2002. Because of a lack of antidote available by the responders, more than 120 casualties among the hostages occurred from asphyxiation. Several characteristics of CWAs lend themselves to terrorist use. Chemical substrates used in CWAs are widely available, and recipes for CWA production may be found on the Internet. CWAs are transported easily and may be delivered by a variety of routes. Chemical agents often are difficult to protect against and quickly incapacitate the intended targets. Most civilian medical communities are inadequately prepared to deal with a chemical terrorist attack.
Types of chemical weapon agents CWAs comprise a diverse group of hazardous substances. Major categories of CWAs include the following:
Physical properties CWAs generally are stored and transported as liquids and deployed as either liquid aerosols or vapors. Victims usually are exposed to agents via one or more of 3 routes: skin (liquid and high vapor concentrations), eyes (liquid or vapor), and respiratory tract (vapor inhalation). CWAs are characterized by 2 inversely related physical properties: volatility (ie, tendency of liquids to vaporize, which directly increases with temperature) and persistence (ie, tendency of liquids to remain in a liquid state). In general, volatile liquids pose the dual risk of dermal and inhalation exposure, while persistent liquids are more likely to be absorbed across the skin. The effects of vapors largely are influenced by ambient wind conditions; even a slight breeze can blow nerve agent vapor away from its intended target. Effects of vapor are enhanced markedly when deployed within an enclosed space. Clinical effects Depending on the agent and the type and amount (concentration) of exposure, CWA effects may be immediate or delayed. Large inhalation exposures to nerve agents or mustards are likely to be lethal immediately. Small dermal exposures to nerve agents and mustards are particularly insidious and generally require expectant observation for variable periods because of possible delayed effects. Specific clinical effects of CWAs are as varied as the agents. Medical management To appropriately manage CWA exposures, emergency care personnel are required to protect themselves by performing the following:
Personal protective equipment The primary responsibility of those who treat victims of CWAs is to protect themselves by wearing adequate PPE. First responders are at serious risk from the chemically contaminated environment (hot zone), either from direct contact with persistent liquid or from inhaling vapor. First responders and emergency care providers also are at risk from handling skin and clothing of victims contaminated with liquid CWAs (secondary skin and inhalation exposure). Conversely, providing care to those exposed only to vapor CWAs poses little risk to emergency care providers outside the hot zone. Regardless, until identification of the substance is made and it is deemed nontoxic, responders should wear their PPE. Standard protective garments are inadequate for most CWAs. Double layers of latex gloves are useless against liquid nerve and blister agents, and surgical masks and air-purifying respirators are inadequate against nerve agent vapors. Levels of personal protective equipment US regulatory agencies mandate the use of appropriate levels of PPE.
Decontamination
Supportive and specific therapy Supportive therapy for victims of CWAs generally follows the universally accepted algorithm of first ensuring the adequacy of airway, breathing, and circulation, with one important exception. Severe nerve agent poisoning may require immediate administration of parenteral atropine. Many CWAs only can be treated supportively. Specific, well-established antidotes are available only for nerve agent and cyanide exposures. Since no laboratory tests are available to rapidly confirm exposure to CWAs, treatment is based on clinical criteria.
Inhibition of AChE may not account for all of the toxic effects of nerve agents. These agents also are known to bind directly to nicotinic receptors and cardiac muscarinic receptors. They also antagonize gamma-aminobutyric acid (GABA) neurotransmission and stimulate glutamate N-methyl-d-aspartate (NMDA) receptors. These latter actions may partly mediate nerve agent–induced seizures and CNS neuropathology.
All nerve agents rapidly penetrate skin and clothing. Nerve agent vapors are heavier than air and tend to sink into low places (eg, trenches, basements).
Liquid exposure Liquid agents easily penetrate skin and clothing. Onset of symptoms occurs from 30 minutes to 18 hours following dermal exposure. Minimal liquid exposure (eg, a small droplet on the skin) may cause local sweating and muscle fasciculation, followed by nausea, vomiting, diarrhea, and generalized weakness. Even with decontamination, signs and symptoms may persist for hours. In contrast, persons with severe liquid exposures may be briefly asymptomatic (1-30 min) but rapidly may suffer abrupt loss of consciousness, convulsions, generalized muscular fasciculation, flaccid paralysis, copious secretions (nose, mouth, lungs), bronchoconstriction, apnea, and death. Vapor exposure Vapor inhalation produces clinical toxicity within seconds to several minutes. Effects may be local or systemic. Exposure to even a small amount of vapor usually results in at least one of the following categories of complaints: (1) ocular (miosis, blurred vision, eye pain, conjunctival injection), (2) nasal (rhinorrhea), or (3) pulmonary (bronchoconstriction, bronchorrhea, dyspnea). Exposure to a vapor concentration of 3.0 mg/m3 for 1 minute causes miosis and rhinorrhea. Inhalation of a high concentration of vapor results in loss of consciousness after only one breath, convulsions, respiratory arrest, and death. For example, breathing 10 mg /m3 of sarin vapor for only 10 minutes (100 mg/m3 for 1 min) causes death in approximately one half of exposed individuals. Severe vapor exposures also are characterized by generalized fasciculations, hypersecretions (mouth, lungs), and intense bronchoconstriction with respiratory compromise. Respiratory tract Nerve agents act on the upper respiratory tract to produce profuse watery nasal discharge, hypersalivation, and weakness of the tongue and pharynx muscles. Laryngeal muscles are paralyzed, resulting in stridor. In the lower respiratory tract, nerve agents produce copious bronchial secretions and intense bronchoconstriction. If untreated, the combination of hypersecretion, bronchoconstriction, respiratory muscle paralysis, and CNS depression rapidly progresses to respiratory failure and death. Nerve agents depress the central respiratory drive directly. Thus, early death following large vapor exposure likely results from primary respiratory arrest, not from neuromuscular blockade, bronchorrhea, or bronchoconstriction. Cardiovascular system The cardiovascular effects of nerve agents vary and depend on the balance between their nicotinic receptor–potentiating effects at autonomic ganglia and their muscarinic receptor–potentiating effects at parasympathetic postganglionic fibers that innervate the heart. Sinus tachydysrhythmias with or without hypertension (sympathetic tone predomination) or bradydysrhythmias with or without variable atrioventricular blockade and hypotension (parasympathetic tone predomination) may occur. Superimposed hypoxia may produce tachycardia or precipitate ventricular tachydysrhythmias. Nerve agent–induced prolonged QT and torsades de pointes have been described in animals. In victims of the Tokyo sarin gas attack, sinus tachycardia and hypertension were common cardiovascular abnormalities, while sinus bradycardia was uncommon. Central nervous system Nerve agents produce a variety of neurologic signs and symptoms by acting on cholinergic receptors throughout the CNS. The most important clinical signs of neurotoxicity are a rapidly decreasing level of consciousness (sometimes within seconds of exposure) and generalized seizures. Symptoms such as headache, vertigo, paresthesias, anxiety, insomnia, depression, and emotional lability also have been reported. Musculoskeletal system Nerve agents initially stimulate and then paralyze neurotransmission at the neuromuscular junction. With minimal exposure, exposed persons may complain of vague weakness or difficulty walking. More significant exposures resemble the clinical effects that result from succinylcholine, with initial fasciculations followed by flaccid paralysis and apnea. Ocular Nerve agent liquid or vapor readily penetrates the conjunctiva and exerts direct muscarinic parasympathetic effects. This results in constriction of the iris (miosis, blurred and dim vision, headache), constriction of the ciliary muscle (pain, nausea, vomiting), and stimulation of the lacrimal glands (tearing, redness). Although miosis is the most consistent clinical finding after vapor exposure to nerve agents (occurred in 99% of persons exposed in Tokyo sarin attack), it may be absent or delayed in dermal exposure. Duration of miosis varies according to the extent of ocular exposure (up to 45 d).
In the Tokyo subway sarin attack, 27% of patients with clinical manifestations of moderate poisoning had plasma cholinesterase activity in the normal range. Moreover, different organophosphates variably inhibit RBC and plasma cholinesterase. For example, in mild-to-moderate exposures to sarin or VX, RBC cholinesterase activity is decreased to a much greater extent than plasma cholinesterase activity. Since plasma cholinesterase is produced by the liver, its activity also may be depressed in certain conditions (eg, liver disease, pregnancy, infections) or with certain drugs (eg, oral contraceptives). Conversely, a 20-25% reduction in RBC cholinesterase activity tends to correlate with severe clinical toxicity and, despite the exception noted above, activity of both enzymes approaches zero in most severely poisoned victims. Nevertheless, treatment decisions should be clinically based. Never withhold treatment from a symptomatic patient while awaiting laboratory confirmation. Conversely, decreased cholinesterase activity in the absence of clinical signs of toxicity is not an indication for treatment. |
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Conversely, victims exposed to nerve agent vapor pose little risk to emergency care providers outside the hot zone; residual agent is not present and off-gassing may occur but rarely in significant amounts. In the Tokyo sarin attack, approximately 90% of exposed persons reported to medical facilities by private or public transportation without notable contamination of others. Additionally, secondary injury to hospital staff was minimal and did not necessitate specific treatment. Unless a clear history of vapor exposure only is obtained, emergency medical personnel should assume that liquid contamination is present and wear PPE. For most nerve agent exposures, first responders require level A PPE inside the hot zone, and hospital personnel involved in decontamination should wear level B PPE.
Treat seizures with adequate oxygenation and liberal doses of benzodiazepines titrated to effect. Termination of seizure activity may reflect onset of flaccid paralysis from the nerve agent rather than adequacy of antiseizure therapy. A bedside electroencephalograph (EEG) may be required to assess ongoing seizure activity. Animal data suggest that routine administration of diazepam reduces incidence of seizures and decreases severity of pathologic brain injury following nerve agent exposure.
Atropine sulfate Symptomatic patients require immediate treatment with atropine. Atropine blocks muscarinic effects of nerve agents (eg, bronchorrhea, bronchoconstriction), improving ventilation by drying secretions and decreasing airway resistance. Atropine also blocks other muscarinic effects, such as nausea, vomiting, abdominal cramping, bradycardia, and diaphoresis. Atropine does not have nicotinic effects and thus does not reverse toxicity at autonomic ganglia and neuromuscular junctions. Atropine does not prevent or reverse paralysis. Atropine therapy is guided by clinical signs and symptoms. Titrate dosing to the desired clinical effect. The goals of atropine therapy are to dry secretions and eliminate bronchoconstriction. Administer more atropine if assisted ventilation remains difficult or secretions persist. Heart rate and pupil size are poor clinical indicators of adequate atropinization. Presence of tachycardia should not dissuade the clinician from initiating or continuing atropine therapy. Miosis may be absent or delayed in dermal exposures and is not reversed by systemic atropine.
Up to 20 mg of atropine may be required the first day, unlike with organophosphate insecticide poisoning, where as much as 3000 mg of atropine may be required over 1 day. In the Tokyo sarin attack, only 19% of poisoned patients required more than 2 mg of atropine. Severely poisoned patients required 1.5-15 mg of atropine. Oxime therapy Oximes are nucleophilic substances that bind to the phosphate moiety of the nerve agent more avidly than AChE to reactivate the nerve agent–inhibited enzyme. Reactivation is impossible once dealkylation or "aging" of phosphorylated AChE occurs. Once aging occurs, new AChE must be synthesized. The rate of aging varies among nerve agents. Aging occurs within 2 minutes after soman exposure, 5-8 hours after sarin exposure, and more than 40 hours after tabun and VX exposure. Pralidoxime chloride (2-PAM) is the only conventional oxime available for clinical use in the US. Administer pralidoxime to symptomatic patients as early as possible, ideally concurrent with adequate doses of atropine. Pralidoxime has its greatest effect at the neuromuscular junction.
Slowly administer pralidoxime IV to minimize adverse effects such as hypertension, headache, blurred vision, epigastric pain, nausea, and vomiting. When IV access cannot be established, 2-PAM also may be given IM (1 mg with 3 mL sterile saline). With adequate decontamination and appropriate initial therapy, serious signs and symptoms of nerve agent toxicity rarely last more than a couple of hours. In the unusual event that toxicity persists or worsens clinically, administer repeat doses of 2-PAM at hourly intervals. In the Tokyo sarin attack, severely poisoned patients required 1-36 g. Since 2-PAM is excreted in the urine, lower repeat doses for patients with renal failure and maintain adequate hydration. If hypertension increases during pralidoxime administration, IV phentolamine may help (adults: 5 mg IV; children: 1 mg IV). Mark I kit Mark I kit was designed for military self-administration in the field. It consists of two spring-loaded IM Autoinjectors containing 2 mg of atropine and 600 mg of pralidoxime, respectively. These antidote kits are not yet available for civilian use. Hemodialysis Japanese physicians reported successful use of hemodialysis and hemoperfusion in one severely intoxicated victim of the Tokyo Subway sarin attack who remained unresponsive to pharmacotherapy.
Cholinesterase levels alone should not guide disposition. Some sources recommend observation of asymptomatic patients exposed to nerve gas vapor for 1 hour. In reality, patients who present after inhaling nerve agent vapor have experienced peak effects long before arriving at the hospital, and no further absorption or worsening is expected. When patients experience no signs or symptoms other than eye findings, they may be discharged. Unlike with organophosphate insecticides, nerve agents have not been associated with delayed neuropathy.
Skin
Chemical burns secondary to mustard often appear deceptively superficial on initial presentation. Earliest symptoms are pruritus, burning, and stinging pain over exposed areas. Moist, thinner skin is affected more severely. Affected areas appear erythematous and edematous. If contamination is more extensive, superficial bullae occur within 24 hours of exposure. Most burns are partial thickness, but full-thickness burns with deep bullae and ulcers may result from exposure to higher concentrations. Severe exposures clinically and histologically may resemble scalded skin syndrome or toxic epidermal necrolysis. Blister fluid does not contain active mustard and is not toxic.
Eyes
Eyes are especially sensitive to the effects of mustard. Ocular symptoms begin 4-8 hours postexposure. Earliest symptoms include burning pain, foreign body sensation, photophobia, tearing, and visual blurring. Clinical manifestations include eyelid edema, conjunctival injection and edema, chemosis, iritis, corneal abrasions, edema and ulceration, and decreased visual acuity. Permanent corneal scarring and blindness may occur with severe exposures.
Respiratory tract
Mustards primarily damage upper airway mucosa. Inhalation of mustard vapor produces a direct inflammatory effect on the respiratory tract, with damage occurring in a progressive downward pattern. The lower respiratory tract and lung parenchyma rarely are affected. Following a variable latent period of 2-24 hours, injury is characterized by hemorrhagic inflammation and airway erosion.
Upper respiratory tract is affected first, evidenced by sinusitis, sinus congestion, sore throat, and hoarseness. Lower respiratory tract symptoms include cough, dyspnea, and respiratory distress. Direct necrotic effect of mustard on airway mucosa produces epithelial sloughing and pseudomembrane formation, causing small and large airway obstruction.
In severe cases, late pulmonary sequelae include bronchopneumonia and bronchial obstruction. Pulmonary edema rarely occurs, because mustard rarely affects the lung parenchyma and alveoli. Patients with extensive mucosal involvement may suffer fatal respiratory compromise as late as several days after exposure.
Gastrointestinal tract
Mustard damages rapidly proliferating cells of the intestinal mucosa. GI involvement results in abdominal pain, nausea, vomiting, diarrhea, and weight loss.
Hematopoietic system
Mustards cause unpredictable bone marrow suppression, as leukocyte precursors begin dying 3-5 days after exposure. A leukopenic nadir usually occurs in 3-14 days, depending on the severity of exposure. Anemia and thrombocytopenia are late findings. Complete bone marrow aplasia has been reported.
Personal protective equipment Liquid mustard contamination poses a dermal contact risk for emergency care personnel. Specialized protective military garments containing a charcoal layer to absorb penetrating sulfur mustard provide protection for up to 6 hours. These protective garments (chemical protective overgarment, battle dress overgarment, mission-oriented protective posture) are not available outside the military. Level A PPE provides the best protection for civilian first responders, and hospital-based emergency care personnel involved in subsequent decontamination should wear level A PPE.
Decontamination Decontamination within 2 minutes of exposure is the most important intervention for patients with dermal exposure, since mustard rapidly becomes fixed to tissues, and its effects are irreversible. The classic description is an initial lack of signs and symptoms, which does not lessen the urgency to decontaminate patients as soon as possible.
Remove clothing immediately and wash the underlying skin with soap and water. Ocular exposure requires immediate copious irrigation with saline or water. Next, decontaminate the skin with 0.5% hypochlorite solution or with alkaline soap and water, which chemically inactivates sulfur mustard. Because mustard is relatively insoluble in water, water alone has limited value as a decontaminant. Decontamination after the first few minutes of exposure does not prevent subsequent damage but at least protects emergency care personnel from further contact exposure.
Supportive care Treatment of mustard exposure proceeds according to symptoms. Since the effects of mustards typically are delayed, persons with complaints immediately after exposure may have an additional injury. Patients with signs of upper airway obstruction require endotracheal intubation or the creation of a surgical airway. Also consider endotracheal intubation for persons with severe exposures. Use the largest endotracheal tube that can pass through, since sloughing epithelium may obstruct smaller tubes. Have patients inhale moist air. Mucolytics also are recommended for those with respiratory complaints.
Avoid overhydration, since fluid losses generally are less than with thermal burns. Monitor fluid and electrolyte status and replace losses accordingly. Mustard-induced burns are especially painful, warranting the liberal use of narcotic analgesia. Adequate burn care is essential, since skin lesions heal slowly and are prone to infection. Severe burns may require debridement, irrigation, and topical antibiotics, such as silver sulfadiazine. Address tetanus toxoid immunity.
Severe ocular burns require ophthalmologic consultation. Eye care typically includes daily irrigation, topical antibiotic solutions, topical corticosteroids, and mydriatics. Treat minor corneal injuries similarly to corneal abrasions. Apply petroleum jelly to prevent eyelid margins from sticking together. More severe corneal injuries may take as long as 2-3 months to heal. Permanent visual defects are rare.
Specific therapy Although no antidotes currently are available to treat mustard toxicity, several agents are under investigation, including antioxidants (vitamin E), anti-inflammatory drugs (corticosteroids), mustard scavengers (glutathione, N-acetylcysteine), and nitric oxide synthase inhibitors (L-nitroarginine methyl ester).
Administer granulocyte colony-stimulating factor to patients with bone marrow suppression following mustard exposure.
Disposition Patients with significant respiratory tract burns usually require ICU admission and aggressive pulmonary care. Admit patients with significant dermal burns to a burn unit for aggressive wound management, analgesia, and supportive care. Arrange to monitor blood cell counts for 2 weeks following significant exposures. For 12 hours prior to discharge, observe patients who are initially asymptomatic following mustard exposure.
Most patients recover completely. Only a small fraction have chronic ocular or pulmonary damage. Approximately 2% of those exposed to sulfur mustard in World War I died, mostly due to burns, respiratory tract damage, and bone marrow suppression. Sulfur mustard is a known carcinogen, yet a single exposure causes only minimal risk.
CWAs comprise a diverse group of extremely hazardous materials. Emergency physicians should be familiar with the pathophysiology and various clinical presentations produced by CWAs as well as the principles and practices of appropriate medical management. Since deployment of CWAs also places emergency care providers at serious risk of exposure, emergency physicians must be familiar with PPE and decontamination.
As potential weapons of mass destruction, CWAs are capable of causing a catastrophic medical disaster, which would overwhelm any healthcare system. Since civilian victims exposed to CWAs are likely to flee to the nearest hospital, emergency physicians play a key role in preparing emergency departments for the treatment of persons exposed to CWAs.
For excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education article Chemical Warfare.
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