VESICANTS

Sulfur mustard has posed a military threat since its introduction on the battlefield in World War I. Most of this chapter concerns this agent. Unless otherwise noted, the term "mustard" refers to sulfur mustard.

The nitrogen mustards (HN1, HN2, HN3) were synthesized in the 1930's, but were not produced in large amounts for warfare. Mechlorethamine (HN2; Mustargen) became the prototypical cancer chemotherapeutic compound and remained the standard compound for this purpose for many years.

Lewisite (L) was synthesized during the late stages of World War I, but probably has not been used on a battlefield. The Lewisite antidote, British-Anti-Lewisite (BAL), finds medicinal use today as a heavy-metal chelator.

Although classified as a vesicant, phosgene oxime (CX) is a corrosive urticant that also has not seen battlefield use.

Lewisite and phosgene oxime pose only minor potential military threats and will be discussed briefly at the end of this chapter.

Signs and Symptoms: Asymtomatic latent period (hours). Erythema and blisters on the skin; irritation, conjunctivitis and corneal opacity and damage in the eyes; mild upper respiratory signs to marked airway damage; also gastrointestinal effects and bone marrow stem cell suppression.

Management: Decontamination immediately after exposure is the only way to prevent damage. Symptomatic management of lesions.

Vesicant agents, specifically sulfur mustard (H; HD), have been major military threat agents since their introduction in World War I. They constitute both a vapor and a liquid threat to all exposed skin and mucous membranes. Mustard's effects are delayed, appearing hours after exposure. Organs most commonly affected are the skin (with erythema and vesicles), eyes (with mild conjunctivitis to severe eye damage), and airways (with mild irritation of the upper respiratory tract to severe bronchiolar damage leading to necrosis and hemorrhage of the airway mucosa and musculature). Following exposure to large quantities of mustard, presursor cells of the bone marrow are damaged, leading to pancytopenia and increased susceptibility to infection. The gastrointestinal tract may be damaged, and there are sometimes central nervous system signs. There is no specific antidote, and management is symptomatic therapy. Immediate decontamination is the only way to reduce damage.

Sulfur mustard was first synthesized in the early 1800s and was first used on the battlefield during World War I by Germany in July 1917. Despite its introduction late in that conflict, mustard produced the most chemical casualties, although fewer than 5% of these casualties who reached medical treatment facilities died. Italy allegedly used mustard in the 1930s against Abyssinia. Egypt apparently employed mustard in the 1960s against Yemen, and Iraq used mustard in the 1980s against Iran and the Kurds. Mustard is still considered a major threat agent of former Warsaw Pact countries and third world countries.

The U.S. manufactured mustard during World War I (WWI) and World War II (WWII) and maintains a stockpile that is currently undergoing destruction.

Nomenclature: Sulfur mustard manufactured by the Levinstein process contains up to 30% impurities (mostly sulfur) and is known as H. Mustard made by a distillation procedure is almost pure and is known as HD (distilled mustard). An early term for the German agent was HS (probably derived from the WWI slang term Hun Stoffe).

Mustard is an oily liquid with a color ranging from a light yellow to brown. Its odor is that of garlic, onion, or mustard (hence its name), but because of accomodation of the sense of smell, odor should not be relied on for detection. Under temperate conditions mustard evaporates slowly and is primarily a liquid hazard, but its vapor hazard increases with increasing temperature. At 100^oF or above, it is a definite vapor hazard. Mustard freezes at 57^oF and, since a solid is difficult to disperse, it is often mixed with substances with a lower freezing point, e.g., Lewisite (the mixture is HL), or agent T, a closely related vesicant (the mixture is HT) so that the mixture will remain liquid at lower temperatures.

After absorption into the body, mustard rapidly cyclizes (seconds to minutes) in extracellular water. This cyclic compound is extremely reactive and quickly binds to intra- and extra-cellular enzymes, proteins, and other substances. Mustard has many biological actions, but the exact mechanism by which it produces tissue injury is not known. According to one prominent hypothesis, biological damage from mustard results from DNA alkylation and crosslinking in rapidly dividing cells, such as basal keratinocytes, mucosal epithelium, and bone marrow precursor cells. This leads to cellular death and inflammatory reaction, and, in the skin, protease digestion of anchoring filaments at the epidermal-dermal junction and the formation of blisters.

Mustard possesses mild cholinergic activity, which may be responsible for effects such as early gastrointestinal symptoms and miosis.

Mustard reacts with tissue within minutes of entering the body and is no longer an intact molecule. Blood, tissue, and blister fluid do not contain mustard, and one cannot become exposed to mustard by contact with body fluids or tissues.

Topical effects of mustard occur in the eye, airways, and skin. Systemically absorbed mustard may produce effects in the bone marrow, the gastrointestinal tract, and the central nervous system. Direct injury to the GI tract may also occur following ingestion of the compound.

Combined data from U.S. forces in WWI and Iranians in the Iraq-Iran conflict suggest equal incidence of eye, airway, and skin involvement (between 80 and 90% for each). However, there were higher incidences of eye and lung damage in Iranian casualites than in WWI casualties, probably because of the larger amount of evaporation of the agent in the hot climate.

Skin: Erythema is the mildest and earliest form of skin injury after exposure to mustard. It resembles sunburn, and is associated with pruritis or burning, stinging pain. Erythema begins to appear in 2 to 24 hours after vapor exposure with time of onset dependent on Ct, ambient temperature and humidity, and skin site exposed. The skin sites most sensitive are the warm, moist locations with thinner skin, such as the perineum, external genitalia, axillae, antecubital fossae, and neck.

Within the erythematous areas, small vesicles can develop, which may later coalesce to form bullae. The typical bulla, or blister, is large, dome-shaped, thin-walled, translucent, yellowish, and surrounded by erythema. The blister fluid is clear, at first thin and straw-colored, but later yellowish and tending to coagulate. The fluid does not contain mustard and is not a vesicant.

At extremely high doses, such as those from liquid exposure, lesions may develop a central zone of coagulation necrosis with blister formation at the periphery. These lesions take longer to heal and are more prone to secondary infection than the uncomplicated lesions seen at lower exposure levels.

Pulmonary: The primary airway lesion from mustard is necrosis of the mucosa with later damage to the musculature of the airways if the amount of agent is large. The damage begins in the upper airways and descends to the lower airways in a dose-dependent manner. Usually, the terminal airways and alveoli are affected only as a terminal event. Pulmonary edema is not usually present unless the damage is very severe and then it usually is hemorrhagic.

The earliest effects from mustard--perhaps the only effects from a low Ct--involve the nose, the sinuses, and the pharynx. There may be irritation or burning of the nares, epistaxis, sinus pain or irritation, and irritation or soreness of the pharynx. As the Ct increases other effects occur: laryngitis with voice changes and a nonproductive cough. Damage to the trachea and upper bronchi leads to a cough productive of sputum. Lower airway involvement causes dyspnea and an increasingly severe cough with increased quantities of sputum. Terminally, there may be necrosis of the smaller airways with hemorrhagic edema into surrounding alveoli. This hemorrhagic pulmonary edema is rarely a feature.

Necrosis of the airway mucosa with resulting inflammation can cause pseudomembrane formation, and pseudomembranes may occur from the most proximal parts of the airways to the most distal portions. These membranes may cause local airway obstruction at the sites of formation, and detachment may lead to obstruction of lower airways.

The cause of death in mustard poisoning is commonly respiratory failure. Mechanical obstruction by pseudomembranes may be a cause, but more commonly deaths occurring from the third to the sixth day after exposure result from secondary bacterial pneumonia caused by bacterial invasion of denuded repiratory mucosa and necrotic debris. Agent-induced bone marrow suppression is a contributory factor in later, septic deaths from pneumonia.

Ocular: The eyes are the organs most sensitive to mustard vapor injury. The latent period is shorter for eye injury than for skin injury and is also Ct dependent.

After low-dose vapor exposure, irritation, evidenced by reddening of the eyes, may be the only effect. As the dose increases, the spectrum of injury includes progressively more severe conjunctivitis, photophobia, blepharospasm, pain, and corneal damage.

Blisters do not normally form in the eyes. Instead, swelling and loosening of corneal epithelial cells leads to corneal edema and clouding with leukocytes (which affects vision). Corneal vascularization with secondary edema may last for weeks. Severe effects may be followed by scarring between the iris and lens; this scarring may restrict pupillary movements and may predispose victims to glaucoma.

The most severe damage is caused by liquid mustard from airborne droplets or by self-contamination. After extensive eye exposure, severe corneal damage with possible perforation of the cornea and loss of the eye can occur. Eye loss also result from panophthalmitis if appropriate therapy is not instituted.

During World War I, mild conjunctivitis accounted for 75% of the eye injuries, with recovery in 1 to 2 weeks. Severe conjunctivitis with minimal corneal involvement, blepharospasm, edema of the lids and conjunctivae, and orange-peel roughening of the cornea accounted for 15% of the cases, with recovery in 2 to 3 weeks. Mild corneal involvement accounted for 10% of the cases. Those with severe corneal damage accounted for fewer than 1% of cases. Subsequent defective vision later occured in about 0.1% of casualties with mustard-induced eye injuries.

Miosis noted after mustard exposure in both humans and experimental animals is probably from the cholinomimetic activity of mustard.

Gastrointestinal tract: The mucosa of the gastrointestinal (GI) tract is very susceptible to mustard damage, either from systemic absorption or ingestion of the agent. However, reports of severe GI effects from mustard poisoning are relatively infrequent.

Mustard exposure, even exposure to a small amount, will often cause nausea with or without vomiting lasting 24 hours or less. The nausea and vomiting appear not to be a direct effect of the agent on the gastrointestinal tract, but rather they are from a stress reaction, a nonspecific reaction to the odor, or cholinergic stimulation by mustard. Further GI symptoms are usually minimal unless the exposure was severe (even then, GI signs are not common) or unless exposure resulted from ingestion of contaminated food or drink. Diarrhea has been reported; constipation is equally common. Diarrhea (rarely bloody) and vomiting beginning days after a high-dose exposure imply a poor prognosis.

Central nervous system: The CNS effects of mustard remain poorly defined. Animal work demonstrated that mustards (particularly the nitrogen mustards) are convulsants, and there are several human case reports describing people who were exposed to very large amounts and who had neurological effects within several hours after exposure just prior to death. Reports from WWI and again from Iran described people exposed to small amounts of mustard, who appeared sluggish, apathetic, and lethargic. These reports suggested that minor psychological problems can linger for a year or longer.

Mustard binds irreversibly to tissue within several minutes after contact. If decontamination is not done immediately after exposure there is no way to prevent injury, although later decontamination might prevent a more severe lesion.

The clinical effects of mustard are delayed. Signs and symptoms may appear as early as two hours after a high-dose exposure, whereas following a low-dose vapor exposure the latent or asymptomatic period may extend to 24 hours. There are several reports of individuals exposed to very large amounts who died within hours; this type of occurrence is extremely rare. The typical onset time is between four and eight hours. The concentration (C) of the mustard vapor, the time (t) of exposure, the ambient weather, and the body site exposed are factors in the onset time.

It must be emphasized that mustard causes tissue damage within several minutes after contact without causing any concomitant clinical effects, e.g., burning or erythema. Because of the lack of immediate effects, the contaminated person is often unaware of the exposure and does not decontaminate. To prevent injury, decontamination must be done immediately after contact. Later decontamination may prevent further damage, absorption, or spread of the agent.

ORGAN	SEVERITY	EFFECTS	ONSET OF FIRST EFFECT
Eye	Mild	Tearing, itchy, burning, gritty feeling	4-12 hours
	Moderate	Above, plus reddening, swelling of lids, moderate pain	3-6 hours
	Severe	Marked swelling of lids, possible cornea damage, severe pain	1-2 hours
Airways	Mild	Runny nose, sneezing, nosebleed, hoarseness, hacking cough	12-24 hours
	Severe	Above, plus severe productive cough, shortness of breath	2-4 hours
Skin	Mild to severe	Erythema (redness), blisters	2-24 hours

Of the three vesicant agents, mustard is the only one that does not cause immediate pain. The casualty is asymptomatic until the lesion becomes apparent hours later.

In contrast, Lewisite and phosgene oxime in either liquid or vapor form cause immediate pain or irritation to the eye, skin, or respiratory tract. This is sufficient stimulus to decontaminate immediately or to mask. Because of this, lesions from these agents may not be as severe as those from mustard.

Isolated small blisters or a small group of blisters suggest possible exposure to mustard, to plants such as poison ivy or poison oak, to drugs, or to other substances. The physical characteristics of the lesion are not distinctive, therefore the history of exposure is invaluable.

Although the blisters of mustard and Lewisite are slightly different (there is less erythema around the Lewisite blister) this information is of little value in individual cases.

There are no available clinical laboratory tests for mustard exposure. Leukocytosis occurs during the first day and the magnitude of increase in leukocytes during the subsequent days correlates roughly with the amount of tissue injury, primarily to skin or pulmonary tissue. If systemic absorption is large, leukocytes in the peripheral blood will decrease beginning on day three to day five; this decrease indicates damage to precursor cells in the blood-forming organs. The fall may be precipitate, e.g., a decrease of 5,000 to 10,000 cells/day. If the marrow damage is severe, erythrocytes and thrombocytes may later decrease, but the casualty usually recovers or dies before this is apparent. A leukocyte count of 500 or fewer is a sign of an unfavorable prognosis.

Signs of a chemical pneumonitis may appear within the first 2 to 3 days after inhalational exposure. Leukocytosis, fever, and sputum production suggest a bacterial process, but within this time period sputum cultures are usually negative for pathogens. Organisms commonly invade the damaged airway tissue at days three to five, and a change in the fever pattern, an increase in leukocytosis, and a change in the character of the sputum in this time period suggest a bacterial process. Sputum Gram stain and culture should be done for identification of the specific organism.

Damaged skin should be cultured routinely, particularly if there is an increase in the exudate or an increase in the inflammatory reaction.

Although gastrointestinal bleeding is unusual, declining hematocrit values should prompt serial analyses of stool for occult blood.

There is no clinical laboratory test for mustard in blood or tissue, nor is one expected as mustard is biotransformed and bound to tissues within minutes after absorption. A method for analysis of urine for thiodiglycol, a metabolite of mustard, is in the investigational stage.

The management of a patient exposed to mustard may be simple, as in the provision of symptomatic care for a sunburn-like erythema, or extremely complex as providing total management for a severely ill patient with burns, immunosuppression, and multi-system involvement. The following are suggested therapeutic measures for each organ system. Guidelines for general patient care are not intended to take the place of sound clinical judgment, especially in the management of complicated cases.

Skin: Erythema should be treated with calamine or other soothing lotion or cream (e.g., 0.25% camphor and menthol, calamine) to reduce burning and itching. Small blisters (under 1-2 cm) should be left intact, but because larger ones will eventually break (the blister fluid does not contain mustard) they should be carefully unroofed. Denuded areas should be irrigated 3-4 times daily with saline, another sterile solution, or soapy water and then liberally covered with a topical antibiotic such as silver sulfadiazine or mafenide acetate to a thickness of 1-2 mm. If an antibiotic cream is not available, sterile petrolatum will be useful. Modified Dakins solution (sodium hypochlorite) was used in WWI and in Iranian casualties for irrigation and as an antiseptic.

Multiple or large areas of vesication suggest the need for hospitalization and whirlpool bath irrigation.

Systemic analgesics should be used liberally, particularly before manipulation of the patient or irrigation of the burn areas. Systemic antipruritics such as trimeprazine should be tried if needed. Monitoring of fluids and electrolytes is important in any sick patient, but it must be recognized that fluid loss is not of the magnitude seen with thermal burns. Clinicians accustomed to treating patients with thermal burns must resist the temptation to overhydrate a mustard casualty with a similar amount of burned body surface.

Eyes: Conjunctival irritation from a low Ct will respond to any of a number of available ophthalmic solutions after the eyes are thoroughly irrigated. Regular application of homatropine (or other anticholinergic drug) ophthalmic ointment will reduce or prevent future synechiae formation, and a topical antibiotic applied several times a day will reduce the incidence and severity of infection. Vaseline or a similar substance should be applied to the edges of the lids regularly to prevent them from sticking together. This prevents adhesions and later scarring during healing and also permits drainage of any underlying infection. Topical analgesics may be useful initially if blepharospasm is too severe to permit an adequate examination, but topical analgesics should otherwise be avoided, and systemic analgesics should be given for eye pain. Topical steroids are not of proven value, but their use during the first day or two might reduce inflammation. Further use should be relegated to an ophthalmologist. Sunglasses may reduce discomfort from photophobia.

The patient should be constantly reassured that complete healing and restoration of vision will be the outcome.

Pulmonary: Upper airway symptoms (sore throat, non-productive cough, hoarseness) may respond to steam inhalation and cough suppressants. Although a productive cough and dyspnea accompanied by fever and leukocytosis occurring 12 to 24 hours after exposure may suggest a bacterial process to the clinician, he must resist the urge to use antibiotics for this process, which in fact is a sterile bronchitis or pneumonitis. Infection often occurs on about the third day and its presence is signaled by an increased fever, an increase in the pulmonary infiltrate by x-ray, and an increase in sputum production and a change in sputum character to purulent. Appropriate antibiotic therapy should await confirmation of the clinical impression by positive sputum studies (Gram stain and culture).

Intubation should be performed early before laryngeal spasm or edema makes it difficult or impossible. Intubation permits better ventilation and facilitates suction of the necrotic and inflammatory debris. Oxygen may be needed, and early use of PEEP or CPAP may be of benefit. If there is a suggestion of pseudomembrane formation, bronchoscopy should be done to permit suctioning of the necrotic debris by direct vision.

Bronchodilators may be of benefit for bronchospasm. If they fail, steroids may be tried. There is little evidence that the routine use of steroids is beneficial. The need for continuous use of assisted or controlled ventilation suggests a poor prognosis.

Death often occurs between the fifth and tenth day after exposure because of pulmonary insufficiency and infection complicated by a compromised immune response from agent-induced bone marrow damage.

Gastrointestinal: Atropine (0.4-0.6 mg, i.m. or i.v.), another anticholinergic drug, or antiemetic should control the early nausea and vomiting. Prolonged vomiting or voluminous diarrhea beginning days after exposure suggests direct involvement of the gastrointestinal tract by severe systemic poisoning, a poor prognostic sign.

Bone marrow: Sterilization of the gut by non-absorbable antibiotics should be considered to reduce the possibility of sepsis from enteric organisms. Cellular replacement (bone marrow transplants or transfusions) may be successful as intact mustard does not persist beyond the few minutes following absorption and would not damage the new cells.

General: A patient severely ill from mustard poisoning requires the general supportive care provided for any severely ill patient as well as the specific care given to a burn patient. Liberal use of systemic analgesics and antipruritics, as needed, maintenance of fluid and electrolyte balance, and other supportive measures are necessary. Parenteral food supplements including vitamins may also be helpful.

Other: Sulfur donors such as sodium thiosulfate decreased systemic effects and elevated the LD₅₀ when given before exposure or within 20 minutes after exposure in experimental animals. Activated charcoal given orally to casualties was of no value. Hemodialysis was not only ineffective, but was harmful in several casualties. The rapid biotransformation of the mustard molecule suggests that none of these measures would be beneficial hours or days after exposure.

Most mustard casualties will be triaged as delayed. Those with skin lesions covering several percent to 50% of the body surface area (BSA) will require further medical care, but do not need immediate life-saving assistance. (In contrast, patients with thermal burns covering 20% to 70% of their BSA are considered immediate because of their fluid requirements.) Those with mild to moderate pulmonary effects will also eventually require further care, but are not in the immediate category for triage. Eye injuries from other causes require immediate care, but by the time the mustard eye lesion develops there is no possibility of reducing the injury. These casualties are also in the delayed category.

Patients with skin lesions covering a small percent of BSA (under 5%) when these lesions are not in vital areas (a burn on the face might prevent mask donning) are triaged as minimal. Clinical judgement should dictate whether these patients should be evacuated for care or whether they can return to duty. The tactical situation will also be a factor in the decision. Patients with minor eye injuries to include irritation and reddening can be treated and returned to duty. Those with slight upper respiratory complaints of a hacking cough and an irritated throat which developed 12 hours or longer after exposure might be given symptomatic therapy and returned to duty.

The only mustard casualties who might be triaged as immediate are those with moderately severe to severe pulmonary signs and symptoms. Two factors should temper this decision: (1) Casualties who develop severe pulmonary effects within four to six hours of exposure will probably not survive despite maximal medical care, and it might be better to expend limited medical resources elsewhere. (2) If evacuation to a maximal medical care facility is required, the casualty may survive the lengthy trip, but during the delay his lesion may progress to an irreversible stage.

A mustard casualty who has severe pulmonary effects that developed within 4 to 6 hours of exposure should be triaged as expectant. A casualty who has over 50% BSA burns from mustard liquid might also be categorized as expectant, but this decision would depend on available medical resources at the far rear echelons of medical care. (The LD₅₀ for liquid mustard is about 7 grams, or between one and one and a half teaspoons of liquid. This amount will cover about 25% BSA, so an individual with a 50% BSA burn could possibly have 2 LD₅₀s on his skin. This person might be saved, but at great expenditure of medical resources.)

Casualties with minor skin, eye, or pulmonary injuries might be returned to duty as soon as they are given symptomatic therapy at a medical facility. The range of return-to-duty times for those with more severe but treatable injuries is from one week to a year or longer.

Those with eye injuries should recover in 1 to 3 weeks except for the low percentage of casualties with severe injuries or complications. Casualties with mild to moderate pulmonary injuries should return in a week to a month. Healing of mild skin lesions will enable the casualty to return within several weeks, but patients with large skin lesions will require hospitalization for many months.

Repeated symptomatic exposures to mustard over a period of years (as in manufacturing workers) seem to be well established as a causal factor in an increased incidence of upper airway cancer. However, the association between a single exposure to mustard and airway cancer is not well established. A single, severe exposure to mustard may have contributed to other airway problems, such as chronic bronchitis, based on WWI data.

Several eye diseases, such as chronic conjunctivitis and delayed keratitis, may follow a single, severe exposure of the eye to mustard. Skin scarring and pigment changes may follow a severe skin lesion from mustard; cancer sometimes develops in scarred skin.

Mustard is classed as a mutagen and carcinogen based on laboratory studies. However, there are no data to implicate mustard as a reproductive toxin in man, and there is no evidence that mustard is a causative factor in non-airway, non-skin cancer in man.

Signs and Symptoms: Lewisite causes immediate pain or irritation of skin and mucous membranes. Erythema and blisters on the skin and eye and airway damage similar to those seen after mustard exposure develop later.

Management: Immediate decontamination; symptomatic management of lesions the same as for mustard lesions; a specific antidote (BAL) will decrease systemic effects.

Lewisite is a vesicant that damages the eyes, skin, and airways by direct contact. After absorption, it causes an increase in capillary permeability to produce hypovolemia, shock, and organ damage. Exposure to Lewisite causes immediate pain or irritation, although lesions require hours to become full-blown. Management of a Lewisite casualty is similar to management of a mustard casualty, although a specific antidote, British-Anti-Lewisite (BAL; dimercaprol) will alleviate some effects.

Lewisite was first synthesized in 1918 by Dr. Wilford Lee Lewis, but production was too late for its use in World War I. It has not been used in warfare, although it may be stockpiled by some countries. Lewisite is sometimes mixed with mustard to achieve a lower freezing point of the mixture for ground dispersal and aerial spraying.

Lewisite is an oily, colorless liquid with the odor of geraniums. It is more volatile than mustard.

Although Lewisite contains trivalent arsenic and combines with thiol groups in many enzymes, its exact mechanism of biological activity is unknown.

Toxicities: Lewisite causes nasal irritation at a Ct of about 8 mg"min/m³, and its odor is noted at a Ct of about 20 mg"min/m³. Lewisite causes vesication and death from inhalation at the same Cts as mustard. Liquid Lewisite causes vesication at about 14 Fg, and the LD₅₀ is about 2.8 grams on the skin.

Organ Systems: Unlike mustard, Lewisite vapor or liquid causes immediate pain or irritation. A person with a droplet of Lewisite on his skin will note the burning and will immediately take steps to try to remove it. The vapor is so irritating that a person will seek to mask or to leave the contaminated area if possible. Because this warning causes the person exposed to take immediate steps to decontaminate, the Lewisite lesion will probably not be as severe as the lesion from mustard, as exposure to mustard is often undetected and decontamination is not done.

There are almost no data on humans exposed to Lewisite, and the following is based on animal investigations.

Skin: Within about five minutes after contact liquid Lewisite will produce a grayish area of dead epithelium. Erythema and blister formation follow more rapidly than in a similar lesion from mustard, although the full lesion does not develop for 12 to 18 hours. The lesion has more tissue necrosis and tissue sloughing than does a mustard lesion.

Eye: Lewisite causes pain and blepharospasm on contact. Edema of the conjunctiva and lids follows, and the eyes may be swollen shut within an hour. Iritis and corneal damage may follow if the dose is high. Liquid Lewisite causes severe eye damage within minutes of contact.

Respiratory: The extreme irritancy of Lewisite to the nasal area and upper airways causes the person to mask or exit the area. Scanty data indicate that Lewisite causes the same airway signs and symptoms as does mustard. The airway mucosa is the primary target and damage progresses down the airways in a dose-dependent manner. Pseudomembrane formation is prominent. Pulmonary edema, which occurs rarely and usually only to a minimal degree after mustard exposure, may complicate exposure to Lewisite.

Other: Available data suggest that Lewisite causes an increase in permeability of systemic capillaries with resulting intravascular fluid loss, hypovolemia, shock, and organ congestion. This may lead to hepatic or renal necrosis with more prominent gastrointestinal effects (including vomiting and diarrhea) than after mustard.

Physical Findings: The findings are similar to those caused by mustard. As noted, the tissue damage at the site of the skin lesion may be more severe.

Pain and irritation from either liquid or vapor Lewisite are immediate. Early tissue destruction is more obvious than after mustard, but the lesion is not full-blown for 12 hours or longer.

Although differences have been reported between the skin lesions from mustard and Lewisite (less surrounding erythema and more tissue destruction characterize Lewisite blisters), these are of little diagnostic assistance in a single patient. The history of immediate pain on contact is absent after mustard exposure and present after Lewisite or phosgene oxime exposures.

Other substances cause erythema and blisters, and often the history of exposure is the most helpful tool in diagnosis.

There is no specific diagnostic test for Lewisite. Leukocytosis, fever, and other signs of tissue destruction will occur.

Early decontamination is the only way of preventing or lessening Lewisite damage. Since this must be accomplished within minutes after exposure, this is self-aid rather than medical management.

The guidelines for the management of a mustard casualty will be useful. Lewisite does not cause damage to hematopoietic organs as mustard does. However, fluid loss from the capillaries necessitates careful attention to fluid balance.

British-Anti-Lewisite (BAL; dimercaprol) was developed as an antidote for Lewisite and is used in medicine as a chelating agent for heavy metals. There is evidence that BAL in oil, given intramuscularly, will reduce the systemic effects of Lewisite. However, BAL itself causes some toxicity, and the user should read the package insert carefully. BAL skin ointment and BAL ophthalmic ointment decrease the severity of skin and eye lesions when applied immediately after early decontamination. However, neither is currently manufactured.

Casualties should be triaged using the guidelines for triage of mustard patients.

Casualties with minor skin lesions who receive symptomatic therapy can be returned to duty quickly. Because Lewisite generally causes more tissue damage than mustard, casualties with eye and larger skin lesions should be triaged as delayed and evacuated. Whether to triage those with pulmonary injury as immediate, delayed, or expectant depends on the severity of the injury and how quickly after exposure it occurred.

Signs and Symptoms: Immediate burning and irritation followed by wheal-like skin lesions and eye and airway damage

Phosgene oxime is an urticant or nettle agent that causes a corrosive type of skin and tissue lesion. It is not a true vesicant, since it does not cause blisters. The vapor is extremely irritating, and both the vapor and liquid cause almost immediate tissue damage upon contact. There is very scanty information on phosgene oxime.

There is no current assessment of the potential of phosgene oxime as a military threat agent.

CX is a solid at temperatures below 95^oF, but the vapor pressure of the solid is high enough to produce symptoms. Traces of many metals cause it to decompose. However, it corrodes most metals.

Toxicities: The estimated LCt₅₀ by inhalation is 1500-2000 mg·min/m³. The LD₅₀ for skin exposure has been estimated as 25 mg/kg.

Skin: Phosgene oxime liquid or vapor causes pain on contact which is followed in turn by blanching with an erythematous ring in 30 seconds, a wheal in 30 minutes, and necrosis later. The extreme pain may persist for days.

Eyes: Phosgene oxime is extremely painful to the eyes. The damage is probably similar to that caused by Lewisite.

Pulmonary: Phosgene oxime is very irritating to the upper airways. This agent causes pulmonary edema after inhalation and after skin application.

Other: Some animal data suggest that phosgene oxime may cause hemorrhagic inflammatory changes in the gastrointestinal tract.

Phosgene oxime causes immediate pain and irritation to all exposed skin and mucous membranes. The time course of damage to other tissue probably parallels that of damage to the skin.

Other causes of urticaria and skin necrosis must be considered. Common urticants do not cause the extreme pain that phosgene oxime does.

Management is supportive. The skin lesion should be managed in the same way that a necrotic ulcerated lesion from another cause would be managed.

Because of the continuing pain, most casualties should be placed in the delayed category and evacuated.

The decision to return a phosgene oxime casualty to duty should be based on healing of the lesion(s) and the casualty's freedom from discomfort.