Vesicants are a class of chemical weapons named for their ability to cause vesicular skin lesions. The 4 organic arsenicals are lewisite (L), methyldichloroarsine (MD), phenyldichloroarsine (PD), and ethyldichloroarsine (ED). These agents, together with the mustard agents and phosgene oxime, make up the vesicant class.[1, 2] Although not as well known as the mustards, the organic arsenicals are a group of potent vesicants that medical planners should not overlook.
Interest in organic arsenicals dates back to the mid-19th century. While investigating possible new fumigants, European chemists discovered that chloroarsines (ie, arsenic-chloride compound in which 1 of the chlorine atoms is replaced by an organic radical) tended to be destructive both to insects and to human tissue. With the start of World War I, both sides employed chemists to create chemical warfare (CW) agents. The trench warfare stalemate created a tactical need for a chemical weapon that was both short acting (eg, nonpersistent, volatile) and lethal. To fill this need, German chemists delivered the first weaponized organic arsenical, MD.
Two additional organic arsenicals, PD and ED, soon augmented MD. While MD, PD, and ED were being deployed on the battlefields of Europe in 1917 and 1918, a team of American researchers, led by Captain Wilford Lee Lewis of the US Army Medical Corps, was working on the fourth and final organic arsenical. Lewisite, as it was named, never was deployed in World War I.
Although mustard vesicants have been used in numerous regional wars since 1918, organic arsenical weapons have had limited use. Lewisite (L) may have been used by Italy against Ethiopia in 1935 and again by Japan in China from 1937-1944. Lewisite became the primary vesicant stockpiled by the Soviet Union.
Today, arsenicals still are considered a threat, not so much from large nation states but from smaller, less developed nations and/or by terrorist organizations. The relative ease of production coupled with their effectiveness against an unprotected population make organic arsenicals a continued threat in the 21st century.[3]
The Agency for Toxic Substances & Disease Registry has established Medical Management Guidelines for lewisite exposure. These guidelines cover both prehospital and emergency department care.
For patient education information, see the First Aid and Injuries Center, as well as Chemical Warfare and Personal Protective Equipment.
The exact mechanism of biological activity and toxicity of the organic arsenicals is unknown. DNA alkylation and/or inhibition of glutathione-scavenging pathways are 2 postulated mechanisms of action. What is certain is that a blistering reaction occurs on any tissue that an arsenical contacts, whether it is skin, eye, or pulmonary tissue. The onset of symptoms after arsenical exposure occurs in seconds as compared to 4-8 hours for mustard exposure. Either a liquid or vapor (ie, gaseous form of a substance at temperatures below boiling point) can cause toxicity. The organic arsenicals tend to have high volatility at room temperature and thus pose a significant vapor threat to exposed personnel.
Animal data and limited human trials demonstrated that organic arsenicals readily penetrate the skin. Within seconds of contact, the chemical fixes itself to the epidermis and dermis. Pain is immediate. Since the agent penetrates deeper, destruction of subcutaneous tissue results.[4] Protease digestion of anchoring filament at the epidermal-dermal junction occurs. The separation of dermis from epidermis together with capillary leakage causes fluid-filled vesicles.
Vapor contact with the conjunctiva may be the victims' first symptom. Severe conjunctival irritation and blepharospasm result upon eye contact. More severe exposure can cause loosening of corneal epithelial cells and swelling and edema of the cornea.
The respiratory tract's mucosa and submucosa are susceptible to vapor exposure. Mucosal damage starts in the nose and descends down the respiratory mucosa in a dose-dependent fashion. Immediate pain, lacrimation, and irritation accompany the damage. Damaged respiratory mucosa slough off, filling the airways with debris. Damage to the lung parenchyma causes the secretion of blood and mucous that, with the pseudomembranes, can cause asphyxiation. In animal studies, large doses of lewisite (L) caused this "dry land drowning" within 10 minutes.
The gastrointestinal tract also is susceptible. Phenyldichloroarsine (PD) vapor in particular produces a phenyl radical that causes vomiting. Vomiting usually develops within 1-2 minutes after exposure to phenyldichloroarsine (PD).
The immediate onset of symptoms following exposure makes severe or systemic toxicity to organic arsenical unlikely. However, if a victim does not have protective gear or cannot move out of a contaminated area, prolonged contact may lead to multiorgan involvement. Blood-borne arsenicals can trigger increased permeability of capillaries throughout the body. Leakage of proteins and plasma then can cause third space fluid shifts, hypovolemia, and shock. Intravascular hemolysis of erythrocytes with subsequent hemolytic anemia may result.
The National Advisory Committee for Acute Exposure Guideline levels for Hazardous Substances has determined the values for lewisite (see the Table below).[5]
Table. Acute Exposure Guideline Levels (AEGLs) for Lewisite[5]
Organic arsenical weapons never have been used within the US. Other sources of arsenic poisoning are common, and arsenic ingestion is the most common cause of acute metal poisoning in the US. Inorganic arsenic is found in insecticides, rodenticides, and herbicides and is used in mining and smelting industries.
International
Any nation or terrorist group that has access to a basic pesticide production facility can produce these agents with relative ease. The former Soviet Union is known to have combined sulfur mustard (H) and lewisite (L) into a binary weapon known as HL. Lewisite is more volatile and persistent in colder climates than mustard. Lewisite remains fluid at lower temperatures, which enables it to be dispersible in winter temperatures. Therefore, a sulfur mustard-lewisite mix can be used in lower temperatures than sulfur mustard.
Mortality/Morbidity
Although vesicants have a relatively low mortality rate when compared to other CW agents, survivors usually require prolonged care and rehabilitation. These requirements placed a tremendous burden on the medical infrastructure during World War I.
Victims of an lewisite (L) attack may remember observing puddles of a brown liquid or of smelling an odor similar to geranium. Methyldichloroarsine (MD) and ethyldichloroarsine (ED) reportedly smell like rotting fruit. Almost instantaneous pain and irritation of the skin, eyes, and nasal pharynx follow exposure. The patient usually relates a history of trying to remove himself or herself from the noxious stimuli.
Signs and symptoms are as follows:
The skin burns and itches. A history of erythema followed by the appearance of vesicles may be obtained.
Eye pain is severe and is accompanied by blepharospasm and/or photophobia.
Extreme irritation of the nasal mucosa and upper airway induces coughing and sneezing. Coughing may become productive, and shortness of breath may appear as the irritation of the airway mucosa progresses.
Phenyldichloroarsine (PD) often precipitates severe vomiting within 1-2 minutes after exposure.
Physical signs of organic arsenical exposure are similar to those of mustard agents. The major difference is the time of onset of signs. Organic arsenicals cause immediate signs, whereas signs of mustard exposure appear after a latent period of several hours.
An erythematous rash appears within 15-30 minutes. This is followed by the development of fluid-filled vesicles.Vesicles initially are filled with clear fluid and may coalesce to form large bullae. In more severe exposures, the vesicular fluid may take on a yellow and then red color, and a central area of necrosis may form.
A lewisite (L) skin lesion has more actual tissue destruction (but less surrounding erythema) than a mustard lesion. Compared with distilled mustard, lewisite (L) is gram-for-gram more toxic. The LD50 (lethal dose for 50% of the population) of lewisite (L) is 2.8 g on the skin.
Conjunctival injection and edema of the lids, cornea, and conjunctiva occur with either a vapor or liquid exposure. Corneal vascularization with secondary edema results and may last for weeks.[6]
One drop of liquid lewisite (L) on the cornea can cause severe corneal damage up to and including perforation.
Vapor damage to the upper respiratory mucosa causes epistaxis, massive rhinorrhea, and lacrimation. Laryngitis and dysphonia changes result from exposure and can lead to laryngospasm.
With larger vapor exposure, destruction of the bronchiolar mucosa and submucosa causes pseudomembrane formation and obstruction.
Systemic signs of organic toxicity may include evidence of hypovolemia and shock.
The US military and the North Atlantic Treaty Organization (NATO) have developed several field tests to detect various CW agents. The field tests that reliably detect L and the other organic arsenicals include the M256A1, individual chemical agent detector (ICAD), miniature chemical agent monitor (MINICAMS), M18A2, M21, M90, M93A1 Fox, chemical agent monitor (CAM), and depot area air monitoring system (DAAMS). Less sophisticated means of detection are M8 detection paper (turns red with lewisite [L]) and M9 paper (turns color when exposed to arsenicals).
With exception of urinary arsenic excretion, no specific tests exist for organic arsenical exposure. Leukocytosis and other nonspecific markers of tissue destruction may appear.
Culture damaged skin routinely to stave off opportunistic skin infections. Also perform sputum Gram stain and culture if the respiratory system is affected.
Massive tissue damage to the respiratory mucosa can cause acute airway compromise from laryngospasm and/or necrotic debris. Emergent endotracheal intubation may be required. Obtain a bronchoscopy consultation if pseudomembrane formation is suggested.
The top 2 priorities are protecting the caregiver and removing the offending agent from the casualty as quickly as possible. Then assess airway, breathing, and circulation (ABCs) as usual. See CBRNE - Personal Protective Equipment.
All medical personnel who may come into contact with vesicant vapor or liquid should wear protective gear.
The activated charcoal in the chemical protective mask adequately adsorbs these agents.
Protective boots, gloves, pants, and jacket (eg, mission-oriented protective posture [MOPP] gear) protect the skin; however, organic arsenicals attack rubber and can cause it to break down with prolonged exposure. This is especially true of lewisite (L). See CBRNE - Chemical Detection Equipment.
Vesicant agents irreversibly bind to the skin within minutes. Remove the agent as quickly as possible. See CBRNE - Chemical Decontamination.
Remove liquids via any means available. The military has specially developed charcoal-based kits (eg, M258A1 kit, M291 kit). If specialized kits are not available, rags, leaves, sticks, or just about any other material can be used to blot off liquid agent.
Flushing the eyes or skin is another solution. Dilute hypochlorite (0.5% solution) can be used on the skin. Live steam or alkaline solutions (eg, sodium hydroxide) can be used to decontaminate closed spaces.
As with any chemical disaster, the emergency department's disaster plan should have a system in place to efficiently triage contaminated patients.
After assessing for life-threatening conditions, additionally decontaminate patients in the triage area as indicated.
Once in the emergency department, reassess ABCs as usual.
Assessment of volume status is a must. Patients who have been in hot protective gear are predisposed to volume depletion and hyperthermia. Correction of fluid and/or electrolyte abnormalities is essential in these patients.
Vesicants may present a hazard from wound contamination. Potential risk to healthcare providers and the surgeon from possibly contaminated wounds arises from agent on foreign bodies in the wound and from thickened agents. Once a victim has been undressed and fully decontaminated, danger to the caretakers is minimal. Occasionally, intact lewisite or equally damaging breakdown products have been found in blister fluid.
Blisters smaller than 2 cm and erythematous areas can be covered with topical antibiotics, calamine lotion, or other soothing creams.
Denude fluid-filled vesicles larger than 2 cm and irrigate them with sterile saline. Apply topical antibiotics such as silver sulfadiazine. Intense pain and itching may require systemic analgesics and antipruritics.
Upper respiratory symptoms can be alleviated with humidified oxygen and cough suppressants. Reserve antibiotics for patients with pulmonary damage who develop fever. Specific antimicrobial therapy then is based on Gram stain and cultures.
Eyes may be irrigated with normal saline, followed by application of topical antibiotics. Petroleum jelly can be applied to the edges of the lids to prevent them from sticking together.
In addition to the medications mentioned in the preceding section, the organic arsenicals have an antidote in the form of British anti-lewisite agent (BAL, dimercaprol). BAL is a chelating agent that was developed at the end of World War I specifically to treat lewisite (L) casualties.
Clinical Context:
Packaged in 3-mL ampules with 100 mg/mL. Formerly supplied as an ophthalmic and dermatologic ointment during World War II; these preparations are no longer available.
As a chelating agent, BAL binds to the arsenic moiety, thereby preventing or reversing its binding to tissue enzymes. The BAL-arsenic moiety then is excreted renally. Dimercaprol currently is used as a chelating agent for heavy metals such as arsenic, gold, and mercury.
Clinical Context:
Useful in prevention of infections. Has bactericidal activity against many gram-positive and gram-negative bacteria, including yeast.
Severe vapor exposure can lead to permanent damage to the respiratory mucosa. Secondary bacterial pneumonia is most common 3-6 days postexposure.
Victims with severe exposure to an organic arsenical can experience long-term complications in a number of organ systems, including neurologic, endocrine, and thermoregulatory disorders. The exact mechanism of these effects is unknown.
Prognosis is good in all but the most severe cases.
Permanent discoloration can occur at blister sites, especially with phenyldichloroarsine (PD).
Patients with mild conjunctival irritation can be expected to fully recover in 1-2 weeks. Patients with moderate conjunctival irritation with mild corneal damage can expect recovery in 4-6 weeks, but severe corneal damage may be irreversible, especially in PD exposure.
Victims who suffered mild-to-moderate pulmonary exposure can expect full recovery in 1-4 weeks. Severe vapor exposure can lead to permanent damage to the respiratory mucosa. This can lead to an increased risk of future infection and/or neoplasia.
Geoffrey M Fitzgerald, MD, Consulting Staff, Concord Emergency Medical Associates
Disclosure: Nothing to disclose.
Coauthor(s)
Timothy Vollmer, MD,
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Zygmunt F Dembek, PhD, MPH, MS, LHD, Associate Professor, Department of Military and Emergency Medicine, Adjunct Assistant Professor, Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
Fred Henretig, MD, Director, Section of Clinical Toxicology, Professor, Medical Director, Delaware Valley Regional Poison Control Center, Departments of Emergency Medicine and Pediatrics, University of Pennsylvania School of Medicine, Children's Hospital
NATO. Blistering agents. Emergency War Surgery NATO Handbook. 2nd US revision. 1988. 88-90.
Hurst CG, Petrali JP, Barillo DJ, Graham JS, Smith WJ, Urbanetti JS, et al. Vesicants. Shirley D. Tourinsky. Medical Aspects of Chemical Warfare. Washington, D.C.: Borden Institute; 2008. 259-310.
