Vesicant or blister agents are cytotoxic alkylating compounds exemplified by chemicals collectively known as "mustard" or "mustard gas" (H). Other blister agents are sulfur mustard (HD), nitrogen mustard (HN), Lewisite (L), an arsenic containing vesicant, and phosgene oxime (CX), a halogenated oxime that is much different in properties and toxicity as the other agents. Mustard vapor injury is a particular threat in hot climates. In addition, humidity or moisture in a hot environment enhances damage to the skin.
These blister agents act as alkylating agents, and for this purpose some have found uses as chemotherapeutic agents in the treatment of some cancers. Alkylating agents bind DNA and cause DNA damage similar to radiation. There action on cell components results in inhibition of cellular division (mitosis) with decreased tissue respiration that leads to cell death. They produce eye, airway, and skin and mucous membrane injury that can be fatal. Systemic effects with extensive exposures include bone marrow inhibition with a drop in the white blood cell count and gastrointestinal tract damage. They primarily exist as viscous liquids that are relatively nonvolatile. Their toxic properties tend to be similar.
DIAGNOSIS
Diagnosis of a blister agent injury, without obvious overt contamination, requires a high index of suspicion when eye, skin, and respiratory signs and symptoms become evident. The first effects of blister agent exposure are eye and airway irritation. Conjuctivitis can occur after 1 hour to a concentration of a blister agent that is barely perceptible by odor. Mild exposure results in tearing and the sensation of eye grit in 4 to 12 hours. Severe eye lesions may occur within 2 hours on heavy exposure. Lewisite and the dichloroarsines can cause gray scarring of the cornea at the point of contact. Severe lacrimation can occur with low doses of phosgene oxime.
Skin damage may not be immediately evident, because the first effects may be painless until deeper skin layers are involved, at which time blisters appear. However, chemical skin injury is readily made when the fluid-filled skin blisters appear and are recognized. After a 1-12 hour (or more) latent period, during which skin burning and itching may occur, erythema or skin redness appears on exposed skin after 2-48 hours. In darker skinned individuals, sulfur mustard lesions may turn coal black in the face, neck, axilla, groin, and genitalia areas. Most American survivors from World War I had scrotal and perianal burns, because of increased moisture and ambient temperature in these areas. This redness (or darkness) is followed by coalescing, blisters on a red base. At this stage, any vesicant on contaminated patients may still pose a hazard to other individuals coming in contact with them, so care needs to be taken in decontamination. Lewisite (L) and phosgene oxime (CX) differ in that pain may be immediately noted on contact, but areas of erythema may recede without blister formation. Lewisite and the dichloroarsines causes a more opaque blister fluid than the mustards. They also lead to deeper injury to the connective tissue that can include muscle and vasculature, with more inflammation. Phosgene oxime causes immediate pain and skin necrosis at the site of contact. In 30 seconds, the contact area becomes blanched and is surrounded by a ring of erythema. A wheal then occurs in 30 minutes. Within 1 day this area turns brown. In 1 to 3 weeks an eschar forms and sloughs off.
Healing and resorption of non-infected blisters occur in 1-3 weeks for all vesicants. Broken blisters must be protected to minimize chances for infection and subsequent scarring of denuded skin. There is no useful medical test to determine if there has been mustard gas exposure.
Respiratory symptoms can include fever, dyspnea, ronchi with moist rales. Chest X-rays can reveal pulmonary edema. Changes consitent with chemical pneumonitis may appear after the first 24 hours. Lewisite and the other organic dichloroarsines due not cause as a significant respiratory injury from vapor concentrations found in the field. Usually skin pain occurs on immediate cutaneous contact and masks are donned, which prevents further respiratory and eye injury.
TREATMENT
Treatment follows decontamination of the patient, and after donning protective gear. Though various agents may vary in their ability to generate local verus systemic pathology, in general, treatment principles remains the same for all vesicants, except the availability of British anti-Lewisite for dichloroarsine exsposure.
Mild eye lesions require little treatment, other than flushing with water immediately. Slow running water is applied as one tilts the head from side to side, pulling the eyelids apart. Steroid and antibiotic ointment to the eye can be applied. Sterile petroleum jelly between the eyelids can provide lubrication, as would boric acid 5%. With eyelid edema that occurs with more severe injuries, the eyelids may be gently opened to provide reassurance to the patient that one is not blind. Pain can be controlled by oral or parenteral narcotics. Photophobia can be eased by placing the patient in a darkened room, and by providing sunglasses or eyeshades. Do not cover the eyes with bandages. Atropine sulfate ointment should be instilled in each eye to obtain good mydriasis in all cases where there are corneal erosions, iritis, cyclitis, or marked photophobia or miosis. Blepharospasm, or eyelid spasm, is treated with atropine sulfate solution 1%, applied three times a day. To prevent infection, a few drops of sodium sulfacetamide 15 % should be instilled every 4 hours. Another antibacterial ophthalmic preparation may be substituted. The eye must not be bandaged and the lids must be kept separated. The patient should be seen by an ophthalmologist as soon as possible.
Treatment of skin lesions also follows decontamination and removal of clothes. Decontamination should be completed within 15 minutes after exposure to minimize any systemic effects. Contaminated hair should be shaved off. Promptly wash off decontaminating solutions within 3-4 minutes to prevent additional skin injury. Sodium hypochlorite 5% or liquid household bleach can be used. If erythema is already present, soap and water is preferred. Leave blisters intact, but if broken, debride to prevent secondary infection. Cleanse with tap water or saline, apply dressings where needed. Silver sufadiazine or mafenide acetate can be applied and the wounds treated as burn wounds. Infected skin wounds require antibiotics as appropriate.
In cases of Lewisite skin injury, dimercaprol (British anti-Lewisite, or BAL) ointment should be used on skin contaminations where blisters have not yet formed. Sometimes BAL itself causes irritation with stinging and itching with wheal formation, but this should resolve in an hour after application. Frequent BAL ointment application does cause a mild dermatitis, so it cannot be used as a protective barrier ointment on skin not contaminated by dichloroarsines. Because of the deeper injury with dichloroarsines like Lewisite, wounds may heal more slowly and skin grafting may be required in the future.
Systemic treatment with parenteral anti-Lewisite is considered when there is 1) greater than 5% area of skin contamination (one square foot) which results in immediate skin blanching or erythema within 30 minutes after exposure, or 2) a burn the size of the palm (1% of skin area) which was not decontaminated withing the first 15 minutes after exposure. There are two type of parenteral BAL therapies which can be used. One can either apply BAL ointment liberally onto the skin, after removing any other protective ointment first, and allow that area to remain covered. The other parenteral method is to give an intramuscular injection of 10% BAL in oil into the buttocks, without injecting into a vessel. The dose given of 10% BAL in oil is 0.5 ml per every 25 pounds body weight, up to a maximum of 4.0 ml for those individuals who weigh 200 pounds or over. Intramuscular injection of BAL in oil (10%) should be repeated every four hours for a total of four doses at alternate sites in the buttocks. In severe cases, the frequency can be shortened between the first and second dose by 2 hours. Also for severe casesone injection can be given per day for 3 to 4 days. One should be aware of symptoms which occur with BAL injections which may last 30 minutes but do not indicate that therapy should be stopped. These symptoms include tightening of the throat, chest pressure, lip burning, lacrimation, eye redness, mouth dryness, aching muscles, abdominal pain, tenderness and increased muscle tone at the injection site, anxiety, nausea, vomiting, and transient increased blood pressure.
Inhalation of vapors from mustards or arsenicals vesicants can result in laryngeal and tracheobronchial mucosal injury. Mild injury with hoarseness and sore throat requires either no treatment or mist inhalation. Moderate exposures result in hyperemia and necrosis of the bronchial epithelium and require hospitalization to prevent secondary infection. Antibiotics are used in an appropriate manner. Pneumonia was the usual cause of death from mustard agents during the pre-antibiotic World War I era. Severe injuries cause tracheobronchial tree casts from pseudomembrane formation. Hypoxia can occur, but subsequent bronchitis and pneumonia from infection were the chief causes of pulmonary-related deaths in World War I (mortality 2%). Pulmonary resuscitation is required if breathing stops. Mustard-Lewisite (HL) mixtures can cause pleural effusion in severe cases. Blister agents at extensive exposure can have systemic toxicity that effects not only the lungs, but the bone marrow, lymph nodes, spleen, and endocrine systems. In these cases, complete blood counts with monitoring of granulocytes, red cells, and platelets should be performed routinely. If granulocyte depletion occurs, isolation and antibiotic prophylaxis may be necessary. Many past fatalities were dut to the combination of pneumonia and bone marrow failure. Anemia and thrombocytopenia should be treated as the situation dictates. If local effects remain mild, systemic effects are not likely to be significant. In severe cases of Lewisite or dichloroarsenine respiratory injury, dyspnea with frothy sputum indicating pulmonary edema indicated intramuscular BAL is necessary.
If ingestion of blistering agent occurs, do not induce vomiting. Milk can be given to drink to mitigate damage. Giving atropine subcutaneously 0.4-0.8 mg can help in reducing systemic or local gastrointestinal activity. Morphine intravenously can be given for intestinal pain with close monitoring for shock. Fluid resuscitation for vomiting and diarrhea will require intravenous saline. Sedatives may be necessary.
PROGNOSIS
With eye injury, temporary blindness occurs, but permanent blindness is rare with vapor exposure. The patient should receive this reassurance except for the severest eye injury. Blindness is more likely to occur when liquid mustard is directly splashed into the eye. With mild eye injury, recovery occurs in 1-2 weeks. More severe involvement with corneal erosions as detected by fluorescein staining can take 2 to 3 months of hospital care before recovery occurs. Corneal involvement beyond erosions with opacification and ulceration (less than 0.1 per cent of mustard casualties in World War I) takes several months for recovery, and then late relapses can yet occur. In these cases blindness may ensue. Eye injuries are more severe with nitrogen mustard than with sulfur mustard. The iris is frequently discolored and atrophied with nitrogen mustard exposure.
With mild blister formation, healing occurs with little scarring, but may take months to heal remaining painful during this time. When secondary infection occurs or in more extensive blistering, scarring can be more severe. Itching may persist after healing. Hypopigmentation or hyperpigmentation can occur as with any healing process. Deeper burns with Lewisite and the dichlorarsines have similar outcomes as second or third degree thermal burns. Repeated exposures over time to mustards or arsenicals as dichloroarsines can cause sensatiziation. Delayed healing beyond 2 months occurs with skin lesions caused by phosgene oxime.
A single low dose exposure to mustard vapor with laryngeal and tracheobronchial mucosal effects may not lead to significant injury once healed. A cough may persist a month or longer. Hoarsness usually lasts only 1 to 2 weeks. However, repeated or chronic low dose exposure can lead to progressive pulmonary fibrosis, chronic bronchitis, and bronchiectasis.
