Sulfur mustard (dichlorethylsulphide) and nitrogen mustard are blistering agents, or vesicants, that have been used in chemical warfare dating to before the nineteenth century. Their historical use is most often remembered in the first and second world wars. The harbinger of sulfur mustard exposure is a subtle smell of onions, horseradish, or garlic. When exposed to sulfur mustard, skin and mucous membranes blister, causing painful and disfiguring burns and airway and pulmonary injury and edema. Systemic manifestations can occur with the higher dose or longer duration of exposure. Treatment is mostly supportive and requires definitive care at burn specialty centers for optimal wound management and skin grafting, as needed.
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Sulfur mustard exposures occur when the skin or mucous membranes come into contact with the aerosolized, semi-solid, or liquid chemical. The severity of an injury is related to duration and route of exposure, a dose of exposure, and ambient and exposed surface temperature and humidity.
Sulfur mustard is lipophilic, and thus causes most severe injury in areas of the skin rich with eccrine and sebaceous glands. The face, axillae, and groin are particularly sensitive to sulfur mustard exposure. Patients usually present with delayed onset of cutaneous burn from 30 minutes after exposure to up to 48 hours later. Sulfur mustard exposure causes blisters and bullae when skin or mucous membranes are exposed, resulting in partial and full thickness burns.
Sulfur mustard exposure causes degeneration of the basement membrane of the skin and mucous membranes and induces inflammatory changes. Apoptosis of cells and basement membrane degeneration cause the characteristic bullae to form. These bullae are filled with a yellow fluid, which itself can cause burns when healthcare workers come into contact with it without appropriate protection.
Respiratory tract injury occurs when the chemical is inhaled, but an evident injury is usually delayed 12 to 48 hours after exposure. The warm, moist environment of the upper airway contributes to increased absorption and severe injury in significant respiratory tract exposures. Sulfur mustard damages the respiratory epithelium causing inflammation and necrosis. Tracheobronchial tree edema ensues, and injury is localized predominantly to the upper airway and large bronchi. This structural damage leads to clinical signs of a cough, hoarseness, excess sputum production, dyspnea and, in more severe high concentration exposures, pulmonary edema, bronchopneumonia and acute respiratory distress syndrome (ARDS). In sulfur mustard exposures, death can occur from acute pulmonary edema or secondary pulmonary infection. Chronic low-level exposures result in chronic bronchitis, decreased lung volumes and chronic cough.
The corneal epithelium is particularly sensitive to sulfur mustard exposure due to the moist and warm environment created by the thin layer of tears over the cornea. Acute manifestations of ocular exposure include acute conjunctivitis, eyelid inflammation, and photophobia. A low dose or short exposure time may cause chemical conjunctivitis; whereas, a high dose or longer exposure time may cause temporary blindness. After an ocular injury, patients may go on to have chronic corneal ulcerations and chemical keratitis.
A gastrointestinal injury is mostly localized to the upper tract, including oropharyngeal, esophageal, and gastric edema, inflammation, and necrosis. Patients with significant gastrointestinal injury can develop nausea and vomiting, abdominal pain, and diarrhea which may be bloody. Sequelae of gastrointestinal exposure described include the development of Barrett’s esophagus and some malignancies.
Large cutaneous exposures or multi-system exposures can affect the hematopoietic system resulting in an initial leukocytosis followed by leukopenia, occasionally pancytopenia. Delayed mortality has been attributed to leukopenia in some cases.
Although in the United States, the manufacture of sulfur mustard in the has ceased, stockpiles of sulfur mustard are located in several storage sites across the country. After the First and Second World Wars, sulfur mustard-containing shells, and other undetonated artillery shells were disposed of in vast chemical dumping off the coast of New Jersey. To this day, periodic exposures occur when fisherman inadvertently dredge up unused shells containing sulfur mustard. There is also the potential for exposure at U.S. stockpile sites. Although none reported recently, chemical agents still have the potential to be employed in modern warfare and were last used against American troops in the Gulf War.
Sulfur mustard is proposed to exert its effects on the cell through a number of pathways. Its absorption leads to increase in free radicals and lipid peroxidation, ultimately causing oxidative cellular injury and apoptosis. In one proposed mechanism, sulfur mustard alkylates deoxyribonucleic acid (DNA) leading to activation of the intracellular repair enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). This exhausts intracellular nicotinamide adenine dinucleotide (NAD+) leading to decreased glycolysis, protease release, and cell injury. Upon cell death, proteases are released from the cell, causing dermal-epidermal separation as blisters. In another proposed mechanism, sulfur mustard inactivates glutathione, which leaves the cell vulnerable to oxidative injury and leads to increased intracellular accumulation of calcium and ultimately cell death. The etiology of acute and delayed toxicity of sulfur mustard exposure is not fully elucidated.
The route of exposure determines the toxicokinetics of sulfur mustard. Sulfur mustard can be found in all solid organs and in the blood after absorption from significant exposure. It has the highest concentration in fat and lipophilic organs and is excreted through the liver and kidneys. The metabolite of sulfur mustard, thiodiglycol, can be detected in urine for two weeks after significant exposures.
History and Physical
Exposure history is important in interviewing these patients. Suspect sulfur mustard exposure when patients describe a smell of onions or garlic at the scene of exposure, or when patients have had recent interaction with old artillery shells. It should be considered as the possible causative agent in mass casualty incidents in patients presenting with burns. Delayed burn after agent exposure is a key feature of sulfur mustard injury.
The physical exam should focus on skin, respiratory, and ocular systems. Painful redness and bullae filled with yellow fluid will be seen on skin exam. Most severe burns will be present on the face, axillae, and in the groin. Lesions may be hyperpigmented. Respiratory distress from upper airway edema may be seen in prolonged respiratory exposure. Eye redness, conjunctivitis, tearing, pain, and eyelid edema may be present.
Evaluation should focus on the airway, breathing, and circulation and be followed with a thorough skin exam. A complete blood count (CBC) can be obtained to assess for leukocytosis or leukopenia. Hepatic function panel and the basic metabolic panel may be obtained to assess for liver injury, kidney injury, or acidemia or electrolyte disturbances in severe injuries. A chest x-ray should be obtained as clinically indicated for a cough, abnormal findings on pulmonary exam or any signs of respiratory distress. A burn specialist should evaluate cutaneous burns, and ocular injury should have urgent ophthalmology referral.
Treatment / Management
When exposure to sulfur mustard is suspected, immediate decontamination including removal of clothing and scrubbing with soap and water is imperative. Management is largely symptomatic treatment and supportive care. Historical treatments such as topical bicarbonate solution and chlorinated soda have been shown to be of no added benefit over soap and water. Cutaneous burns are managed similarly to thermal burns with debridement, antibiotic ointment, collagen-laminated nylon dressings, and fluid resuscitation, as needed. Ocular injuries can be treated with irrigation, antibiotics if secondarily infected, and analgesia. Respiratory symptoms are treated with supplemental oxygen, prophylactic antibiotics, and if needed, mechanical ventilation. Most patients recover completely from sulfur mustard injuries, and mortality is most often from high-concentration exposures over a longer period.
- Chemical burns
- Chlorine toxicity
- Irritants- riot control agents
- Magnesium and thermite poisoning
- Napalm exposure
- Phosgene toxicity
- Sinusitis imaging
- White phosphorus exposure
Pearls and Other Issues
Most patients with low-concentration cutaneous exposure will survive the injuries but may go on to have extensive scarring, as the median lethal dose (LD50) for cutaneous exposure is 100 mg/kg. Sequelae include hypopigmented areas and scars that can be disfiguring depending on location and extent of the injury. Long-term sequelae include the development of malignancies later in life, particularly in long-term, chronic, low-concentration respiratory exposures (such as in Japanese sulfur mustard factory workers).
Enhancing Healthcare Team Outcomes
Management of sulfur mustard poisoning is usually with an interprofessional team that includes poison control, a toxicologist, emergency department physician, nurse practitioner, internist, a burn specialist, and an internist; time is of the essence. When exposure to sulfur mustard is suspected, immediate decontamination including removal of clothing and scrubbing with soap and water is imperative. Management is largely symptomatic treatment and supportive care.
Most patients with low-concentration cutaneous exposure will survive the injuries but may go on to have extensive scarring, as the median lethal dose (LD50) for cutaneous exposure is 100 mg/kg. Sequelae include hypopigmented areas and scars that can be disfiguring depending on the location and extent of the injury. Long-term sequelae include the development of malignancies later in life, particularly in long-term, chronic, low-concentration respiratory exposures (such as in Japanese sulfur mustard factory workers).
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