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SULFUR MUSTARD GAS EXPOSURE: CASE REPORT AND REVIEW OF THE LITERATURE Goverman J.,1*, ** Montecino R.,2** Ibrahim A.,3 Sarhane K.A.,4 Tompkins R.G.,5 Fagan S.P.5 1 2 3 4 5
Department of Surgery, Division of Burns, Harvard Medical School, USA Department of Surgery, VA Eastern Kansas Health Care System - Dwight D. Eisenhower VA Medical Center, USA Department of Surgery, Division of Burns, Massachusetts General Hospital, Harvard Medical School, USA Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, USA Sumner Redstone Burn Center, Massachusetts General Hospital, Harvard Medical School, USA
SUMMArY. This report describes a case of burn injury following exposure to sulfur mustard, a chemical agent used in war. A review of the diagnostic characteristics, clinical manifestations, and therapeutic measures used to treat this uncommon, yet extremely toxic, entity is presented. The aim of this report is to highlight the importance of considering this diagnosis in any war victim, especially during these unfortunate times of rising terrorist activities. Keywords: sulfur mustard gas, mustard gas, burn, chemical burn
Introduction
Sulfur mustard (SM) is a toxic, vesicant, blistering, alkylating nucleophile, and a strong lipophilic chemical agent. It was used extensively during the Gulf War, affecting potentially 100,000 United States (US) soldiers.1 SM exposure is uncommon in the US and therefore a paucity of data can be found related to its presentation and management. Nonetheless, because of its serious implications in various biological systems and with many cities around the world unfortunately witnessing terrorist attacks, a thorough understanding of presenting symptoms, diagnostic aspects, therapeutic options, and preventative measures is warranted. Here we describe a case of burn injury caused by SM exposure and review the salient clinico-pathologic features and treatment principles associated with exposure to this toxic gas. case report
A healthy 21-year-old male, active duty marine sustained burns from mustard gas after a weapons cache exploded in Iraq. He was initially transferred to Germany for medical stabilization and then to Bethesda for definitive care. Follow-up was arranged at our outpatient burn center, as it was closer to the patient’s home. Upon follow-up, the patient complained of new onset burning pain to his
left hand, right upper extremity, right thigh, and left calf persisting for approximately 2 weeks despite the use of oral narcotics. Physical examination revealed extremely tender areas of skin erythema with various size bullous lesions (Fig. 1). The patient was admitted to the burn service for local wound debridement, local wound care (with 1% silver sulfadiazine), and pain control. Debridement of blisters revealed a wound base with superficial partial thickness burn surrounding a central area of mid to deep partial thickness burn. Over the following 48 hours, his wound began to epithelialize, his pain was better controlled, and the patient was discharged. At 2 weeks follow-up, his wounds were noted to be fully epithelialized, and the patient had maintained full range of motion. His only complaints at that time were pruritus and unstable scars (Fig. 2). Discussion
Sulfur mustard gas (dichlorodiethylsulfide) is the prototypical vesicant alkylating agent used in the fabrication 2 of chemical weapons. It was first used by the Germans during World War I (1917) causing over 125,000 casualties. It was then used in World War II and during the IranIraq war (1980-1988) affecting thousands of US soldiers.1,3 It is an oily liquid that can be easily aerosolized by spraying or dispersed by explosive blasts. In temperate climates (as in Europe during World Wars I and II), it vaporizes
* Corresponding author: Jeremy Goverman, MD, FACS, Assistant Surgeon, MGH, Department of Surgery, Division of Burns, Instructor, Harvard Medical School. Massachusetts General Hospital, Bigelow 13 Outpatient Burn Center, 55 Fruit Street, Boston, MA, 02114. Email: [email protected] ** Drs. Goverman and Montecino contributed equally to this manuscript.
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Table I - Onset of symptoms and exposure dose Exposure dose (mg/min/m3) 50 100 - 400 200 – 1000
Fig. 1 - Patient presentation to our outpatient burn clinic. Note diffuse erythema with multiple, large bullous lesions to the right forearm (top) and the dorsum of the left hand (bottom).
Effects Onset of eye pain Onset of respiratory and skin effects Onset of skin burns
Table II - Typical onset of symptoms and signs over time Time after Exposure 30 – 60 minutes 2 – 6 hours 6 – 24 hours
24 – 48 hours 2 – 6 days 6 days – 6 months
Symptoms and Signs Nausea, vomiting, eye pain eye pain, lacrimation, photophobia, rhinorrhea, sneezing, and sore throat Erythema, hoarseness, non-productive cough Skin blistering, productive cough Occular recovery starts, hyperpigmentation, secondary infections Resolution
of action and histological features, and highlight management/treatment principles.
Fig. 2 - Hyperpigmentation of left forearm (top) and right hand (bottom) noted at outpatient followup, 3 weeks after initial presentation.
slowly, posing particular risk in prolonged, closed-space or below grade exposures. At higher temperatures (as in the Persian Gulf during the Iran-Iraq war), vaporization in4 creases markedly and contributes to dispersion. Due to its low volatility, in open areas with little wind, mustard gas can persist in the air for more than a week, especially in temperate climates. Battlefield air concentrations during World War I, for example, approached 19-33 3 mg/mm . At such concentrations, exposure for several minutes can potentially lead to skin and eye injury. Longer exposures (30-60 minutes) can result in severe respiratory injury, systemic poisoning, or even death.5,6 Although SM exposure outside of war zones is rare, burn surgeons should be made aware of the clinical features and treatment of such injuries; and therefore we will outline the salient clinical manifestations, summarize its mechanism
Mechanism of action Sulfur mustard rapidly alkylates the purine bases (adenine & guanine) of DNA which triggers the activation of endonucleases for depurination (excision) of the alkylated bases, leaving apurinic sites where DNA breaks readily occur. This creates a considerable need for DNA repair, activating poly-(ADP ribose) polymerase enzymes that rapidly deplete NAD+. Depletion of NAD+, which typically occurs within an hour of exposure and is highest after four hours, inhibits glycolysis, leading to the release of multiple proteases that ultimately result in tissue necrosis.7-10 Tissue necrosis occurs in the affected system, namely in the skin (producing vesication of the epidermis), in the hematological system (leading to pancytopenia), in the respiratory system (causing respiratory failure), and in the gastrointestinal system (leading to mucositis). Death may occur, and mortality rates in the Iran-Iraq War were reported to be as high as 3-4%.11 Death was attributed to respiratory failure or bone marrow suppression. Clinical Manifestations A 4-12 hour asymptomatic latency period, depending on the extent and dose of exposure (Table I), is not un4,12,13 and victims generally present with multiple common; sites of involvement (Table II). Skin lesions Direct skin exposure to SM gas leads to a dose-dependent injury that ranges from mild erythema and edema 147
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Table III - Skin injury patterns due to liquid mustard SKIN INJURY Mild Injury Moderate Injury Severe Injury
Clinical Manifestations Erythema, edema, first degree burn
Severe edema and vesication Full thickness skin necrosis surrounded by spreading vesication
Mechanism of Injury 3 Ambient doses of 50mg/min/m or direct application of 0.1 to 1.0 mg/cm2 liquid Direct application of 1.0 to 2.5mg/cm2 Ambient doses of 200 to 1,000mg/min/m3 or direct application of more than 2.5mg/cm2
Table IV - Ocular injury patterns due to sulfur mustard EYE INJURY Mild Injury Moderate Injury Severe Injury
Clinical Manifestations Erythema, edema, epiphora, or mild discomfort Severe pain, blepharospasm, periorbital edema, scleral andconjunctival injection, chemosis, iritis, temporary blindness Permanent blindness
to severe necrosis and vesiculation (Table III). Early onset skin lesions consist of erythema, purpura, and bullae of different sizes. Bullae typically appear over already erythematous lesions, but may also form on unaffected sites. Lesions do not form on palms or soles. They typically contain a yellow/straw colored fluid that forms a gel after 24 hours, making drainage of blister fluid more challenging as the clotted material adheres to the dermal bed. If bullae are debrided and drained within the first 24 hours, wounds heal favorably in 1-2 weeks. In contrast, wounds containing bullae drained after 24 hours may result in delayed wound healing (4-6 weeks). Large flaccid bullae may also develop, coalesce, and slough as large sheets of epithelium (Nikolsky’s Sign). The remaining wound bed is a raw, moist, blanching dermis, similar in appearance to a scald. While oral ulcerations are rare, moist or wet skin such as groins and axillae are especially prone to vesica14,15,16 tion. In addition to delayed wound healing and its increased risk of secondary skin infection, patients often develop unstable scars (as our patient did) making them prone to blistering from minor sheer forces. Still in the majority of cases, skin ulcerations heal with minimal to no scarring.15 Utricaria may present during follow-up, the pathophysiology of which is currently unknown; however, it may involve a hypersensitivity reaction or even a psychological component. Days to weeks after exposure, patients may develop areas of scaling over previously erythematous skin. More severe forms of scaling may occur, such as exfoliative erythroderma, but are extremely rare. Late skin manifestations for SM gas exposure most frequently involve varying degrees of pigmentation. Such changes include: 1. Post-inflammatory hypo and/or hyperpigmentation at the site of a previous lesion; 148
Mechanism of Injury Ambient doses of 12-70mg/min/m3 Ambient doses of 100-200 mg/min/m3 Ambient doses more than 200mg/min/m3
Recovery Within two weeks
Three to six weeks Very rare
2. Peri-follicular hypo and/or hyperpigmentation secondary to mild peri-follicular inflammation in the absence of a previous lesion; 3. Generalized hyperpigmentation, affecting the entire surface of the skin; 4. Generalized hypo and hyperpigmented macules and patches resembling tinea versicolor; and 5. Hyperpigmented lesions over areas subjected to chronic pressure. Delayed onset of purpura and ecchymoses are rare 17 manifestations. Histological changes in SM exposed skin have been well described. Three to six hours after exposure the nuclei of basal keratinocytes become pyknotic. Progression of injury leads to degeneration of basal cells with formation of intracellular and extracellular vacuoles, dissolution of the basal cell layer, and separation of dermis from epi4,13 dermis. This becomes clinically evident as subepidermal bullae with mild dermal and epidermal necrosis. Respiratory Inhalation of sulfur mustard aerosol or vapor can rapidly lead to respiratory failure and death depending on the extent and dose of exposure. Victims initially suffer from tracheobronchitis, with nonspecific symptoms such as sore throat, hoarseness, chest pressure, and non-productive cough. Over the next 12 hours, progression of symptoms leads to sinus pain, tachypnea, bronchospasm, and a productive cough due to sloughed respiratory epithelium and an increase in secretions. Continued exposure may lead to secondary pneumonias, hemorrhagic pulmonary edema, 18,28 and even respiratory failure within 24-48 hours. Chronic pulmonary manifestations include chronic bronchitis, bronchiectasis, reactive airway dyfunction syndrome and emphysema.5 There is also evidence to suggest a slightly
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increased incidence of lung cancer after a latency of 20 19,20 years or more. Eye Mustard reacts quickly upon contact with the tissues of the globe although frank clinical symptoms usually develop gradually, four to eight hours after exposure. Injuries to the globe are also dependent on dose and duration of exposure (Table IV). Initial symptoms include eye pain, photophobia, tearing, and blurred vision.21,22 Physical examination may reveal blepharospasm, periorbital edema, conjunctival and scleral injection/edema, and anterior chamber cellular infiltrates. Visual acuity is often decreased. After several hours, the corneal epithelium may vesicate and slough. Late recurrences of keratitis and worsening opacifications have been described and can lead to recurrent ulcerations, pain, and blindness.23 Gastrointestinal Gastrointestinal manifestations are the result of systemic toxicity. Systemic toxicity is encountered with high dose exposures (more than 1,000mg-min/m3) or from swallowing contaminated food or saliva. Nausea and vomiting are common while diarrhea and gastrointestinal bleeding are not.1 Hematological Bone marrow suppression is also the result of highdose exposure (more than 1,000mg-min/m3) with subsequent systemic toxicity. Leukocytosis develops and lasts for several days before leucopenia manifests. Leucopenia may not be apparent for five to seven days but reaches a nadir in approximately ten days. Thrombocytopenia may ensue but anemia is noted less frequently. Mustard gas-induced bone marrow suppression is an extremely poor prog24 nostic sign. Carcinogenicity Sulfur mustard is a proven carcinogen. Prolonged and/or repeated exposure to a particular system/organ has been shown to increase its risk of cancer.19,20,24,25,27 World War I veterans who suffered mustard gas exposure in the battlefield had a small but probably significant increase in the incidence of lung cancer compared to veterans not exposed to the gas. Significant increases in the incidence of upper respiratory tract, oropharynx, and skin malignancies, have also been reported among patients who suffered occupational exposure to mustard gas. Management and Treatment Principles Regular clothing does not afford adequate protection. Specialized military protective garments are needed; these have a layer of charcoal to absorb the penetrating sulfur mustard and provide approximately six hours of protection after exposure.
Patients presenting with signs and symptoms of upper airway obstruction (i.e. stridor) require immediate endotracheal intubation or, in the presence of severe upper airway edema, treacheotomy. Once the skin is exposed, rapid removal of the SM substance is crucial as it becomes irreversibly fixed in the tissues within minutes. Mustard scavengers, antioxidants, NAD+ precursors, polymerase inhibitors, and corticosteroids have all shown value in animal models; however, currently there is no accepted antidote for the treatment of SM gas exposure in humans. Increased survival and fewer pathological organ effects were noted after administration of parenteral doses of sodium tiosulfate (3000mg/kg), vitamin E (20mg/kg), or dexamethasone (8mg/kg) within 15 minutes of exposure. The combination of all three was the most effec23,26 tive. It is likely that thiosulfate acts as a mustard scavenger, vitamin E as an antioxidant, and corticosteroids act by inhibiting lipooxygenase activity thereby decreasing the synthesis of prostaglandins and leukotrienes. In a rabbit model of mustard gas burns, the topical administration of cortisone following exposure decreased edema and led to shallower skin lesions. Healing time, however, was not ef16 fected. As mustard is relatively water insoluble, clothing and jewelry must be destroyed. The eyes should be copiously irrigated with water or saline. The skin is washed with mild soap and water with particular attention to the axillae, groin, and perineum. Should water supplies be limited, adsorbent powders such as talc, flour, and Fuller’s earth can be dispersed over affected areas and wiped with moist gauze. The skin can also be decontaminated with chloramine powder and 0.5% hypochlorite solution. These compounds inactivate sulfur mustard, producing free chloride.29 The U.S. military currently utilizes M258A1 kits for skin decontamination: these kits contain two sets of two towelettes, one containing phenol and hydroxide, the other containing chloramine. conclusion
Sulfur mustard is the first vesicant used as a chemical weapon causing a high number of injuries on the battlefields of World War I, and is still considered a major chemical agent. Owing to its ease of manufacture and extent of existing stockpiles, mustard was reportedly used in a number of isolated incidents since World War I. Its deleterious metabolic and tissue injury effects span almost every system in the body, and may lead to permanent disability and even death. A systematic multi-disciplinary approach is required for the care of injured patients, and this requires a comprehensive understanding of the various physiologic aspects of this type of burn. If mustard is ever used again, medical personnel must be prepared to accept and care for large numbers of casualties, who will require longterm care. 149
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rÉSUMÉ. Ce rapport décrit un cas de brûlure suite à une exposition au gaz moutarde, un agent chimique utilisé dans la guerre. On présente un examen des caractéristiques de diagnostic, les manifestations cliniques et les mesures thérapeutiques utilisés pour traiter ce phénomène rare, mais extrêmement toxique. L’objectif de ce rapport est de mettre en évidence l’importance de considérer ce diagnostic dans toute victime de la guerre, surtout en ces temps malheureux de la hausse des activités terroristes. Mots-clés: soufre du gaz moutarde, l’ypérite, brûlure, brûlure chimique BIBLIoGrAPHY
1. Wormser U: Toxicology of mustard gas. Trends in pharmacological sciences, 12:164-7, 1991. 2. Atiyeh BS, Hayek SN, Gunn SWA: Armed conflict and burn injuries: A brief review. Annals of burns and fire disasters, 18: 456, 2005. 3. Borak J, Sidell FR: Agents of chemical warfare: sulfur mustard. Annals of emergency medicine, 21: 303-8, 1992. 4. Papirmeister B, Gross C, Petrali J, Hixson C: Pathology produced by sulfur mustard in human skin grafts on athymic nude mice. J Toxicol Cutan Ocul Toxicol, 3: 371-408, 1984. 5. Brooks SM, Weiss MA, Bernstein IL: Reactive airways dysfunction syndrome (RADS). Persistent asthma syndrome after high level irritant exposures. Chest, 88: 376-84, 1985. 6. Devereaux A, Amundson DE, Parrish JS, Lazarus AA: Vesicants and nerve agents in chemical warfare. Decontamination and treatment strategies for a changed world. Postgraduate medicine, 112: 90-6, 2002. 7. Dixon M, Needham DM: Biochemical research on chemical warfare agents. Nature, 158: 432-8, 1946. 8. Lindahl T: DNA glycosylases, endonucleases for apurinic/apyrimidinic sites, and base excision-repair. Progress in nucleic acid research and molecular biology, 22: 135-92, 1979. 9. Papirmeister B, Gross C, Petrali J, Hixson C: Pathology produced by sulfur mustard in human skin grafts on athymic nude mice I: Gross and light microscopic changes. J Toxicol Cutan Ocular Toxicol, 3: 371-91, 1984. 10. Renshaw B: Mechanisms in production of cutaneous injuries by sulfur and nitrogen mustards in Chemical Warfare Agents and related chemical problems, 479–518, Washington, DC, 1946. 11. Dunn P: The chemical war: Iran revisited – 1986. NBC Defense Technol. Int, 32-9, 1986. 12. Nagy SM, Golumbic C, Stein WH, Fruton JS, Bergmann M: The penetration of vesicant vapors into human skin. The Journal of general physiology, 29: 441-69, 1946. 13. Papirmeister B, Gross CL, Meier HL, Petrali JP, Johnson JB: Molecular basis for mustard-induced vesication. Fundamental and applied toxicology : Official journal of the Society of Toxicology, 5: 134-49, 1985. 14. Momeni AZ, Enshaeih S, Meghdadi M, Amindjavaheri M: Skin manifestations of mustard gas. A clinical study of 535 patients exposed to mustard gas. Archives of dermatology, 128: 775-80, 1992. 15. Poursaleh Z, Ghanei M, Babamahmoodi F, Izadi M, Harandi AA, Emadi SE, Emadi SN: Pathogenesis and treatment of skin lesions caused by sulfur mustard. Cutaneous and ocular toxicology, 31: 241-9, 2012. 16. Vogt RF, Dannenberg AM, Schofield BH, Hynes NA, Papirmeister B: Pathogenesis of skin lesions caused by sulfur mustard. Fundamental and applied toxicology. Official journal of the Society
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of Toxicology, 4: 71-83, 1984. 17. Emadi SN, Mortazavi M, Mortazavi H: Late cutaneous manifestations 14 to 20 years after wartime exposure to sulfur mustard gas: A long-term investigation. Archives of dermatology, 144: 1059-61, 2008. 18. Haber L: The Poisonous Cloud. Oxford Claredon Press, England, 1986. 19. Beebe GW: Lung cancer in World War I veterans: Possible relation to mustard-gas injury and 1918 influenza epidemic. Journal of the National Cancer Institute, 25: 1231-52, 1960. 20. Norman JE: Lung cancer mortality in World War I veterans with mustard-gas injury: 1919-1965. Journal of the National Cancer Institute, 54: 311-7, 1975. 21. Atkinson WS: Delayed keratitis due to mustard gas (dichlorodiethyl sulfide burns) report of two cases. Archives of ophthalmology, 40: 291-301, 1948. 22. Geeraets WJ, Abedi S, Blanke RV: Acute corneal injury by mustard gas. Southern medical journal, 70: 348-50, 1977. 23. Vojvodić V, Milosavljević Z, Bosković B, Bojanić N: The protective effect of different drugs in rats poisoned by sulfur and nitrogen mustards. Fundamental and applied toxicology. Official journal of the Society of Toxicology, 5: 160-8, 1985. 24. Kehe K, Szinicz L: Medical aspects of sulphur mustard poisoning. Toxicology, 214: 198 209, 2005. 25. Manning KP, Skegg DC, Stell PM, Doll R: Cancer of the larynx and other occupational hazards of mustard gas workers. Clinical otolaryngology and allied sciences, 6: 165-70, 1981. 26. Al-Kaisy AA, Salih Sahib A: Role of the antioxidant effect of vitamin e with vitamin c and topical povidone-iodine ointment in the treatment of burns. Annals of burns and fire disasters, 18: 1930, 2005. 27. Inada S, Hiragun K, Seo K, Yamura T: Multiple Bowen’s disease observed in former workers of a poison gas factory in Japan, with special reference to mustard gas exposure. The Journal of dermatology, 5: 49-60, 1978. 28. Urbanetti J: Battlefield chemical inhalation injury. In: Loke J (Ed): “Pathophysiology and Treatment of Inhalation Injuries”, 281-348, Marcel Dekker Inc, New York, 1988. 29. Trapp R: The Detoxification and Natural Degradation of Chemical Warfare Agents. T. & Francis Ed, Stockholm International Peace Research Institute, London, 1985.
Conflict of interest. None Funding. None
This paper was accepted on 5 May 2014.
SULFUR MUSTARD GAS EXPOSURE: CASE REPORT AND REVIEW OF THE LITERATURE Goverman J.,1*, ** Montecino R.,2** Ibrahim A.,3 Sarhane K.A.,4 Tompkins R.G.,5 Fagan S.P.5 1 2 3 4 5
Department of Surgery, Division of Burns, Harvard Medical School, USA Department of Surgery, VA Eastern Kansas Health Care System - Dwight D. Eisenhower VA Medical Center, USA Department of Surgery, Division of Burns, Massachusetts General Hospital, Harvard Medical School, USA Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, USA Sumner Redstone Burn Center, Massachusetts General Hospital, Harvard Medical School, USA
SUMMArY. This report describes a case of burn injury following exposure to sulfur mustard, a chemical agent used in war. A review of the diagnostic characteristics, clinical manifestations, and therapeutic measures used to treat this uncommon, yet extremely toxic, entity is presented. The aim of this report is to highlight the importance of considering this diagnosis in any war victim, especially during these unfortunate times of rising terrorist activities. Keywords: sulfur mustard gas, mustard gas, burn, chemical burn
Introduction
Sulfur mustard (SM) is a toxic, vesicant, blistering, alkylating nucleophile, and a strong lipophilic chemical agent. It was used extensively during the Gulf War, affecting potentially 100,000 United States (US) soldiers.1 SM exposure is uncommon in the US and therefore a paucity of data can be found related to its presentation and management. Nonetheless, because of its serious implications in various biological systems and with many cities around the world unfortunately witnessing terrorist attacks, a thorough understanding of presenting symptoms, diagnostic aspects, therapeutic options, and preventative measures is warranted. Here we describe a case of burn injury caused by SM exposure and review the salient clinico-pathologic features and treatment principles associated with exposure to this toxic gas. case report
A healthy 21-year-old male, active duty marine sustained burns from mustard gas after a weapons cache exploded in Iraq. He was initially transferred to Germany for medical stabilization and then to Bethesda for definitive care. Follow-up was arranged at our outpatient burn center, as it was closer to the patient’s home. Upon follow-up, the patient complained of new onset burning pain to his
left hand, right upper extremity, right thigh, and left calf persisting for approximately 2 weeks despite the use of oral narcotics. Physical examination revealed extremely tender areas of skin erythema with various size bullous lesions (Fig. 1). The patient was admitted to the burn service for local wound debridement, local wound care (with 1% silver sulfadiazine), and pain control. Debridement of blisters revealed a wound base with superficial partial thickness burn surrounding a central area of mid to deep partial thickness burn. Over the following 48 hours, his wound began to epithelialize, his pain was better controlled, and the patient was discharged. At 2 weeks follow-up, his wounds were noted to be fully epithelialized, and the patient had maintained full range of motion. His only complaints at that time were pruritus and unstable scars (Fig. 2). Discussion
Sulfur mustard gas (dichlorodiethylsulfide) is the prototypical vesicant alkylating agent used in the fabrication 2 of chemical weapons. It was first used by the Germans during World War I (1917) causing over 125,000 casualties. It was then used in World War II and during the IranIraq war (1980-1988) affecting thousands of US soldiers.1,3 It is an oily liquid that can be easily aerosolized by spraying or dispersed by explosive blasts. In temperate climates (as in Europe during World Wars I and II), it vaporizes
* Corresponding author: Jeremy Goverman, MD, FACS, Assistant Surgeon, MGH, Department of Surgery, Division of Burns, Instructor, Harvard Medical School. Massachusetts General Hospital, Bigelow 13 Outpatient Burn Center, 55 Fruit Street, Boston, MA, 02114. Email: [email protected] ** Drs. Goverman and Montecino contributed equally to this manuscript.
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Table I - Onset of symptoms and exposure dose Exposure dose (mg/min/m3) 50 100 - 400 200 – 1000
Fig. 1 - Patient presentation to our outpatient burn clinic. Note diffuse erythema with multiple, large bullous lesions to the right forearm (top) and the dorsum of the left hand (bottom).
Effects Onset of eye pain Onset of respiratory and skin effects Onset of skin burns
Table II - Typical onset of symptoms and signs over time Time after Exposure 30 – 60 minutes 2 – 6 hours 6 – 24 hours
24 – 48 hours 2 – 6 days 6 days – 6 months
Symptoms and Signs Nausea, vomiting, eye pain eye pain, lacrimation, photophobia, rhinorrhea, sneezing, and sore throat Erythema, hoarseness, non-productive cough Skin blistering, productive cough Occular recovery starts, hyperpigmentation, secondary infections Resolution
of action and histological features, and highlight management/treatment principles.
Fig. 2 - Hyperpigmentation of left forearm (top) and right hand (bottom) noted at outpatient followup, 3 weeks after initial presentation.
slowly, posing particular risk in prolonged, closed-space or below grade exposures. At higher temperatures (as in the Persian Gulf during the Iran-Iraq war), vaporization in4 creases markedly and contributes to dispersion. Due to its low volatility, in open areas with little wind, mustard gas can persist in the air for more than a week, especially in temperate climates. Battlefield air concentrations during World War I, for example, approached 19-33 3 mg/mm . At such concentrations, exposure for several minutes can potentially lead to skin and eye injury. Longer exposures (30-60 minutes) can result in severe respiratory injury, systemic poisoning, or even death.5,6 Although SM exposure outside of war zones is rare, burn surgeons should be made aware of the clinical features and treatment of such injuries; and therefore we will outline the salient clinical manifestations, summarize its mechanism
Mechanism of action Sulfur mustard rapidly alkylates the purine bases (adenine & guanine) of DNA which triggers the activation of endonucleases for depurination (excision) of the alkylated bases, leaving apurinic sites where DNA breaks readily occur. This creates a considerable need for DNA repair, activating poly-(ADP ribose) polymerase enzymes that rapidly deplete NAD+. Depletion of NAD+, which typically occurs within an hour of exposure and is highest after four hours, inhibits glycolysis, leading to the release of multiple proteases that ultimately result in tissue necrosis.7-10 Tissue necrosis occurs in the affected system, namely in the skin (producing vesication of the epidermis), in the hematological system (leading to pancytopenia), in the respiratory system (causing respiratory failure), and in the gastrointestinal system (leading to mucositis). Death may occur, and mortality rates in the Iran-Iraq War were reported to be as high as 3-4%.11 Death was attributed to respiratory failure or bone marrow suppression. Clinical Manifestations A 4-12 hour asymptomatic latency period, depending on the extent and dose of exposure (Table I), is not un4,12,13 and victims generally present with multiple common; sites of involvement (Table II). Skin lesions Direct skin exposure to SM gas leads to a dose-dependent injury that ranges from mild erythema and edema 147
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Table III - Skin injury patterns due to liquid mustard SKIN INJURY Mild Injury Moderate Injury Severe Injury
Clinical Manifestations Erythema, edema, first degree burn
Severe edema and vesication Full thickness skin necrosis surrounded by spreading vesication
Mechanism of Injury 3 Ambient doses of 50mg/min/m or direct application of 0.1 to 1.0 mg/cm2 liquid Direct application of 1.0 to 2.5mg/cm2 Ambient doses of 200 to 1,000mg/min/m3 or direct application of more than 2.5mg/cm2
Table IV - Ocular injury patterns due to sulfur mustard EYE INJURY Mild Injury Moderate Injury Severe Injury
Clinical Manifestations Erythema, edema, epiphora, or mild discomfort Severe pain, blepharospasm, periorbital edema, scleral andconjunctival injection, chemosis, iritis, temporary blindness Permanent blindness
to severe necrosis and vesiculation (Table III). Early onset skin lesions consist of erythema, purpura, and bullae of different sizes. Bullae typically appear over already erythematous lesions, but may also form on unaffected sites. Lesions do not form on palms or soles. They typically contain a yellow/straw colored fluid that forms a gel after 24 hours, making drainage of blister fluid more challenging as the clotted material adheres to the dermal bed. If bullae are debrided and drained within the first 24 hours, wounds heal favorably in 1-2 weeks. In contrast, wounds containing bullae drained after 24 hours may result in delayed wound healing (4-6 weeks). Large flaccid bullae may also develop, coalesce, and slough as large sheets of epithelium (Nikolsky’s Sign). The remaining wound bed is a raw, moist, blanching dermis, similar in appearance to a scald. While oral ulcerations are rare, moist or wet skin such as groins and axillae are especially prone to vesica14,15,16 tion. In addition to delayed wound healing and its increased risk of secondary skin infection, patients often develop unstable scars (as our patient did) making them prone to blistering from minor sheer forces. Still in the majority of cases, skin ulcerations heal with minimal to no scarring.15 Utricaria may present during follow-up, the pathophysiology of which is currently unknown; however, it may involve a hypersensitivity reaction or even a psychological component. Days to weeks after exposure, patients may develop areas of scaling over previously erythematous skin. More severe forms of scaling may occur, such as exfoliative erythroderma, but are extremely rare. Late skin manifestations for SM gas exposure most frequently involve varying degrees of pigmentation. Such changes include: 1. Post-inflammatory hypo and/or hyperpigmentation at the site of a previous lesion; 148
Mechanism of Injury Ambient doses of 12-70mg/min/m3 Ambient doses of 100-200 mg/min/m3 Ambient doses more than 200mg/min/m3
Recovery Within two weeks
Three to six weeks Very rare
2. Peri-follicular hypo and/or hyperpigmentation secondary to mild peri-follicular inflammation in the absence of a previous lesion; 3. Generalized hyperpigmentation, affecting the entire surface of the skin; 4. Generalized hypo and hyperpigmented macules and patches resembling tinea versicolor; and 5. Hyperpigmented lesions over areas subjected to chronic pressure. Delayed onset of purpura and ecchymoses are rare 17 manifestations. Histological changes in SM exposed skin have been well described. Three to six hours after exposure the nuclei of basal keratinocytes become pyknotic. Progression of injury leads to degeneration of basal cells with formation of intracellular and extracellular vacuoles, dissolution of the basal cell layer, and separation of dermis from epi4,13 dermis. This becomes clinically evident as subepidermal bullae with mild dermal and epidermal necrosis. Respiratory Inhalation of sulfur mustard aerosol or vapor can rapidly lead to respiratory failure and death depending on the extent and dose of exposure. Victims initially suffer from tracheobronchitis, with nonspecific symptoms such as sore throat, hoarseness, chest pressure, and non-productive cough. Over the next 12 hours, progression of symptoms leads to sinus pain, tachypnea, bronchospasm, and a productive cough due to sloughed respiratory epithelium and an increase in secretions. Continued exposure may lead to secondary pneumonias, hemorrhagic pulmonary edema, 18,28 and even respiratory failure within 24-48 hours. Chronic pulmonary manifestations include chronic bronchitis, bronchiectasis, reactive airway dyfunction syndrome and emphysema.5 There is also evidence to suggest a slightly
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increased incidence of lung cancer after a latency of 20 19,20 years or more. Eye Mustard reacts quickly upon contact with the tissues of the globe although frank clinical symptoms usually develop gradually, four to eight hours after exposure. Injuries to the globe are also dependent on dose and duration of exposure (Table IV). Initial symptoms include eye pain, photophobia, tearing, and blurred vision.21,22 Physical examination may reveal blepharospasm, periorbital edema, conjunctival and scleral injection/edema, and anterior chamber cellular infiltrates. Visual acuity is often decreased. After several hours, the corneal epithelium may vesicate and slough. Late recurrences of keratitis and worsening opacifications have been described and can lead to recurrent ulcerations, pain, and blindness.23 Gastrointestinal Gastrointestinal manifestations are the result of systemic toxicity. Systemic toxicity is encountered with high dose exposures (more than 1,000mg-min/m3) or from swallowing contaminated food or saliva. Nausea and vomiting are common while diarrhea and gastrointestinal bleeding are not.1 Hematological Bone marrow suppression is also the result of highdose exposure (more than 1,000mg-min/m3) with subsequent systemic toxicity. Leukocytosis develops and lasts for several days before leucopenia manifests. Leucopenia may not be apparent for five to seven days but reaches a nadir in approximately ten days. Thrombocytopenia may ensue but anemia is noted less frequently. Mustard gas-induced bone marrow suppression is an extremely poor prog24 nostic sign. Carcinogenicity Sulfur mustard is a proven carcinogen. Prolonged and/or repeated exposure to a particular system/organ has been shown to increase its risk of cancer.19,20,24,25,27 World War I veterans who suffered mustard gas exposure in the battlefield had a small but probably significant increase in the incidence of lung cancer compared to veterans not exposed to the gas. Significant increases in the incidence of upper respiratory tract, oropharynx, and skin malignancies, have also been reported among patients who suffered occupational exposure to mustard gas. Management and Treatment Principles Regular clothing does not afford adequate protection. Specialized military protective garments are needed; these have a layer of charcoal to absorb the penetrating sulfur mustard and provide approximately six hours of protection after exposure.
Patients presenting with signs and symptoms of upper airway obstruction (i.e. stridor) require immediate endotracheal intubation or, in the presence of severe upper airway edema, treacheotomy. Once the skin is exposed, rapid removal of the SM substance is crucial as it becomes irreversibly fixed in the tissues within minutes. Mustard scavengers, antioxidants, NAD+ precursors, polymerase inhibitors, and corticosteroids have all shown value in animal models; however, currently there is no accepted antidote for the treatment of SM gas exposure in humans. Increased survival and fewer pathological organ effects were noted after administration of parenteral doses of sodium tiosulfate (3000mg/kg), vitamin E (20mg/kg), or dexamethasone (8mg/kg) within 15 minutes of exposure. The combination of all three was the most effec23,26 tive. It is likely that thiosulfate acts as a mustard scavenger, vitamin E as an antioxidant, and corticosteroids act by inhibiting lipooxygenase activity thereby decreasing the synthesis of prostaglandins and leukotrienes. In a rabbit model of mustard gas burns, the topical administration of cortisone following exposure decreased edema and led to shallower skin lesions. Healing time, however, was not ef16 fected. As mustard is relatively water insoluble, clothing and jewelry must be destroyed. The eyes should be copiously irrigated with water or saline. The skin is washed with mild soap and water with particular attention to the axillae, groin, and perineum. Should water supplies be limited, adsorbent powders such as talc, flour, and Fuller’s earth can be dispersed over affected areas and wiped with moist gauze. The skin can also be decontaminated with chloramine powder and 0.5% hypochlorite solution. These compounds inactivate sulfur mustard, producing free chloride.29 The U.S. military currently utilizes M258A1 kits for skin decontamination: these kits contain two sets of two towelettes, one containing phenol and hydroxide, the other containing chloramine. conclusion
Sulfur mustard is the first vesicant used as a chemical weapon causing a high number of injuries on the battlefields of World War I, and is still considered a major chemical agent. Owing to its ease of manufacture and extent of existing stockpiles, mustard was reportedly used in a number of isolated incidents since World War I. Its deleterious metabolic and tissue injury effects span almost every system in the body, and may lead to permanent disability and even death. A systematic multi-disciplinary approach is required for the care of injured patients, and this requires a comprehensive understanding of the various physiologic aspects of this type of burn. If mustard is ever used again, medical personnel must be prepared to accept and care for large numbers of casualties, who will require longterm care. 149
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rÉSUMÉ. Ce rapport décrit un cas de brûlure suite à une exposition au gaz moutarde, un agent chimique utilisé dans la guerre. On présente un examen des caractéristiques de diagnostic, les manifestations cliniques et les mesures thérapeutiques utilisés pour traiter ce phénomène rare, mais extrêmement toxique. L’objectif de ce rapport est de mettre en évidence l’importance de considérer ce diagnostic dans toute victime de la guerre, surtout en ces temps malheureux de la hausse des activités terroristes. Mots-clés: soufre du gaz moutarde, l’ypérite, brûlure, brûlure chimique BIBLIoGrAPHY
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Conflict of interest. None Funding. None
This paper was accepted on 5 May 2014.
