sign in sign up
<<
Home , Blister agent, CNS (chemical weapon), HN3 (nitrogen mustard), Lewisite, Phosgene oxime

J R Army Med Corps 2002; 149: 358-370 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

Vesicants ( Agents)

MUSTARD AND remained when the sulphur atom was MUSTARDS substituted by a nitrogen atomThus it became possible to synthesise the nitrogen Introduction mustards with similar properties, of which Blister or vesicant agents are likely to be used there are three: both to produce casualties and to force (1)N-ethyl-2,2'di(chloroethyl)amine, opposing troops to wear full protective (HN1). equipment. These will degrade fighting (2)N methyl-2,2'di(chloroethyl)amine, rather than kill (although very severe (HN2). exposure to vesicants can be fatal). Blister (3) 2,2',2"tri(chloroethyl)amine, (HN3). agents can be thickened in order to enhance persistency and contaminate terrain, ships, All of the above nitrogen mustards are aircraft, vehicles or equipment. The vesicant alkylating agents and HN2 was introduced in agents include sulphur mustard (H - HD 1935 as the first chemotherapeutic refers to distilled mustard), agentFrom a military standpoint, HN3 is the (HN), the vesicants such as principal representative of the group of (L) (this may well be used in a nitrogen mustards and is the only nitrogen mixture with H), and the halogenated mustard likely to be used in war oximes, eg. oxime, (CX) whose properties and effects are very different from Physical and Chemical those of the other vesicants. Properties Vesicants burn and blister the skin or any The mustards are able to penetrate most other part of the body surface they contact. tissues they come into contact with and a They act on the eyes, mucous membranes, great number of materials: woods, leather, , skin and blood-forming organs: bone rubber, plants, etc. Mustards are very marrow and spleen. They damage the persistent in cold and temperate climates. In http://militaryhealth.bmj.com/ respiratory tract when inhaled and cause warmer climates the persistence of mustards vomiting and diarrhoea when ingestedBlister is reduced but the hazard from vapour agents may also cause bone marrow increases. It is possible to increase the suppression and have effects on other germ persistency by thickening mustard with finely cells. powdered material such as chlorinated rubberThese thickened mustards are very MUSTARD AGENTS difficult to remove by decontaminating Sulphur mustard was used extensively in processes and has been used more recently Mustards may be hydrolysed in but in Iran/IraqProtection against these agents thorough mixing is required for this to be can only be achieved by a full protective achieved. Alkalinity and higher temperatures on September 24, 2021 by guest. Protected copyright. ensemble. The respirator alone protects increase the rate of hydrolysis. In running against eye and damage, but does not water, the contact surfaces are frequently give sufficient protection against systemic changed and persistency is only a few days, effects. Extensive, slow healing skin lesions but in stagnant water, they can persist for and other effects will place a heavy burden several months. Mustard is more dense than on the medical services. water, but small droplets remain on the water Sulphur mustard is the best known of surface and present a special hazard in these agents. It was first synthesised in 1822, contaminated areas. Spreading can also and its vesicant properties were discovered in occur when decontaminating the skin with the middle of the nineteenth century. It was aqueous solutions; this effect can be used for the first time as a CW agent in 1917 minimised by flushing with copious amounts near Ypres,Belgium, from which it derives its of water and emulsifying agents. French name (Yperite). Mustard is 2,2'- The bivalent sulphur atom of sulphur di(chloro-ethyl)-sulphide. It is also known by mustard confers very good reducing the name "Lost" in German. properties. Oxidants will oxidise mustard to a In the US, the symbol HD has been given greater or lesser extent (depending on their to the distilled product; this abbreviation will strength) to sulphoxide, sulfone or sulphate. be used in this section. In 1935 it was Of these, only the sulfone has appreciable discovered that the vesicant properties vesicant properties. Nitrogen mustards are 359 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

much less easily oxidised than sulphur Chemical inactivation is often effected by mustard. chlorinating compounds incorporated into adsorbing powders, ointments, solutions or Detection organic solvents.Water should not be used to Mustard agents can be detected by a variety decontaminate mustard (except for the eyes) of means - single and three colour detector – this will disperse the agent over the skin. papers will detect liquid agent and are available for individual issue. Monitoring Additional Procedures devices for vapour hazard and water testing Time is of the essence - decontamination kits are also available. within 2 minutes of contact may prevent or greatly reduce the clinical effects of mustard Protection exposure. However, a degree of protection is Ordinary clothing gives little or no provided by late decontamination. Chemical protection against mustard agents - a inactivation using chlorination is effective respirator, NBC suit, gloves and foot against mustard and Lewisite, less so against protection are required. Due to slow HN3, and is ineffective against phosgene absorption of mustard by many materials, oxime. In the case of thickened mustard, protective equipment must be changed where the usual procedure is inadequate, the regularly. There is no drug available to bulk of the agent may have to be scraped off prevent the effects of mustard on the skin with a knife or similar objectThis should be and the mucous membranes; the only followed by wetting the surface with a cloth practical preventative method is physical drenched in an organic solvent, e.g., petrol protection. Anti-Gas barrier creams were (unleaded gasoline) and subsequent developed in WW2 and subsequently (Figure application of the usual decontaminating 17); work to develop and deploy more procedure. If water is available in abundant effective protective topical barrier creams is amounts, these procedures should be progressing in some NATO countries. followed by copious washingIf the combat clothing is contaminated, it should be removed as soon as possible. Mechanism of Action The exact mechanism of action is not known, however, work over the last decade has revealed many specific mechanisms which may contribute to the development of the mustard injuryCentral to many of these

mechanisms is the ability of sulphur and http://militaryhealth.bmj.com/ nitrogen mustards to alkylate a very wide range of biologically important mole- culesSulphur and nitrogen mustards are Fig 17. Anti Gas ointments and cake from post-WW2. bifunctional alkylating agents, containing two reactive chloroethyl functions. Inter- Decontamination action products with cellular components Exposure to mustard is not always noticed can occur via formation of ethylene- immediately because of the latent and sign- sulfonium (sulphur mustards) or ethyleni- free period that may occur after skin monium ions (nitrogen mustards) through exposure. cyclisation and subsequent binding. In deoxyribonucleic acid (DNA), mono- on September 24, 2021 by guest. Protected copyright. Decontamination of Mucous Membranes and functional adducts are predominantly Eye formed (the second chloroethyl function is The substances used for skin decon- converted into hydroxyethyl), but bi- tamination are generally too irritant to be functional binding, leading to formation of used on mucous membranes and the eyes. cross-links, does occur. Additionally, alky- The affected tissues should be flushed lation of ribonucleic acid (RNA), proteins, immediately with water from a water bottle cellular membrane components and cross- (canteen). The eyes can be flushed with links between DNA and proteins can be the copious amounts of water, or (if available) cause of cellular damage. Guanine is affected isotonic sodium bicarbonate (1.26%) or most of the DNA- and RNA-bases. saline (0.9%) The binding of reactive sulphur or nitrogen mustard species to DNA produces a range of Decontamination of the Skin effects. Each soldier is given the means for a - Due to their relative instability, N7- preliminary decontamination of the skin; this alkylated guanine residues may be is based on physical adsorption or on the released from the DNA. Upon DNA combination of physical adsorption and replication, the remaining apurinic sites chemical inactivation. Physical adsorption do not provide a proper template of can be achieved by adsorbing powders. information, resulting in erroneous 360 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

incorporation of nucleotides. This may significantly. A latent period of 4 -12 hours lead to mutations and synthesis of non- follows mild exposure, after which there is functional proteins. lachrymation and a sensation of grit in the - After damage to DNA, cellular repair eyes. The conjunctivae and the lids become mechanisms may not be error free These red and oedematous. Serious exposure processes thus may also give rise to irritates the eyes after 1 to 3 hours and erroneous DNA replication. produces severe lesions. - Crosslinks, in particular interstrand crosslinks, between two guanines for Mustard burns of the eyes may be divided example, may play an important role in thus: the cytotoxicity of the sulphur and - Mild (75% of cases in World nitrogen mustards. They inhibit the DNA War 1) - recovery takes 1 to 2 weeks. replication process. - Severe conjunctivitis with minimal corneal involvement (15% of cases in World War Toxicity 1), blepharospasm, oedema of the lids and Three distinct levels of biological action can conjunctivae occur, as may "orange-peel be discerned following exposure to mustards: roughening" of the cornea - recovery takes cytostatic, mutagenic and cytotoxic effects. 2 to 5 weeks. In the present state of knowledge, the - Mild corneal involvement (10% of cases possibility that some effects might be due to in World War 1), areas of corneal erosion reactions with cellular membranes or critical stain green with fluorescein dyes, super- enzymes cannot be dismissed.The actions of ficial corneal scarring and vascularisation mustards partly resemble those of ionising occurs as does iritis. Temporary relapses radiation and as such, mustards have been occur and convalescence may take 2 to 3 referred to as radiomimetic compounds. months. Hospital care is indicated for Actively proliferating cells are affected most; casualties of this type. thus basal epidermal cells, the haemopoietic - Severe corneal involvement (about 0.1% system and the mucosal lining of the of World War 1 mustard casualties). intestine are particularly vulnerable. Ischaemic necrosis of the conjunctivae may be seen; dense corneal opacification CLINICAL-PATHOLOGICAL with deep ulceration and vascularisation EFFECTS occurs. Convalescence may take several months and patients are predisposed to Eyes late relapses even after many yearsLate The eyes are more susceptible to mustard relapses have a bad prognosis and are than either the respiratory tract or the skin refractory to therapy. (Figure 18). Mild effects may follow http://militaryhealth.bmj.com/ exposure to concentrations barely percept- Skin ible by odour of about 1 hourThis exposure The hallmark of sulphur mustard exposure is does not effect the respiratory tract latency - a symptom and sign free period for on September 24, 2021 by guest. Protected copyright.

Fig 18. Mustard vapour burns to the eye. 361 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

some hours after exposure. The duration of this period and the severity of the lesions is dependent upon the level and type of exposure, environmental temperature and probably on the individual. High temperature, hydrated, thin or delicate and occluded skin are associated with more severe lesions and shorter latent periods for a given dose. Some people are markedly more sensitive to mustard than others. Burns may be the result of either vapour or liquid exposure. Fig 20. Mustard vapour burns to the axilla – Iran/Iraq The sequence of skin changes normally Wa r. seen is as follows: blistering. - Erythema (2-48 hour post exposure). This - Deep burning leading to complete epidermal may be very striking and reminiscent of loss. This is particularly likely to occur on scarlet fever. Slight oedema of the skin the eyelids, penis and scrotum since the may occur. Itching is common and may be epidermis in these sites is particularly thin, intense(This sequence is reminiscent of naturally moist and often occluded. that seen in sun burn.) - Blistering. Erythema is followed by the Lesions tend to be painful and some development of numerous small vesicles patients complain of very severe pain. which may coalesce to form larger Healing of skin lesions is slow. The areas blistersBlisters are not painful per se, which were markedly erythematous darken though they may be uncomfortable and and may become very hyperpigmented - feel tenseBlisters at points of flexure - brownish-purple to black discolouration of anterior aspects of elbows and posterior some areas may occur.These changes tend to aspects of knees - can seriously impede disappear over a period of several weeks with movement. Mustard are delicate desquamation leading to the appearance of and may be ruptured easily by contact areas of hypopigmentation. The appearance with bed linen, bandages or during of such areas alongside those of transport of casualties. Crops of new hyperpigmentation may be striking. blisters may appear as late as the second The sensitivity of the skin depends on its week post exposure. Blister fluid is not thickness and upon the density of sweat and vesicant and does not produce secondary sebaceous glands. Apart from mucous membranes the most sensitive areas are the

face (Figure 19), axilla (Figure 20), genitalia, http://militaryhealth.bmj.com/ neck, skin between the fingers and the nail beds. The palm of the hand, sole of the foot and the skin of the scalp are very resistant. If only a small dose is applied to the skin, the effect is limited to erythema and after several days the colour changes from red to brown. The itch diminishes progressively and the epidermis desquamates. At higher doses blister formation starts, generally between 4 and 24 hours after contact, and this blistering on September 24, 2021 by guest. Protected copyright. can go on for several days before reaching its maximum. They are often more than 1 cm2 and may be very large and pendulous (Figure 21). Their domes, which are thin and yellowish, contain a relatively clear or slightly yellow liquid. The blisters are fragile and usually rupture spontaneously giving way to a suppurating and necrotic wound. The necrosis of the epidermal cells is extended to the underlying tissues, especially to the dermis. The damaged tissues are covered with necrotic debris and are extremely susceptible to infection. The regeneration of these tissues is very slow, taking from several weeks to several months, much longer than the time required for the restoration of skin destroyed by physical means or by caustic compounds. Fig 19. Mustard vapour burns to the face – Iran/Iraq War. Healing may result in scarring and fragile 362 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

cause signs similar to those of irradiation: headache, gastrointestinal pain, nausea, vomiting, leucopenia and anaemia. Mustard agents may cause a general depletion of all elements of the bone marrow.The cells of the granulocyte series and megakaryocytes appear more susceptible to damage than those of the erythropoietic system. A reactive leucocytosis may occur during the first three days, followed 10 days post exposure by a Fig 21. Large blisters from sulphur mustard vapour. decrease in the peripheral white cell count. The development of a severe leucopenia or skin which may be easily damaged by an aplastic anaemia makes survival unlikely. trauma, but the overall prognosis of these Absorption of high doses may result in lesions is better than comparable thermal CNS excitation leading to convulsions, burns followed by CNS depression. The systemic fluid derangement seen as a Cardiac irregularities may occur with atrio- consequence of these injuries is appreciably ventricular block and cardiac arrest may less than for thermal burns, and therefore the followHypotension, refractory to standard overall outcome is better resucitation, has been described on a number of occasions following severe exposureThe Respiratory Tract prognosis of these rare hypotensive cases is Mustard attacks all the mucous membranes hopeless and no universally accepted of the respiratory tract. After an average mechanism has been advanced. latent period of 4 to 8 hours (range 2 to 48 hours depending on dose), mustard irritates TREATMENT OF MUSTARD and congests the mucous membranes of the LESIONS nasal cavity and the throat, as well as the epithelium of the trachea and large bronchi. Prophylaxis Symptoms start with rhinorrhoea, burning There is no drug therapy available for pain in the throat and hoarseness of the preventing the effects of mustard. voice. This pain may make the patient reluctant to . A dry cough gives way to copious expectoration.The vocal cords often Therapy There is no specific therapy available for the become damaged, resulting in aphonia. treatment of mustard lesions. Airway secretions and fragments of necrotic The aim of therapy is to:

epithelium may obstruct the airways; rales http://militaryhealth.bmj.com/ and reduced air entry can be detected by - Relieve symptoms. auscultation.There is pronounced dyspnoea. - Prevent infections. The damaged lower airways become infected - Promote healing. easily, predisposing to bronchopneumonia after approximately 48 hours. If the inhaled Eye Lesions dose has been sufficiently high the victim will The ocular effects of mustard are very die in a few days, either from pulmonary painful. Use of local analgesics may increase oedema or mechanical asphyxia due to corneal damage and are not recommended; fragments of necrotic tissue obstructing the systemic analgesics (narcotics) should trachea or bronchi, or from superimposed therefore be used as required. Secondary bacterial infection (facilitated by an impaired infection is a serious complication and on September 24, 2021 by guest. Protected copyright. immune response). increases the amount of corneal scarring. To prevent infection, appropriate anti-bacterial Gastrointestinal Tract preparations should be used.When the lesion Ingestion of contaminated food or water may proves more serious (blistering of the eyelids, cause destruction of mucous membranes. In blepharospasm, etc.), the anti-bacterial the case of ingestion of large amounts, preparation should be applied at more perforation of the gastrointestinal tract with frequent intervals. Patients with corneal subsequent mediastinitis or peritonitis may lesions should receive mydriatics to prevent occurSymptoms include nausea, vomiting, adhesions between the iris and cornea. In pain, diarrhoea and prostration. These case of troublesome secretions accumulating, features may make casualties reluctant to eat. the eyes may be carefully irrigated with a Vomit and faeces may be bloodstained. 0.9% sterile saline solution and sterile Hypovolaemic shock may occur from the loss petroleum jelly (VaselineTM) may be applied of fluids and electrolytes from prolonged to the eyelids to prevent sticking. The eyes vomiting and diarrhoea. should not be covered with a bandage; if necessary, protect them with dark or opaque Systemic Action gogglesWhen the eyelids can be separated Systemically absorbed mustards by any without too much pain, the cornea should be route, including severe skin exposure, may examined for lesions with fluorescein 363 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

solution, followed by lavage. A green spot as soon as possibleRoutine wound inspection indicates a lesion, which if severe should be aids in the early detection and institution of treated by an ophthalmologist as soon as appropriate therapy for any complicating possible. In some countries, ophthalmo- bacterial infections. Analgesics should be logists have recommended treatments given as required. Skin grafting is rarely including the use of citrate and ascorbate eye required and when it has been attempted, drops and regular topical steroids. grafts have not taken well. More severe injuries will cause enough In a recent review on the casualties from oedema of the lids, and the Iran-Iraq conflict, it appeared that the blepharospasm to obstruct vision. This healing process and the final outcome were alarms the patients. To allay their fears, the more dependent on the severity of the initial lids may be gently forced open to assure lesion than on the treatment applied. them that they are not blind. The psychological effects of eye lesions, even of Trunk and Neck mild degree, are notable. Casualties with blepharospasm may believe they are Extensive Vesication of the Trunk. permanently blinded and become depressed, All the patients considered under this unless steps are taken to assure them that heading should be evacuated promptly. their sight remains intact. Extensive vesication may occur over a large part of the trunk. Intervening areas of skin Respiratory Tract Lesions may be erythematous with pin-point Mild respiratory tract injury, with hoarseness vesication. These burns are more likely to and sore throat only, usually requires no occur on the back than anteriorly. Some treatment. Cough may be relieved by protection is afforded anteriorly by codeine. and tracheitis may be equipment such as webbing and ammunition treated symptomatically with steam or sterile pouches. The front of the uniform also gives cool mist inhalations. If more severe some anterior protection because it does not respiratory tract injury is suspected, cling to the body. hospitalisation may be advisable. If a Extensive vesication may be followed by bacterial pneumonia occurs, isolation of the fever, nausea and vomiting. These effects specific organisms with their antibiotic tend to occur more readily in tropical sensitivities should be performed, then climates. antibiotic therapy can be targettedIn cases of Secondary bacterial infection may overwhelming exposure, severe diffuse lung complicate the clinical course. The medical damage may result and such casualties may officer in a forward position is not likely to need supported ventilation. see infection of vesicated areas because such

cases will have been evacuated before http://militaryhealth.bmj.com/ Systemic Effects secondary infection develops. Every effort should be made to maintain adequate metabolic status and to replace loss Localised Vesication of the Trunk. of fluids and electrolytes. Infection should be Vesication occurring within the natal cleft treated promptly and vigorously. The use of (between the buttocks) usually requires colony stimulating factors can be evacuation of the casualty. Walking becomes recommended to shorten the duration of difficult, defecation is painful and dressings leucopenia require frequent changing. The lesion is usually most intense at the upper end of the Skin Lesions cleft. Vesication of the buttocks usually on September 24, 2021 by guest. Protected copyright. It is important to ensure that no remaining results from sitting on contaminated ground contamination is present before commencing or in contaminated trousers for prolonged treatment. The skin turns red and itches periods. The vesicated area may extend intensely. This itching can be diminished by forward across the perineum to involve the local applications of cooling preparations, scrotum and the penis. e.g., calamine lotion, corticosteroid Some burns, such as mild erythema preparations or silver sulphadiazine cream. affecting the natal cleft, may not be severe, Severe erythema around the genitalia may but require careful attention because become quite painful and weeping and walking or running aggravates the lesions maceration may ensue. Often, treatment with and may break down injured skin. Single exposure of the area is desirable and care discrete blisters on the buttocks away from must be taken to ensue that secondary the natal cleft do not cause major disability. infection of tissue does not occur. Infection is Blisters on the trunk generally require the most important complicating factor in protective dressings to prevent friction due to the healing of mustard burns. clothing. The medical officer must decide There is no consensus on the need to de- whether dressings should remain in position roof blisters or on the optimum form of during regular duty. treatment (open or covered, dry or wet)Once blisters have broken, it is best to remove their Arms ragged roofs and cover with sterile dressings Most individuals with injuries of 364 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from the arms, when suitably treated, are those of the ankles) often result in permitted to continue with their duties. incapacitation by interfering with Localised vesication produces little or no locomotion.The movement of joints tends to disability. Extensive vesication involving the aggravate existing lesions by increasing axillae and the elbows, volar or dorsal oedema. A further disabling factor is aspects, partially impairs the movement of introduced by the use of firm dressings on the limbs at those joints. Oedema of the mobile joints. surrounding tissue tends to immobilise the Vesication often spreads over the kneecaps, extremities furtherThe dorsal aspects of the upward onto the thighs, and down toward elbow and forearm are common sites of the feet. These burns tend to be extensive severe burns because these parts touch and are associated with oedema, often contaminated ground when men and women extending halfway up the thigh and down the are firing in the prone position. Casualties of leg (Figure 22). Medical officers should this type should be evacuated. Widespread evacuate casualties with such lesions. vesication of the arms results in partial disability. Casualties of this type should be evacuated. Hands Blister agent burns of the hands are frequently encountered following use of sulphur mustard. These burns tend to cause a degree of disability out of proportion to the size of the lesions. Considerable care and judgement are required in correct management. Experience in tropical experimental installations indicates that protective gloves Fig 22. Mustard vapour burns – Iran/Iraq War. provide adequate protection against high doses of vapourYet it is hard to avoid burns It has been shown that the presence of of the hands in a heavily contaminated many superficial blisters on the legs and jungle. The palms are more resistant to thighs alone is not enough to make an vesication but blisters affecting the palms are individual incapable of carrying out routine characteristically painful and slow to heal. military duties. Individuals with such lesions, A solitary lesion of limited extent may having had suitable dressings applied, were result in little or no disability if treated able to take part in daily marches and routine properly. Burns from liquid vesicant on the gun drills. In disposing of these cases, the http://militaryhealth.bmj.com/ dorsum of the hand result in severe local medical officer should consider the mental reactions characterised by intense oedema of and physical status of the individual, his or the backs of the hands and fingers. Pain is her willingness to carry on, and the tactical characteristic and is intensified by movement situation at the time. After suitable dressings of the fingers or wrist. These patients should have been applied, individuals with high be regarded as casualties. An individual morale and robust physique may be returned exposed within the previous 24 hours and to duty. reporting for treatment with apparently A relatively small blister or group of blisters trivial blisters may be totally incapacitated situated in the popliteal area may reduce the the following day. Severe erythema of the efficiency of a man or woman to the degree dorsum of the hand, with vesication that he or she may require evacuation - this on September 24, 2021 by guest. Protected copyright. beginning 12 to 24 hours after exposure, arises from aggravation of the lesions by indicates a lesion that will progress to movement of the limbs and interference with extensive vesication and oedema. Under ambulation. However, blisters affecting this such circumstances the individual should be area are not necessarily incapacitating. evacuated when first seen. More commonly, Vesicant lesions also develop near the ankles the lesions consist of scattered small vesicles at the tops of the boots/shoes. Blistered areas and limited areas of erythema. These lesions occurring at such unprotected points are can be protected satisfactorily and the associated with severe pain due to circulatory individuals returned to duty. impairment and tense oedema of the leg. Exposure to vesicant vapour produces These patients should be evacuated. diffuse erythema of the dorsum of the hand Vapour burns of the legs tend to be most and wrist. Higher doses cause oedema and aggravated in the popliteal spaces. Pin-point vesication as well; patients of this type require vesication is often found here. Higher doses evacuation. cause intense erythema with scattered areas of vesication over the entire surface of the leg. Lower Extremities Such lesions invariably produce casualties If the lower extremities are contaminated and are generally accompanied by severe with liquid vesicant, the knees are the most burns elsewhere, frequently with severe common sites of burns. These lesions (and systemic effects. Mild vapour burns of the 365 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

legs produce irritation and itching common reactions to burns to this region. Severely to all widespread vapours burns. These affected individuals should be evacuated on effects are troublesome but they are not the basis of the apprehension that may be casualty producing, and men or women so suffered as well as the physical discomfort affected may be returned to duty. involved. Extensive vesication of the feet is There is no documented information on uncommon.The soles are protected by shoes specific effects of mustards on female and are comparatively resistant to vesication. genitalia. Burns on the dorsal aspect of the foot are often associated with local reactions like Secondary Bacterial Infection in those seen on the backs of hands. Individuals Blister Agent Burns with these burns, especially if widespread This section considers the problem of over the foot, find it difficult or impossible to secondary bacterial infection after blister wear shoes and will require evacuation. Small agent injuries only as it influences the discrete blisters may be effectively protected disposition of affected personnel in forward to allow wearing of shoes; walking may cause positions. Secondary bacterial infection has little discomfort. often been cited as a common complication of mustard burns of the skin. Observations Male Genitalia from experimental burns indicate that Vapour is a more common cause of burns to compared with the incidence of infection in the male genitalia than is liquid thermal and traumatic wounds, the agentErythema may not be conspicuous.The incidence of sepsis in mustard lesions is most prominent feature of the burn is remarkably low. However, experience from oedema. Fluid accumulates most readily in the clinical situation suggests that the the prepuce, distending its entire experimental studies underestimate the true circumference and forming a characteristic incidence of infection. semitranslucent ring around the corona. In Secondary infection becomes manifest more severe cases, the entire body of the several days after injury. Medical officers are penis becomes oedematous. not likely to see secondary infection with The lesions cause apprehension as well as extensive blister agent burns in forward areas physical discomfort. Occasionally vesication because severely affected patients should is superimposed on the oedema. Ulceration have been evacuated. Infection of small is not infrequent at the tip of the prepuce lesions does not require evacuation. where it may become secondarily infected. In However, infection of multiple lesions is severe cases associated with marked oedema, likely to be an indication for evacuation, as retention of urine may result from both infection is particularly disabling when it mechanical and reflex effects. involves the feet, the hands, the genitalia or http://militaryhealth.bmj.com/ In mild cases, objective changes of the tissues overlying the joints of the limbs. scrotum often tend to pass undetected due to Secondary infection is more likely to occur the normal pigmentation, elasticity, and in severe, rather than mild, vapour injury to looseness of the skin. Even considerable the respiratory tract. Severe respiratory oedema may not be enough to reveal its symptoms will almost invariably be presence. In severe cases the scrotum may associated with severe ocular effects. become grossly enlarged. The rugae may be Respiratory lesions may not develop for partly or completely obliteratedPin-point several days, and by then the individual vesication may occur, usually after a lapse of should have been evacuated as a a few days. The scrotal skin tends to consequence of the ocular effects. Secondary on September 24, 2021 by guest. Protected copyright. breakdown resulting in small, painful ulcers infection is uncommon as a sequel to mild and fissures. Burning is the commonest degrees of mustard conjunctivitis and symptom. As oedema decreases, itching ordinarily would not prevent an individual starts and may persist long after the acute from continuing duty. Mild conjunctival effects have subsided; sometimes the itching burns may be associated with pharyngitis, is intolerable. The scrotum may continue to laryngitis, and tracheitis, increasing in crack and ulcerate for a considerable period, severity for several days. Occasionally more causing pain and irritation. extensive respiratory infection may ensue. Mild exposure of the genital region is followed by a characteristic delay in the Course and Prognosis development of symptoms, often for as long The great majority of mustard casualties as 4 to 10 days. Patients with mild burns survive. Resolution of specific problems can without oedema or vesication, but who be difficult to predict but the following is a complain of irritation and burning, may be guide: safely returned to duty following treatment. In disposing of mild burns of the genitalia, - Ocular lesions: Most are resolved within 14 the medical officer must be confident that days of exposure. the symptoms are not too early to be judged - Skin lesions: Deep skin lesions may be with finality. expected to heal in up to 60 days. Apprehension and anxiety are distressing Superficial lesions heal in 14-21 days. 366 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

- Upper respiratory tract lesions: It is very Physical and Chemical difficult to define a time course for Properties complete recoveryPatients from the Iran- In a pure form Lewisite is a colourless and Iraq conflict were often discharged whilst odourless liquid, but usually contains small still coughing and complaining of amounts of impurities that give it a brownish expectoration. Lung function tests on colour and an odour resembling geranium patients with purely upper respiratory tract oil. Lewisite exists as cis- and trans-isomers. lesions were usually normal on discharge. It is heavier than mustard, poorly soluble in Patients with parenchymal damage often water but soluble in organic solvents showed an abnormal pattern on lung In contact with water, Lewisite is function testing. hydrolysed at an appreciable rate, forming an oxide that is equally vesicant: Long Term Effects of Mustard ClCH=CH-ASCl + H O ClCH=CH- Poisoning 2 2 AsO + 2HCl The long term effects of mustard may be divided into three groups: In contact with strong alkalis, Lewisite is totally decomposed to non-vesicant pro- 1.Personnel exposed to mustard agents may ducts. Oxidizing agents (e.g., hypochlorite, experience prolonged psychological man- peroxide and ) oxidize Lewisite to ifestations including chronic depression, 2-chloroethenylarsonic acid, which is physio- loss of libido and anxiety. logically inactive. 2.Local effects of mustard exposure may include: Detection - (permanent blindness The detection of Lewisite is facilitated by the is extremely rare). fact that it forms coloured products with - Scarring of the skin. many reagents. DraegerTM tubes are available - Chronic obstructive airways disease, which react with organic arsenicalsDetectors including chronic , emphysema are available for use in the field. and reactive airways disease. - Bronchial stenosis; Protection - Gastrointestinal stenosis with dyspepsia Ordinary clothing gives little or no protection after ingestion of agent. against Lewisite; a respirator, NBC suit, - Increased sensitivity to mustard. gloves and foot protection are required. 3. Sulphur mustard is a known . A study of American soldiers exposed to Decontamination sulphur mustard during World War I The decontamination procedure is the same revealed an increased incidence of lung

as for mustard. http://militaryhealth.bmj.com/ cancer (and chronic bronchitis) compared to soldiers who had sustained other Mechanism of Action injuriesA study of British workers involved Lewisite easily penetrates the skin, where it in the production of sulphur mustard exerts its vesicant actionIt can spread during World War II revealed no increase in through the whole body and act as an deaths due to cancer amongst those who arsenical poison. It has been shown that had died since 1945, but an increase in the Lewisite inhibits a great number of enzymes prevalence of laryngeal carcinoma amongst rich in SH-groupsInhibition of the pyruvate those still alive. Some solid tumours take dehydrogenase system is a property common 20 years or more to develop, and although to all trivalent compounds. Lipoic there has been no increase in rates, the long acid is an essential part of the pyruvate on September 24, 2021 by guest. Protected copyright. term effects in mustard casualties from the dehydrogenase system, acting as a co-enzyme Iran/Iraq war are awaited. in the formation of acetyl-Co-A from pyruvate. Lewisite is thought to combine ARSENICAL VESICANTS - with lipoic acid to form a cyclic compound, LEWISITE thereby interfering with energy production within the cell. Introduction

The possessing the -ASCl2 group are CLINICAL-PATHOLOGICAL endowed with vesicant properties. Of these, EFFECTS Lewisite is the best known and the most characteristic. Initially, preparations Eyes contained considerable impurities, but at the Liquid arsenical vesicants cause severe end of World War I it was purified in the US damage to the eye. On contact, pain and (but not used operationally). Lewisite is 2- blepharospasm occur instantly. Oedema of chlorovinyl-dichloroarsine, ClCH=CH- the conjunctivae and lids follows rapidly and ASCl2. close the eye within an hour. Inflammation of the iris is usually evident by this time. After a few hours, the oedema of the lids begins to subside, but haziness of the cornea develops 367 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

and iritis increases.The corneal injury, which corrosive burns). Erythema is similar to that varies with the severity of the exposure, may caused by mustard but is accompanied by either heal without residual effects, induce more pain. Itching and irritation persist for pannus formation or progress to massive only about 24 hours, independent of whether necrosis. The iritis may subside without a blister develops. Blisters are often well permanent impairment of vision if the developed in 12 hours and are painful at first, exposure is mild. After heavy exposure, in contrast to the relatively painless mustard hypopyon may ensue, terminating in blister. After 48 to 72 hours, the pain lessens. necrosis, depigmentation of the iris and synechia formation. Liquid arsenical Respiratory Tract vesicants instantly produce a grey scarring of The vapours of arsenical vesicants are so the cornea, like an acid burn, at the point of irritating to the respiratory tract that contact. Necrosis and separation of both conscious casualties will immediately put on bulbar and palpebral conjunctivae may a mask to avoid the vapour. No severe follow very heavy exposure. All injured eyes respiratory injuries are likely to occur except are susceptible to secondary infection. Mild among the wounded who cannot put on conjunctivitis due to arsenical vesicants heals respirators, and the careless, who are caught in a few days without specific treatment. without respirators. The respiratory lesions Severe exposure may cause permanent injury are similar to those produced by mustard or blindness. except that in the most severe cases, pulmonary oedema may be accompanied by Skin pleural effusion. Pathology Systemic Effects Liquid arsenical vesicants produce more Liquid arsenical vesicants on the skin and severe lesions of the skin than liquid inhaled vapour are absorbed systemically and mustardFull thickness injury to the skin may cause systemic poisoning. A occurs and burns may penetrate to manifestation of this is a change in capillary connective tissue and muscle and cause permeability; there may be loss of sufficient greater vascular damage and more severe fluid from the bloodstream to cause inflammatory reaction than in mustard haemoconcentration, shock and death. In burns. In large, deep, arsenical vesicant non-fatal cases, haemolysis of erythrocytes burns, there may be considerable necrosis of may occur with a resultant haemolytic tissue and gangrene. anaemia. The excretion of oxidised products Despite the overall severity of these skin into the bile by the liver produces focal lesions, the spontaneous rate of healing is necrosis of that organ, necrosis of the mucosa considerably faster than that of comparable of the biliary passages with peribiliary http://militaryhealth.bmj.com/ mustard burnsExposure of the skin is haemorrhages and some injury of the followed shortly by erythema, then by intestinal mucosa. Acute systemic poisoning vesication which tends to cover the entire from large skin burns causes pulmonary area of erythema. The surrounding halo of oedema, diarrhoea, restlessness, weakness, erythema is less noticeable than with subnormal temperature and hypo- mustard blisters, although the two are often tensionSome symptoms associated with indistinguishable. The yellowish blister fluid may occur, such as is slightly more opaque than that of the nephritis with proteinurea and neuropathy. mustard blister and microscopically, contains more inflammatory cells. Research has shown that blister fluid contains hydrolysis TREATMENT OF LEWISITE on September 24, 2021 by guest. Protected copyright. products which may present a further LESIONS vesicant risk to the patient if the blister fluid An antidote for Lewisite is (2, 3- remains in contact with normal skinStandard dimercapto-propanol, CH2SH - CHSH - clinical protective measures should prevent CH2OH, BAL). It is known as British Anti injury to health care providers when dealing Lewisite (BAL). Purified dimercaprol is a with these patients. colourless liquid, soluble 1 part in 15 parts of water and more soluble in peanut oil or in Symptoms ethanol. It can combine with arsenic, Stinging pain is felt usually within 10 - 20 forming a water soluble complex that can be seconds after contact with liquid arsenical excreted. With , the complex vesicants. The pain increases in severity with formed possesses a pentagon with two penetration and in a few minutes becomes a carbon atoms, two sulphur atoms and one deep, aching pain. Pain on contact with arsenic atom at the corners. This is the same liquid arsenical vesicants usually gives mechanism by which Lewisite blocks two sufficient warning, so decontamination may adjacent SH groups of pyruvate dehydro- be begun promptly and deep burns thus genase system. The therapeutic action of avoided in conscious victims. After about 5 dimercaprol can thus be explained by the law minutes of contact, a grey area of dead of mass action: dimercaprol provides the epithelium is evident (resembling that seen in organism with a great number of adjacent 368 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

SH groups that displaces the arsenic bound - Cough with dyspnoea and frothy sputum, to enzymes.The enzymes are reactivated and which may be blood tinged and other signs can resume their normal biological activity. of pulmonary oedema. However, the toxicity of dimercaprol itself - A skin burn the size of the palm of the must be considered. It sometimes provokes hand or larger, caused by a liquid arsenical local irritation. blister agent which was not Topical formulations of BAL suffer from decontaminated within the first 15 problems of chemical stability and this minutes. seriously limits their shelf lifeBAL would not - Skin contamination by a liquid arsenical be used by all NATO nations; other water vesicant covering 5% or more of the body soluble dimercaprol analogues exist such as surface, in which there is evidence of 2,3-dimercapto-1-propanesulfonic acid immediate skin damage (grey or dead- (DMPS) and meso-dimercaptosuccinic acid white blanching of the skin), or in which (DMSA). erythema develops over the area within 30 minutes. Eyes The following approaches may be employed: Dimercaprol eye ointment may diminish the effects of Lewisite if applied within 2-5 - Local neutralisation on and within the skin minutes of exposure. In severe cases, the by a liberal application of BAL ointment. systemic use of morphine may be necessary The affected skin should be left covered for control of pain. When the conjunctival with a layer of ointment. Silver oedema subsides enough to permit sulphadiazine is contraindicated in the ophthalmic examination, the cornea should presence of BAL be stained with fluorescein to detect erosions - Intramuscular injection of BAL in oil and the iris should be examined for iritis. (10%). Atropine sulphate ointment should be - Alternative systemic treatment using 2,3- instilled to obtain and maintain good dimercapto-1-propanesulphonic acid mydriasis in all cases with corneal erosions, (DMPS) and meso-dimercaptosuccinic iritis cyclitis or with marked photophobia or acid (DMSA). miosis. Antibiotics may be used to combat The maximum dosage of BAL is 3 mg.kg-1 infection. Sterile petroleum jelly (VaselineTM) (200 mg for an average person) applied to the lid margins will help prevent intramuscularly repeated every 4 hours for 2 their sticking together. Irrigations of the eye days, every 6 hours on the third day and should be copious, employing isotonic every 12 hours for up to 10 solutions. Occlusive dressings or pressure on daysAdministration must be by deep the globe must be avoided. intramuscular injection with special attention

being given to aseptic techniqueThese http://militaryhealth.bmj.com/ Skin injections are painful and may result in tissue BAL ointment may be applied to skin necrosis at the injection site. When given by exposed to Lewisite before actual vesication injection they may produce alarming has begun, but application after vesication reactions in some individualsSymptoms and also has benefit. BAL ointment is spread on signs include: the skin in a thin film and allowed to remain in situ for at least 5 minutes. Occasionally, - Increased systolic and diastolic pressure. BAL ointment causes stinging, itching or - Tachycardia. urticarial weals. This condition lasts only an - Nausea and vomiting. hour or so and should not cause alarm. Mild - Headache. dermatitis may occur if BAL ointment is - Burning sensation of lips. on September 24, 2021 by guest. Protected copyright. frequently applied on the same area of skin - Feeling of constriction of the chest. (this property precludes its use as a - Conjunctivitis. protective ointment). Dimercaprol is - Lachrymation. chemically incompatible with silver - Rhinorrhoea. sulphadiazine and the two should not be - Sweating. used together. - Anxiety and unrest. The treatment of the erythema, blisters The side effects of BAL are so severe that and denuded areas is identical to that for the use of modern alternatives should be similar mustard lesions. A severe full consideredThe newer chelating agents thickness burn involving a large surface area (DMSA and DMPS) are water soluble and is similar to a thermal injury and must be do not produce these alarming side effects managed by intravenous fluid replacement when used systemically. The advantages of to avoid hypovolaemic shock. Morphine and these compounds are that they are: splinting of the affected parts may be necessary to relieve pain. - substantially more effective than BAL systemically. - water soluble, active when given orally and Treatment of Systemic Effects relatively non-toxic. The following are indications for the use of systemic treatment: BAL produces mobilisation of arsenic 369 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

from most tissues but is less effective in so Protection doing than DMSA and DMPS. BAL given Ordinary clothing gives little or no protection to rabbits poisoned with sodium arsenite against ; a respirator, produced an increase in brain arsenic levels. NBC suit, gloves and foot protection are DMPS on the other hand produced a required. marked fall in brain arsenic levels. DMSA and DMPS have been identified as Decontamination having an anti-Lewisite action. Of the series Chemical inactivation using alkalis is DMPS, DMSA and BAL when tested for effective, whereas chlorination is ineffective capacity to reverse or prevent pyruvate against phosgene oxime. The eyes should be dehydrogenase inhibition by sodium flushed immediately using water or isotonic arsenite, DMPS proved the most potent and sodium bicarbonate solution if available. BAL the least potent drug. Physical removal of the agent should be The evidence supports the use of the more carried out as soon as possible. recently developed chelating agents (DMSA and DMPS) in preference to BAL for the Mechanism of Action treatment of systemic Lewisite poisoning. In low concentrations, phosgene oxime Maintenance of metabolic status and severely irritates the eyes and respiratory replacement of fluids and electrolytes is organs. In high concentrations, it also attacks important, particulary in the case of the skin. A few milligrams applied to the skin hypovolaemic shock complicating severe cause severe irritation, intense pain, and exposure. The specific haematological, subsequently a necrotising wound. Very few hepatic and renal effects arising from compounds are as painful and destructive to systemic poisoning by arsenical compounds the tissues. Systemic toxicity has been such as Lewisite may require specialist and described from parenteral absorption. The possibly intensive medical management. exact mode of action is not known. The effects are said to be caused by phosgene Course and Prognosis oxime reacting with SH- and H N groups. The long term effects of exposure to are unknown. Burns severe enough to cause Clinical-Pathological Effects shock and systemic poisoning are life- Phosgene oxime also affects the eyes, causing threatening. Even if the patient survives the corneal lesions and blindness and may effect acute effects, the prognosis must be guarded the respiratory tract resulting in pulmonary for several weeks. oedema.The action on the skin is immediate; phosgene oxime provokes irritation resem- HALOGENATED OXIMES bling that caused by a stinging nettle. A few

The urticant properties of the halogenated milligrams cause intense pain which radiates http://militaryhealth.bmj.com/ oximes were discovered long before World from the point of application. Within a War II. To this group belong diiodo- minute the affected area turns white and is formoxime, dibromoformoxime, mono- surrounded by a zone of erythema which chloroformoxime and dichloroformoxime. resembles a wagon wheel in appearance. The latter oxime is the most irritant of the Within 1 hour the area becomes swollen and series; it is commonly known as phosgene within 24 hours the lesion turns yellow and oxime, symbolised by CX. Its chemical blisters appear. Some days later, the area formula is CCl2 = NOH. shows desquamation with necrosis of the skin followed by crust formation and a Physical and Chemical

purulent discharge. on September 24, 2021 by guest. Protected copyright. Properties of Phosgene Oxime Phosgene oxime is a white crystalline Treatment powder. It melts at 39 - 40°C, and boils at There is no antidote availableThe lesions 129°C. By the use of additives, it is possible should be treated as any other ulcerated to liquify phosgene oxime at room necrotic skin lesion (e.g., thermal burn) with temperature. It is fairly soluble in water and due consideration of other supportive in organic solvents. In aqueous solution, measures. Systemic analgesia may be phosgene oxime is hydrolysed fairly rapidly, requiredPulmonary oedema should be especially in the presence of alkali. It has a treated appropriately. high vapour pressure and its odour is very unpleasant and irritating. Even as a dry solid, Course and Prognosis phosgene oxime decomposes spontaneously There is no clinical experience with and has to be stored at low temperatures. casualties arising from this agent and hence accurate prognosis is uncertain. Detection There are no automatic detectors available for use in the field, but the characteristic signs and symptoms of phosgene oxime exposure may suggest its use. 370 J R Army Med Corps: first published as 10.1136/jramc-148-04-05 on 1 December 2002. Downloaded from

Further Reading Renshaw B. "Mechanisms in Production of Cutaneous Auguson WS, Sivak A, Marley WS. Chemical Casualty Injuries by sulphur and Nitrogen Mustards," in Bush, Treatment Protocol Development – Treatment Approaches. V.(ed): Agents and Related Chemical Cambridge, Mass, Arthur D Little, Inc.Vol II-IV, 1986. Problems. Washington, DC, Office of Scientific Research Buscher H. Green and Yellow Cross, Tras. Conway N, and Development, Part 3, Ch 23, 1946, pp 479-518. (1944). Cincinnati, Kettering Laboratory of Applied Treatment of Chemical Agent Casualties and Conventional Physiology, University of Cincinnati, 1931. Military chemical Injuries. FM 8--285, Washington, DC, Cullumbine, H. : Its Mode of Action and the HQ, Dept of the Army, Feb. 1990. Treatment of its Local and General Effects. Porton Down, Vedder EB. The Vesicants,The Medical Aspects of Chemical United Kingdom, Chemical Defence Establishment. Warfare. Baltimore, Williams and Wilkins Co., Ch 8, Gross CL, Meier HL. et al. "Sulphur Mustard Lowers 1925, pp 125-166. NAD Concentrations in Human Skin Grafted to Vesicant Injury to the Eye, Part II, Laboratory Studies. Athymic Nude Mice." Toxical Appl Pharmacol, 81:85-90, Bulletin, Johns Hopkins Hosp., 948; 82:81-352. 1985. Wada S, Miyanishi M. et al. "Mustard Gas as a Cause of Norman JE, Jr. "Lung Cancer Mortality in world War Respiratory Neoplasia in Man." Lancet, 1968: 1:1161- One Veterans with Mustard Gas Injury: 1919-1965." J 1163. Natl Cancer Inst., 54:311-317, 1975. Warthin AS,Well CV. The Medical Aspects of Mustard Gas Papirmeister B, Gross CL. et al. "Molecular Basis for Poisoning. St. Louis. CV Mosby Co., 1919. Mustard-Induced Vesication." Fund Appl Toxicol, 5:S134- Willems JL. "Clinical Management of Mustard Gas S149, 1985. Casualties. "Annales Medicinae Militaris Belgicae, 1989, Papirmeister B, Gross CL. et al. "Pathology Produced by Vol 3 supp. Heymans Institute of Pharmacology, Sulphur Mustard in Human Skin Grafts on Athymic University of Ghent Medical School and royal School of Nude Mice: I. Gross and Light Microscopic Changes." the Medical Services, Leopoldskazerne, B-900 Ghent, J Toxical-Cut and Ocular Toxicology, 3:371-391, 1984. Belgium. Papirmeister B, Gross CL et al. "Pathology Produced by Yamada A. "On the Late Injuries Following sulphur Mustard in Human Skin Grafts on Athymic Occupational Inhalation of Mustard Gas, with Special Nude Mice: II. Ultrastructural Changes." J Toxicol-cut Reference to Carcinoma of the Respiratory Tract." Acta and Ocular Toxicolgy, 3:393-408, 1984. Pathologica Jpn, 13:131-155, 1963. Potential Military Chemical/BiologicalAgents and Compounds. FM 3-9,Washington, DC, HQ, Dept of the Army, 1990. http://militaryhealth.bmj.com/ on September 24, 2021 by guest. Protected copyright.