Pediatric Annals

Vesicant Agents and Children

Clifton E Yu, FAAP, MD; Thomas R Burklow, MD; James M Madsen, MD, MPH

Abstract

Chemical agents that cause blisters or vesicles to form upon contact with the skin historically have been referred to as blister agents or vesicants. The three major compounds wimin this category are sulfur mustard, the nitrogen mustards, and Lewisite. Although the nitrogen mustards and Lewisite were initially synthesized as chemical warfare agents, only sulfur mustard has actually been used in conflict. A form of nitrogen mustard was used for many years as a chemotherapeutic agent. Sulfur mustard is also the only agent in this class that is stockpiled in the United States, and it is thought to be in the chemical arsenals of at least a dozen other countries as well.1 For this reason, the following discussion focuses on the medical effects, treatment, and unique pediatric concerns of sulfur mustard exposure.

Unfortunately, sulfur mustard has a long legacy of use against human beings since its introduction as a chemical warfare agent in World War I. In that conflict it was by far the single greatest cause of chemical casualties on both sides despite the relatively low mortality associated with its use against well-protected troops. Since that time there have been numerous instances in which it was allegedly used: Italy sprayed mustard in parts of Ethiopia in 1935; Japan used it during its invasion of China in 1938; Egypt is thought to have used mustard against Yemen in the mid-1960s; and more recently, the United Nations has confirmed the use of mustard on numerous occasions by Iraq during its war with Iran from 1980 to 1988, resulting in an estimated 45 000 casualties.1"3 More alarmingly, in 1988 the Iraqi government unleashed sulfur mustard on its own Kurdish minority population, exposing thousands of civilians, including children, to its toxic effects, thereby completing the evolution of the use of sulfur mustard from battlefield warfare to civilian terrorism.4"5

The suitability of sulfur mustard as a chemical weapon can be attributed to several factors. Although considerably less lethal than weapons such as nerve agents, mustard results in a significant degree of prolonged morbidity. For example, the average length of hospitalization for World War I sulfur mustard victims was 42 days.1 Local medical resources therefore quickly can become strained by a large number of exposed individuals. A second factor is the ability of sulfur mustard to cause local damage to three separate organ systems - skin, airways, and eyes - and in larger doses to induce potentially fatal systemic effects as well. The risk of skin damage forces first responders to don bulky full-body contamination gear that can lead to excessive heat retention and in some cases to claustrophobia. Unlike many other chemical agents, the clinical effects of sulfur mustard exposure are delayed, typically for hours. Consequently, victims may not recognize that they have been exposed until hours after the exposure. Despite the presence of this clinically asymptomatic latent period, sulfur mustard begins to damage tissue within minutes of exposure, making decontamination significantly less effective if delayed. Lastly, despite its existence for more than 150 years, there is still no known antidote for sulfur mustard, making any form of therapy largely supportive.

CHARACTERISTICS

Sulfur mustard is an alkylating agent mat is toxic to rapidly reproducing and poorly differentiated cells. Under ambient environmental conditions it exists as an oily brown liquid with an odor of garlic or mustard, although it is actually a solid below 14°C (58°F). Despite its relatively low volatility, mustard vapor effects are a significant concern particularly in warmer climates. Because of its persistence in the environment, prolonged exposure may occur if effective environmental decontamination does not take place. Both vapor and liquid sulfur…

Chemical agents that cause blisters or vesicles to form upon contact with the skin historically have been referred to as blister agents or vesicants. The three major compounds wimin this category are sulfur mustard, the nitrogen mustards, and Lewisite. Although the nitrogen mustards and Lewisite were initially synthesized as chemical warfare agents, only sulfur mustard has actually been used in conflict. A form of nitrogen mustard was used for many years as a chemotherapeutic agent. Sulfur mustard is also the only agent in this class that is stockpiled in the United States, and it is thought to be in the chemical arsenals of at least a dozen other countries as well.1 For this reason, the following discussion focuses on the medical effects, treatment, and unique pediatric concerns of sulfur mustard exposure.

Unfortunately, sulfur mustard has a long legacy of use against human beings since its introduction as a chemical warfare agent in World War I. In that conflict it was by far the single greatest cause of chemical casualties on both sides despite the relatively low mortality associated with its use against well-protected troops. Since that time there have been numerous instances in which it was allegedly used: Italy sprayed mustard in parts of Ethiopia in 1935; Japan used it during its invasion of China in 1938; Egypt is thought to have used mustard against Yemen in the mid-1960s; and more recently, the United Nations has confirmed the use of mustard on numerous occasions by Iraq during its war with Iran from 1980 to 1988, resulting in an estimated 45 000 casualties.1"3 More alarmingly, in 1988 the Iraqi government unleashed sulfur mustard on its own Kurdish minority population, exposing thousands of civilians, including children, to its toxic effects, thereby completing the evolution of the use of sulfur mustard from battlefield warfare to civilian terrorism.4"5

The suitability of sulfur mustard as a chemical weapon can be attributed to several factors. Although considerably less lethal than weapons such as nerve agents, mustard results in a significant degree of prolonged morbidity. For example, the average length of hospitalization for World War I sulfur mustard victims was 42 days.1 Local medical resources therefore quickly can become strained by a large number of exposed individuals. A second factor is the ability of sulfur mustard to cause local damage to three separate organ systems - skin, airways, and eyes - and in larger doses to induce potentially fatal systemic effects as well. The risk of skin damage forces first responders to don bulky full-body contamination gear that can lead to excessive heat retention and in some cases to claustrophobia. Unlike many other chemical agents, the clinical effects of sulfur mustard exposure are delayed, typically for hours. Consequently, victims may not recognize that they have been exposed until hours after the exposure. Despite the presence of this clinically asymptomatic latent period, sulfur mustard begins to damage tissue within minutes of exposure, making decontamination significantly less effective if delayed. Lastly, despite its existence for more than 150 years, there is still no known antidote for sulfur mustard, making any form of therapy largely supportive.

CHARACTERISTICS

Sulfur mustard is an alkylating agent mat is toxic to rapidly reproducing and poorly differentiated cells. Under ambient environmental conditions it exists as an oily brown liquid with an odor of garlic or mustard, although it is actually a solid below 14°C (58°F). Despite its relatively low volatility, mustard vapor effects are a significant concern particularly in warmer climates. Because of its persistence in the environment, prolonged exposure may occur if effective environmental decontamination does not take place. Both vapor and liquid sulfur mustard can readily penetrate most clothing, although rubber overgarments are protective for several hours.6

CLINICAL EFFECTS

The first clinical signs of exposure to sulfur mustard involve local effects on the organ systems it first comes into contact with: the eyes, the skin, and respiratory tract. With inhalation or significant absorption, systemic effects involving the gastrointestinal and hematopoietic systems may also occur.

The first skin findings usually consist of erythema occurring about 4 to 8 hours after exposure, and this may be accompanied or even preceded by pruritus. If the exposure is mild, this may be the only skin manifestation. More typically, large yellowish blisters begin to form over the next 24 hours, and the erythema spreads, particularly to the groin, axilla, and neck areas because penetration is enhanced by moisture, heat, and thin skin.7 The blisters may burst spontaneously, resulting in a painful ulcer that may take weeks or months to heal. It is important to emphasize that the blister fluid does not contain free mustard and is therefore not hazardous. If the sulfur mustard exposure is significant, skin sloughing may occur directly, bypassing blister formation altogether.

The eyes are the organs that are mt sensitive to the effects of sulfur mustard, but unless there is direct liquid exposure, as with the skin, the signs and symptoms are also delayed. Within 4 to 6 hours of contact, irritation and pain may occur, followed progressively by photophobia, worsening conjunctivitis, and potential corneal ulceration. Significant liquid exposures may lead to perforation of the globe, but the widely reported "blindness" associated with vapor exposure reflects not optic-nerve damage but rather simple eye closure from intense eye pain and reflex blepharospasm. Severe lid edema secondary to toxic effects to the soft tissues around the eyes can also be a common finding.

Following inhalation of sulfur mustard vapor, respiratory effects typically begin within 6 hours. Initially, there is hoarseness and cough, followed by a characteristically toneless voice. With more significant exposure, there may be more rapid onset of these symptoms. With severe inhalation, necrosis of the airway mucosa can result in a sterile tracheobronchitis with pseudomembrane formation leading to airway obstruction.7 Bacterial superinfection may ensue later, resulting in bronchopneumonia, respiratory failure, and death. These are all so-called Type I effects, that is, effects on the proximal, or tracheobronchial, component of the respiratory tree. Damage to the peripheral, or gas-exchange, compartment of the respiratory tract is termed Type ? damage and is heralded by dyspnea. Although not characteristic of sulfur mustard exposure at low to moderate doses, it can be seen after severe exposures.

Gastrointestinal symptoms, consisting of nausea and vomiting at approximately the same time as the skin lesions, are not uncommon and are thought to be secondary to the cholinergic activity of sulfur mustard. These symptoms are usually self-limiting and not severe, although if there is a significant exposure, similar symptoms may recur days later from injury to gastrointestinal mucosa.1 Other organ systems that may be involved include the central nervous system and bone marrow. Commonly reported complaints from battlefield victims have included lethargy, headaches, malaise, and depression. To what extent sulfur mustard as opposed to exposure to other stressors has been directly responsible for these symptoms is unclear, but the clinician should be aware of their potential development. In severe exposures, varying degrees of leukopenia secondary to the myelosuppressive effects of sulfur mustard may also be seen, typically after 3 to 5 days.1

TREATMENT

The most important and effective treatment for victims of sulfur mustard exposure is prompt decontamination. Unfortunately, sulfur mustard penetrates the skin and exerts its irreversible effects within 3 to 10 minutes after contact, making self-decontamination the most expethent approach in many circumstances.3 Initial steps include removal of all clothing and physical elimination of any mustard residue on the skin. After basic life support measures are ensured, decontamination with warm water and soap should take place as soon as possible. The use of bleach, which acts relatively slowly and predisposes to liquefactive epithelial damage that can promote further penetration of the agent, is increasingly controversial; if used at all on the skin, the hypochlorite concentration should not exceed 0.5 % (that is, a 1:10 dilution of standard household bleach).1·7 The most important aspect of decontamination is speed, and the most effective method is physical removal. In addition to physically scraping, picking, or plucking the agent from the skin or clothing, adsorption - applying a substance such as charcoal, flour, powdered soap, or earth to the exposed surfaces to temporarily bind the agent - followed by flushing or rinsing with water can be helpful. Ideally, decontamination should be performed before transport to a medical facility, but if the patient is too unstable or arrives via personal transportation, decontamination may need to take place at the facility prior to entering the treatment areas. Even if delayed, decontamination must be a priority to prevent spread to other areas of the skin, to avoid further absorption, and to protect those who come into contact with the victim.

Subsequent to decontamination, the remainder of the therapy is supportive because of the lack of a specific antidote. The skin is treated similarly to that of a burn victim, with topical and systemic analgesia, incision of larger busters, frequent irrigation, and application of topical antibiotics, such as silver sulfadiazine. As with burns, the temptation to use systemic antibiotics should be avoided in the early stages to prevent selection of resistant organisms.

Eye treatment should be approached with the goal of preventing infection and scarring. Irrigation with copious amounts of water, followed by the use of cycloplegics for comfort and prevention of synechiae formation should immediately take place. Topical antibiotics should then be applied as with any patient with corneal damage, along with petroleum jelly (or another ointment) to the eyelids to prevent sticking, adhesion, and later scarring.

Pulmonary management depends on the kind of symptoms (Type I versus Type II) and their severity, and ranges from comfort measures such as cough suppressants and throat lozenges for mild proximal-compartment (upper-airway) symptoms, through bronchoscopic identification and removal of pseudomembranes, to early intubation and mechanical ventilation with positive end-expiratory pressure for significant peripheral-compartment (lower-respiratory) findings and hypoxia. Despite aggressive therapy, however, prolonged intubation for more than 5 to 10 days is a poor prognostic indicator.1 As with the skin, prophylactic administration of systemic antibiotics should be avoided despite the not uncommon findings of fever, leukocytosis, and cough. If signs and symptoms have worsened after 3 to 4 days and there is radiographic evidence of consolidation, antibiotic therapy should then be contemplated.

Because of fluid losses from the damaged skin and gastrointestinal losses through vomiting, parenteral fluids may be needed, although generally not to the degree required for thermal burn victims. Antiemetics may be helpful in the rare instances of severe vomiting.

PEDIATRIC EFFECTS

The effects of sulfur mustard on children tend to be more severe than on adults for a variety of reasons touched on elsewhere in this issue. Victims of sulfur mustard exposure have included children, and its studied effects have confirmed what many had suspected: the pediatric population is indeed more vulnerable than adults with regard to almost every organ system.

First and foremost is the skin. Children have thinner and more delicate skin, accounting for the findings in a series from Iran that reported a shorter duration from exposure to onset of dermatological manifestations, such as erythema and blister formation, as well as greater severity of these lesions.8 For this reason, children may comprise the initial index cases in a mass civilian exposure. Likewise, the decontamination with bleach solution that is often recommended for adults may in fact be more caustic to the injured, more delicate skin of the child, prompting many to emphasize (even more than for adult populations) decontamination with soap and water or just plain water instead.9

Sulfur mustard vapor has a density more than five times that of air, so as it slowly vaporizes in the environment it hovers inches above the ground.1 The medical consequences for children who live in this zone of high vapor concentration are many. Eye findings are more frequent, perhaps also because of the lesser likelihood of self-protection and the postulated higher frequency of hand-eye contact, especially in young children. Facial involvement tended to also be more frequent in Iranian children perhaps for the same reasons. Because of their higher minute ventilation, as well as their close proximity to the ground, children were also shown to be more susceptible to pulmonary injury.8 Gastrointestinal manifestations may also be more prominent, and with their lower intravascular volume reserve, children may suffer more from dehydration and may need closer attention to fluid replacement.

Lastly, the clinical effects of sulfur mustard can be extremely painful. Appropriate pain control in the child who is unable to give voice to apparent discomfort should receive primary attention.

CONCLUSION

There is already a significant body of knowledge about the use and effects of vesicants not only in military victims but in civilians, including children, as well. The unique vulnerabilities of children arise from physiological factors inherent in this population as well as from a lower likelihood of awareness and protection. These factors make it imperative that appropriate preparations be made at all levels in the continuum of care for the pediatric vesicant casualty. Preparation must include and integrate resources from community responders, including clinicians, to hospital-based services.

REFERENCES

1. Sidell FR, Takafuji ET, Franz DR, eds. Textbook of Military Medicine. Part I: Medical Aspects of Chemical and Biological Warfare. Washington DC: Office of the Surgeon General, Walter Reed Army Medical Center; 1997.

2. Barranco VP. Mustard gas and the dermatologist. Int J Dermatol. 1991;30:684-686.

3. Smith WJ, Dunn MA. Medical defense against blistering chemical warfare agents. Arch Dermatol. 1991;127:1207-1213.

4. Marshall E. Chemical genocide in Iraq? Science. 1988;241:1752.

5. Hu H, Cook-Deegan R, Shukri A. The use of chemical weapons: conducting an investigation using survey epidemiology. JAMA. 1989;262:640-643.

6. Aasted A, Darre E, Wulf HC. Mustard gas: clinical, toxicological, and mutagenic aspects based on modern experience. Ann Plast Surg. 1987;19:330-333.

7. US Army Medical Research Institute of Chemical Defense. Medical Management of Chemical Casualties. 3rd ed. Aberdeen Proving Ground, MD: US Army Medical Research Institute of Chemical Defense; 2000.

8. Momeni A, Aminjavaheri M. Skin manifestations of mustard gas in a group of 14 children and teenagers: a clinical study. Int J Dermatol. 1994;33:184-187.

9. Momeni A, Enshaeih S, Meghdadi M, Amindjavaheri M. Skin manifestations of mustard gas: a clinical study of 535 patients exposed to mustard gas. Arch Dermatol. 1992,128:775-780.

10.3928/0090-4481-20030401-09

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