The term war gas is generally a misnomer. Sulfur mustard and nerve agents are liquids at normal temperatures and pressures, and many riot-control agents are solids. These weapons are most efficiently dispersed as aerosols, which probably leads to the confusion with gases. Some chemical weapons (eg, chlorine, phosgene, hydrogen cyanide) are truly gases, and although they are generally considered obsolete for battlefield use, they might still be used as improvisational agents, especially in terrorist attacks.
Liquid chemical weapons have a certain degree of volatility and may evaporate into poisonous vapors. Volatility is inversely related to persistence, the tendency to remain in the environment. Persistent agents, such as mustard or VX, can contaminate an area for prolonged periods, denying the enemy free movement and use of contaminated material. The toxic hazard from semipersistent agents like sarin or nonpersistent agents like hydrogen cyanide dissipates more rapidly.
Aerosols, gases, and vapors are highly subject to local atmospheric conditions. Less dispersion occurs with atmospheric inversion layers and in the absence of wind, as typically occurs at night or in the early morning. Enclosed spaces also prevent wind dispersion and even simple dilution. Except for hydrogen cyanide, CW gases and vapors are all denser than air and will pool in low-lying areas.
As a practical example, consider the 1995 sarin release in the Tokyo subway system. The number of fatalities could have been much higher had it been effectively aerosolized instead of simply allowed to evaporate. Photos from the attack show severely affected or deceased victims in very close proximity to mildly affected, ambulatory individuals. Presumably, sarin concentrations decreased so rapidly as distance from the source increased that few victims were significantly contaminated. After removal from high-concentration areas, the victims’ bodies posed less threat to bystanders because of dilution and improved ventilation. Even so, some health care professionals were secondarily exposed, as the victims were not disrobed prior to entering the hospitals. Up to 46% of hospital staff in areas with poor ventilation reported symptoms consistent with mild acute poisoning, although cholinesterase levels were not reported.52,53,56 About one-third of rescue workers in the 1994 Matsumoto sarin incident also developed mild toxicity. Rescuers arriving at the scene later were less likely to develop symptoms,49 suggesting that the vapor had dissipated over time.
Preparation for CBW Incidents
A rational medical response to CBW events differs from the common response to isolated toxicologic incidents. Health care professionals must learn about these unconventional weapons and the expected “toxidromes” that may occur.1 In addition, health care professionals must protect themselves and their facilities first, or ultimately no one will receive care. New medicolegal and ethical considerations will arise in CBW mass-casualty events that otherwise infrequently occur. The greatest good for the greatest number of victims may preclude heroic interventions in a few critical patients. Charges of negligence may later arise regarding delays in treatment or failure to diagnose subtle signs of disease, even if such actions were unavoidable at the time. Even if physicians become well versed in the appropriate response to CBW incidents, the question remains as to how many will be willing to continue working in the presence of an actual public health disaster.30
The responses to chemical and biologic weapons will also differ.26 Chemical weapons, like conventional explosives, generally produce clinical effects within seconds to hours, making a “scene” or “hot zone” evident. The first responders for a chemical event will be fire and police authorities, hazmat teams, and emergency medical services. Patients will be brought to local health care facilities and the disease process, although perhaps not the specific etiology or diagnosis, will be recognized rapidly. With biologic weapons, the victims will not all present for care at the same time in the same place. First responders will be local and distant emergency departments (EDs) and primary care offices, highlighting the need for training in these specialties.
Recommendations for sustained health care facility domestic preparedness include improved training to promptly recognize CBW mass casualty events, efforts to protect health care professionals, and establishing decontamination and triage protocols.40Table 132–3 lists some specific recommendations. Several facets of the response to a CBW event are still being refined, such as the optimal choice of personal protective equipment, determining who needs decontamination and by what means, and what is to be done with wastewater produced by mass decontamination.36,40 On a tactical level, communication can be severely impaired by personal protective gear, which points out the need for loudspeakers or other forms of public address.40,81
TABLE 132–3.Recommendations for Health Care Facility Response to Chemical and/or Biological Warfare or Weapons Incidents ||Download (.pdf) TABLE 132–3. Recommendations for Health Care Facility Response to Chemical and/or Biological Warfare or Weapons Incidents
|• Immediate access to personal protective equipment for health care professionals |
|• Decontamination facilities that can be made operational with minimal delay |
|• Triage of victims into those able to decontaminate themselves (decreasing the workload for health care providers) and those requiring assistance |
|• Decontamination facilities permitting simultaneous use by multiple persons and providing some measure of visual privacy |
|• A brief sign-in process where patients are assigned numbers and given identically numbered plastic bags to contain and identify their clothing and valuables |
|• Provision of food, water, and psychological support for staff, who may be required to perform for extended periods |
|• Secondary triage to separate persons requiring immediate medical treatment from those with minor or no apparent injuries who are sent to a holding area for observation |
|• Providing victims with written information regarding the agent involved, potential short and long term effects, recommended treatment, stress reactions, and possible avenues for further assistance |
|• Careful handling of information released to the media to prevent conflicting or erroneous reports |
|• Instituting postexposure surveillance |
Individual clinicians and hospitals caring for victims of known or suspected CBW incidents should contact their local department of health, which may in turn report the incident to outside agencies such as the US Federal Bureau of Investigation and the Centers for Disease Control and Prevention (Table 132–4).
TABLE 132–4.Chemical and/or Biological Warfare or Weapons Phone Numbers/Contacts ||Download (.pdf) TABLE 132–4. Chemical and/or Biological Warfare or Weapons Phone Numbers/Contacts
CDC Emergency Preparedness and Response:
Emergency Response Line: (770) 488–7100
CDC Division of Bioterrorism Preparedness and Response: (404) 639–0385
US Army Medical Research Institute of Chemical Defense Emergency Response Line:
(410) 436-3276 or (410) 322-6822
Federal Bureau of Investigation (FBI):
Find your local FBI field office at:
National Response Center:
For reporting releases of hazardous substances: www.nrc.uscg.mil/
(800) 424–8802, or (202) 267-2675
Decontamination serves two functions: (1) to prevent further absorption and spread of a noxious substance on a given casualty, and (2) to prevent spread to other persons. Chemical weapons that are exclusively gases at normal temperatures and pressures such as chlorine, phosgene, or hydrogen cyanide only require removing the victim from the area of exposure. Isolated aerosol or vapor exposures, as from volatilized nerve agents or sulfur mustard, are also terminated by leaving the area and may require no skin decontamination of the victims.46,71 Japanese experience with sarin suggests that clothing should be removed from victims of nerve agent vapor exposure and placed in airtight receptacles, such as sealed plastic bags. Some of the secondary exposures to sarin were thought to have occurred as nerve agent that had condensed on the victims’ clothing revaporized into the ambient air, and this caution probably holds true also for sulfur mustard vapor exposures.
Chemical weapons dispersed as liquids present the greatest need for decontamination. Because nerve agents are highly potent and have rapid onset of effects, some victims with significant dermal contamination may not survive to reach medical care.71 Liquid-contaminated clothing must be removed, and, if able, victims should remove their own clothing to prevent cross-contamination.
Decontamination should be done as soon as practicable, to prevent progression of disease, and should occur outside of health care facilities to prevent contamination of the working environment and secondary casualties. Decontamination near the incident scene would be ideal in terms of timeliness, although logistically this will not be possible in many situations. Field decontamination prior to transport will also help to avoid loss of vehicles from being contaminated and taken out of service. Evidence supports the likelihood that contaminated victims will present at health care facilities on their own, or be transported for care without decontamination.36 In mass-casualty incidents, decontamination efforts may benefit from separating victims into those who can remove their own clothing and shower themselves with minimal direction and assistance, and the more seriously affected who will require full assistance. The degree of protective gear required by the decontamination personnel cannot be predicted in advance, and may be difficult to objectively determine at the time of the incident. Level C personal protective equipment may be sufficient for most hospital settings when the source is defined (eg, receiving and decontamination areas); however, if health care professionals begin to develop symptoms, then level B gear with supplied air would become necessary54 (Chap. 131). When the source of the contamination is not yet known, level B gear should be used. Chemically contaminated victims presenting to a health care facility should, if possible, be denied entrance until decontaminated. Patients who have already entered a health care facility and are only later determined to be a contamination hazard present a more difficult problem. If the situation allows, such patients should be taken outside for decontamination before returning, and the previous care area cordoned off until any remaining safety hazard has been assessed and eliminated. However, in a mass-casualty disaster, such efforts at remediation may not be practical.
Nerve agents are hydrolyzed and inactivated by solutions that release chlorine, such as household bleach, or solutions that are sufficiently alkaline. To avoid potential dermal and mucous membrane injury, a 1:10 dilution of household bleach in water (producing a 0.5% sodium hypochlorite solution) is recommended, not only for nerve agents, but also for sulfur mustard and many biologic agents.40,44,73 Alternatives include regular soap and water or copious water alone. Rapid washing is more important than the choice of cleaning solution because 15 to 20 minutes is necessary for hypochlorite solutions to inactivate chemical agents.40 Care should be taken to clean the hair, intertriginous areas, axillae, and groin.73
Decontamination after sulfur mustard exposure is more problematic than for nerve agents. First, it is more likely that significantly contaminated victims will survive to reach medical care, and they may remain asymptomatic for several hours. In addition, the biochemical damage becomes irreversible long before symptoms develop. Decontamination within 1 to 2 minutes is the only effective means of limiting tissue damage from mustard.75 However, the actual means of mustard decontamination are identical to those for nerve agents. Victims must be disrobed and thoroughly showered. Dilute hypochlorite solutions (eg, 0.5% sodium hypochlorite, a 1:10 dilution of household bleach) are advocated to inactivate mustard, but copious water irrigation will also suffice.46 Symptomatic victims of mustard exposure should still be decontaminated, although it is unlikely to benefit that particular individual it can prevent the spread of mustard to others.75 Lewisite and phosgene oxime must also be decontaminated quickly, although they produce immediate symptoms, making it more likely that victims will present promptly when decontamination is most effective.
Water irrigation is generally recommended for riot control agent exposures because hypochlorite solutions may exacerbate skin lesions.46 Inadequately decontaminated patients exposed to lacrimators can produce secondary cases among health care professionals, so any contaminated clothing should be removed and bagged.
Significant issues remain regarding decontamination measures. The number of people potentially requiring decontamination may easily outstrip capacity. Incidents with hundreds or thousands of victims may necessitate communal showers, selective decontamination, or both. Decontamination wastewater should ideally be contained and treated, but few facilities have the capability or funds to do this. However, wastewater may be a minor issue, since with large scale chemical weapons events the wastewater represents only a small percentage of the total environmental impact.40
The actual release of chemical or biologic weapons can be characterized as a low-probability, high-consequence event. Potential sources for civilian exposure include terrorist attacks, inadvertent releases from domestic stockpiles, direct military attacks, and industrial events. Terrorists may sabotage military or industrial stockpiles or directly attack the populace. Experience has shown that physicians are much more likely to encounter hoaxes,13 isolated cases,62 or limited incidents with a modest number of casualties.80 Riot control agents are exceptions, in that treating riot control agent and pepper spray victims is a routine occurrence in many urban EDs.
Technical and organizational obstacles decrease the chance of major CBW terrorist events. Obtaining or producing chemical or biologic weapons, although simpler than for nuclear weapons, is only part of the process. Effective dissemination is difficult if the goal is to maximize casualties. Proper milling of biologics to produce stable, respirable aerosols requires technical sophistication probably only attainable with governmental research support. Low-technology attacks such as food contamination, poisoning of livestock, and enclosed-space weapons dispersal appear more likely to occur than attacks resulting in hundreds, thousands, or millions of casualties. Smaller attacks, or merely threatening use of chemical or biologic weapons, may be equally consequential from a terrorist’s perspective if they exert comparable political influence with significant psychosocial impact.
The chemicals most likely to be used militarily appear to be sulfur mustard and the nerve agents. A “low-tech” terrorist attack could involve the release of toxic industrial chemicals, such as chlorine, phosgene, or ammonia gas as chemical “agents of opportunity.”
Either the threat or the actual use of CBW agents presents unique psychologic stressors. Even among trained persons, a CBW-contaminated environment will produce high stress through the necessity of wearing protective gear, potential exposure to agents, high workload intensity, and interactions with the dead and dying. Disorders of mood, cognition, and behavior will be common among exposed or potentially exposed victims as a result of the uncertainty, fear, and panic that may accompany a CBW incident, even a hoax. The psychological casualties will probably outnumber victims requiring medical treatment. Civilians without training, including some health care professionals, are likely to confuse somatic symptoms with true exposure. Medical resources may easily be overwhelmed unless triage can identify those who will benefit most from appropriate counseling, education, and psychologic support. Psychiatrists and other disaster mental health personnel should be enlisted in plans to manage CBW incidents for their expertise in treating anxiety, fear, panic, somatization, and grief.15
In Israel during the Gulf War, anxiety-related somatic reactions to missile attacks were reported in 18% to 38% of persons surveyed,11 and more than 500 people sought medical attention in EDs for anxiety.59 Among 5510 people seeking medical attention after the Tokyo subway sarin release, only about 25% were hospitalized.70 Some of the “victims” presented days or even weeks after the incident, apparently feeling unwell and thinking they were exposed.53,57 Civilian survivors of chemical attacks in the 1980–1988 Iran–Iraq war report increased symptoms of depression, anxiety, and posttraumatic stress disorder compared to those exposed to low-intensity conventional warfare.23 In one longitudinal study of American Persian Gulf War veterans, 4.6% reported their belief that they were exposed to CBW agents, despite the lack of any convincing evidence of deliberate exposures, nor of unintended exposure to any significant levels of chemical agents. Greater combat stress was associated with a higher incidence in belief in such exposures.76 Another study reported a 64% incidence in belief of CBW agent exposure among Gulf War veterans.9 Reported indicators supporting these beliefs included receiving an alert, having physical symptoms, and being told to use protective gear. Belief in exposure to biologics correlated with having received an alert about chemicals, suggesting that CW alerts can spread misinformation and confusion among recipients.
Uncontrolled release of information may compound terror and increase psychologic casualties. Imagine the influx of patients resulting from a news report suggesting that anyone with dizziness or nausea be checked for nerve agent toxicity, or that fever and cough indicate infection with anthrax.
Israeli Experience during the 1990–1991 Gulf War
Israel is probably one of the best prepared countries for CBW disasters. In late 1990, the civilian population was supplied with rubber gas masks, atropine syringes, and Fuller’s earth decontamination powder.59 Major Israeli hospitals conduct chemical practice drills every 3 to 5 years.81 These drills identify several key lessons, including designating specific hospitals for chemical casualties, blocking hospital access to a single guarded entrance to prevent internal contamination, and extending nurses’ authority to initiate treatment by established protocols. The Israeli plan provides two tiers of triage. The first triage occurs outside of the hospital by protected medical personnel who perform only life-saving interventions, such as intubation, hemorrhage control, and antidotal therapy. Patients are then decontaminated and enter the hospital. Afterward, patients are triaged again according to severity of illness into separate areas in which dedicated health care teams provide the appropriate interventions.64,81
Thirty-nine ballistic missiles with conventional warheads were launched against Israel from Iraq in early 1991, with only six missiles causing direct casualties. Many more “injuries” resulted from CBW defensive measures and psychologic stress than from physical trauma. Out of 1060 injuries reported from EDs during this time period, 234 persons were directly wounded in explosions (most injuries were minor), and there were only two fatalities from trauma.32,59 More than 200 people presented for medical evaluation after self-injection of atropine, a few requiring admission to the hospital.3,32,59 About 540 people sought care for acute anxiety reactions. Some suffocated from improperly used gas masks, fell and injured themselves when rushing to rooms sealed against CBW agents, or were poisoned by carbon monoxide in these airtight rooms.32,59 Increased rates of myocardial infarction and cerebrovascular accidents were also observed.59 A survey of hospital staff members found that only 42% would report for duty following a chemical weapon attack.65
Pregnancy does not appear to be a significant factor in the treatment of women victims of chemical weapons. In the Tokyo subway sarin attack, five victims were identified at one hospital as being pregnant. These women were only mildly affected and were admitted for observation. All had healthy babies, the first one born 3 weeks after the incident.53,55,57 In Israel, no obstetric complications occurred among women wearing gas masks during labor and delivery.18,59
Children differ substantially from adults with regard to chemical weapons effects and decontamination efforts. Children breathe at a lower elevation above the ground and at a higher rate than adults. Because nearly all chemical weapon gases and vapors are heavier than air, children will be exposed to higher concentrations than adults in the same exposure setting, and will likely exhibit symptoms earlier.5,61,86 Children may also be more susceptible to vesicants and nerve agents than adults with equivalent exposures.60,86 Children have thinner and more delicate skin, allowing for more systemic absorption and more rapid onset of injury with sulfur mustard. The blood–brain barrier of a child may also be less resistant than in adults and the activity of endogenous detoxifying enzymes, such as paraoxonase, is less, allowing for greater toxicity with nerve agents. Additionally, children with organic phosphorus compound poisoning less frequently exhibit a muscarinic toxic syndrome than adults, and often present with isolated central nervous system (CNS) depression.60
The decontamination of children is another feature that requires an age-adjusted approach. Children have a larger surface area-to-mass ratio and may be more likely to carry a toxic or fatal dose of a chemical weapon on their skin. Most children will need assistance and supervision during decontamination procedures; keeping a mother or other adult guardian with a child should help with both decontamination and thermoregulation.61
Physical Characteristics and Toxicity
Nerve agents are extremely potent organic phosphorus compound cholinesterase inhibitors, and are the most toxic of the known chemical weapons (Fig. 132–1).46 For example, sarin is 1000-fold more potent in vitro than the pesticide parathion.71 Aerosol doses of nerve agents causing 50% human mortality (LD50) range from 400 mg/minute/m3 for tabun down to 10 mg/minute/m3 for VX, compared with 2500 to 5000 mg/minute/m3 for hydrogen cyanide. Dermal exposure LD50s for nerve agents range from 1700 mg for sarin down to only 6 to 10 mg for VX.46,71 Pure nerve agents are clear and colorless. Tabun has a faint fruity odor, and soman has been variably described as smelling sweet, musty, fruity, spicy, nutty, or like camphor. Most subjects exposed to sarin and VX have been unable to describe the odor.41,71 The G agents tabun (GA), sarin (GB), and soman (GD) are volatile and present a significant vapor hazard. Sarin is the most volatile, only slightly less so than water. VX is an oily liquid with low volatility and higher environmental persistence.41,46,71 Other G and V agents have been developed, including cyclosarin (GF) and Russian VX (VR).
The pathophysiology of nerve agents is essentially identical to that from organic phosphorus compound insecticides (Chap. 113), differing only in terms of potency and physical characteristics of the xenobiotics. The resultant toxic syndrome includes muscarinic (salivation, lacrimation, urination, defecation, GI cramping, emesis) and nicotinic (muscle fasciculation, weakness, paralysis) signs, and central effects (loss of consciousness, seizures, respiratory depression).29,69,73
Nerve agent vapor exposures produce rapid effects, within seconds to minutes, whereas the effects from liquid exposure may be delayed as the agent is absorbed through the skin.71 Vapor or aerosol exposures have historically been more common, whether through experiments or from unintentional releases in the laboratory69 or in terrorist attacks.48,57 Aerosol or vapor exposure initially affects the eyes, nose, and respiratory tract. Miosis is common, resulting from direct contact of nerve agent with the eye, and may persist for several weeks.69,73 Other ocular effects include conjunctival injection and blurring and dimming of the vision. Dim vision is often ascribed to pupillary constriction, but central neural mechanisms also play a role.71 Ciliary spasm produces ocular pain, headache, nausea, and vomiting, often exacerbated by near-vision accommodation.29 Rhinorrhea, airway secretions, bronchoconstriction, and dyspnea occur with increasing exposures. With a large vapor exposure, one or two breaths may produce loss of consciousness within seconds, followed by seizures, paralysis, and apnea within minutes.44
In the 1995 Tokyo subway sarin incident, ocular effects were most common after sarin vapor exposure, as patients manifested miosis (89%–99% of symptomatic victims), eye pain, dim vision, and decreased visual acuity.29,57 Other common complaints were cough, throat tightness, nausea, headache, dizziness, chest discomfort, and abdominal cramping.43,78 Among 111 patients admitted to one hospital, the most common presenting signs and symptoms were miosis (99%), headache (74.8%), dyspnea (63.1%), nausea (60.4%), eye pain (45%), blurred vision (39.6%), dim vision (37.8%), and weakness (36.9%).53,57 Excessive secretions were less common, as rhinorrhea occurred in approximately one-quarter of patients admitted to one hospital,57 and in none of 58 patients at another.78 Secondary exposures occurred among emergency medical technicians (EMTs) and hospital personnel in both the Tokyo43,52,53 and Matsumoto48,49 terrorist sarin releases, apparently from evaporation of nerve agent that had condensed on the primary victims’ clothing.
Liquid nerve agents can permeate ordinary clothing, allowing for percutaneous absorption and rendering the clothing of those patients’ potential hazards to health care personnel prior to proper decontamination. Mild dermal exposure produces localized sweating and muscle fasciculations after an asymptomatic period lasting up to 18 hours. Moderate skin exposure produces systemic effects with nausea, vomiting, diarrhea, and generalized weakness. Substantial dermal contamination will produce earlier and more severe symptoms, often with abrupt onset. Severe toxicity from any route of exposure causes loss of consciousness, seizures, generalized fasciculations, flaccid paralysis, apnea, and/or incontinence.46,71,73 Cardiovascular effects are less predictable, as either bradycardia (muscarinic) or tachycardia (nicotinic) may occur.44 In the Tokyo sarin event, tachycardia and hypertension were more common than bradycardia.51,78 Subtle CNS effects may continue for weeks, but typically resolve if no anoxic brain injury occurred.
Long-term effects from nerve agent exposure have mostly been limited to psychologic sequelae.67 Neither delayed peripheral neuropathy nor the intermediate syndrome has been reliably described in humans exposed to nerve agents.73,74 Follow-up studies from the Japanese sarin incidents show that neuropathy and ataxia, when initially present, resolved within 3 days to 3 months.85 The main persistent sequela is posttraumatic stress disorder, found in up to 8% of victims.28,85
Treatment of Nerve Agent Exposure
In critically ill patients, antidotal treatment may be necessary before or during the decontamination process; but generally, decontamination should occur before other treatment is instituted.
Atropine is the standard anticholinergic antidote for the muscarinic effects of nerve agents.17 Atropine does not reverse nicotinic effects but does have some central effects and may thus assist in halting seizure activity.29,41,71
Atropine is administered parenterally, either by the intravenous (IV) or intramuscular (IM) route, and the dose is determined by titration to effect. The standard adult dose determined by the US military is 2 mg, an amount expected to produce substantial benefit in reversing nerve agent toxicity but one that should be tolerated by a healthy unexposed adult unintentionally receiving the drug.71 Current recommendations place the minimum initial dose of atropine in adults at 2 mg; dosing in children begins at 0.05 mg/kg for mild to moderate symptoms and 0.1 mg/kg for severe symptoms up to the adult dose.5 Severely poisoned adult patients receive an initial dose of 5 to 6 mg.29,71 Repeat doses are given every 2 to 5 minutes until resolution of muscarinic signs of toxicity. Therapeutic endpoints are drying of respiratory secretions and resolution of bronchoconstriction, bradycardia, and/or seizures (if initially present). Neither reversal of miosis nor development of tachycardia is a reliable marker to guide atropine therapy.29 The total amount of atropine necessary to treat nerve agent poisoning is often much less than required for organic phosphorus insecticide toxicity of a similar degree. Typically, less than 20 mg is required in the first 24 hours, even in severe cases.29,71,73 Fewer than 20% of moderately ill patients admitted to one hospital for sarin poisoning in Tokyo required more than 2 mg atropine.57
American troops in the 1990–1991 Gulf War were issued three MARK I kits for immediate field treatment of nerve agent poisoning. These kits are now also known as NAAKs, for nerve agent antidote kits. Each kit contains two autoinjectors: an AtroPen containing 2 mg of atropine in 0.7 mL diluent, and a ComboPen containing 600 mg of pralidoxime chloride (pyridine-2-aldoxime, 2-PAM) in 2 mL diluent.71 These autoinjectors permit rapid IM injections of antidote through protective clothing and are given in the lateral thigh.17 Treatment algorithms guided the number of MARK I kits to administer. In general, conscious casualties not in severe distress self-administer one kit (2 mg atropine), moderate to severe cases receive three kits (6 mg atropine) initially, and all receive additional doses as necessary, every 5 to 10 minutes.17,46,71 A combination atropine (2.1 mg) plus pralidoxime chloride (600 mg) autoinjector is available that gives both drugs with a single injection (Antidotes in Depth: A32).
In a nerve agent mass casualty incident, a hospital’s intravenous atropine supplies may be rapidly depleted. Alternative sources include atropine from ambulances, ophthalmic and veterinary preparations, or substituting an antimuscarinic such as glycopyrrolate.29 Atropine might also be stored as a bulk powder formulation and rapidly reconstituted for injection when needed.20
Oximes are nucleophilic compounds that reactivate organic phosphorus compound-inhibited cholinesterase enzymes by removing the dialkylphosphoryl moiety. The only oxime approved in the United States by the Food and Drug Administration is 2-PAM, a monopyridinium compound. Other pralidoxime salts are used elsewhere, such as the methanesulfonate salt of pralidoxime (P2S) in the United Kingdom and 2-PAM methiodide in Japan. Other oximes include the bispyridinium compounds trimedoxime (TMB4) and obidoxime (toxogonin) used in other European countries.41,57,71 Oximes should be given in conjunction with atropine, as they are not particularly effective in reversing muscarinic effects when given alone. Oximes are the only available nerve agent antidotes that can reverse the neuromuscular nicotinic effects of fasciculations, weakness, and flaccid paralysis (Antidotes in Depth: A33).
Oximes are effective only if administered before irreversible dealkylation, or “aging,” of the organic phosphorus compound-cholinesterase complex occurs. Soman has an aging half-life of 2 to 6 minutes in humans.16 It is unlikely that soman-poisoned victims will reach medical care early enough for oxime therapy to be of great benefit. For comparison, tabun has an aging half-life of about 14 hours, sarin 3 to 5 hours, and VX 48 hours.16 Pralidoxime is effective against sarin and VX in animal studies but not against tabun because of ineffective nucleophilic attack against that particular agent, and not because of aging issues. Obidoxime also is effective against sarin but not against tabun.41
The bispyridinium Hagedorn (H-series) oximes, particularly HI-6 and HLö-7, are also studied in the context of nerve agent toxicity.41 HI-6 appears beneficial against soman poisoning (possibly through direct pharmacologic action and/or reactivation of aged soman-inhibited ChE) but is not very effective against tabun. HLö-7 has reactivating activity for both soman- and tabun-inhibited ChE and may thus represent a universal oxime antidote for nerve agents. Administration of HI-6 and HLö-7 by autoinjector is difficult because they are not stable in aqueous solution.
For more details about pralidoxime administration, dosing, and adverse events, see Antidotes in Depth: A33. The ComboPen autoinjector in MARK I kits contains 600 mg pralidoxime, which produces a therapeutic maximal serum concentration of 6.5 μg/mL in average human volunteers.71 However, when possible, pralidoxime is optimally administered IV. Repeat pralidoxime dosing or continuous infusions are less likely to be needed for nerve agents than for organic phosphorus compound insecticides because severe effects are shorter-lived in properly decontaminated patients.29
Severe human nerve agent toxicity rapidly induces convulsions, which persist for a few minutes until the onset of flaccid paralysis. Diazepam is more beneficial than other anticonvulsants and simple γ-aminobutyric acid channel agonists due to its effects on choline transport across the blood–brain barrier and acetylcholine turnover.41 US military doctrine is to administer 10 mg diazepam IM by autoinjector at the onset of severe toxicity whether seizures are present or not. Thus, whenever three MARK I kits are used, a victim is also given diazepam. Additional autoinjectors are given by medical personnel as necessary for seizures.46 The reason for the IM route of diazepam suggested above is related to timely administration under field conditions. If intravenous access is feasible, then IV diazepam in 5-mg doses IV every 15 minutes (≤ 15 mg) is recommended41 (Antidotes in Depth: A23).
Although diazepam is the most well studied benzodiazepine in the treatment of nerve agent toxicity, other medications in the same class such as lorazepam and midazolam should have similar beneficial effects. Armed service personnel of the United Kingdom have been supplied with ComboPens containing atropine sulfate (2 mg), pralidoxime mesylate (P2S; 30 mg), and avizafone (10 mg), a water-soluble prodrug of diazepam.84
The first large-scale use of pyridostigmine as a pretreatment for nerve agent toxicity occurred during Operation Desert Storm in 1991.33 Pyridostigmine is a carbamate acetylcholinesterase inhibitor that is freely and spontaneously reversible, whereas nerve agent inhibition is permanent once “aging” occurs. Toxicity from rapidly aging nerve agents such as soman (GD) can probably not be reversed by standard oxime therapy in realistic clinical situations. Almost paradoxically, then, a carbamate can occupy cholinesterase, blocking access of nerve agent to the active site, and thereby protect the enzyme from permanent inhibition. Following nerve agent exposure, pyridostigmine is rapidly hydrolyzed from acetylcholinesterase and can also be easily displaced by oximes, regenerating functional enzyme. Between 20% and 40% cholinesterase inhibition is desired to protect against nerve agents.17 Doses of 60 mg of pyridostigmine bromide reduces cholinesterase activity by 28.4% in healthy individuals. Asthmatics taking 30 mg doses had a mean 24.3% reduction in cholinesterase activity without significant reductions in respiratory function or in response to inhaled atropine.58 In animal studies, pyridostigmine confers a benefit against soman and tabun, but not against sarin or VX.17 Also, it must be recognized that pyridostigmine is not an antidote, but is instead a pretreatment adjunct that greatly enhances the efficacy of atropine and oxime therapy.73
US troops in the 1990–1991 Gulf War took 30 mg pyridostigmine bromide orally every 8 hours when under threat of nerve agent attack. Cholinergic side effects, mostly gastrointestinal, were common but rarely required treatment.33 Israeli soldiers taking the same dose also reported a range of mostly cholinergic symptoms but also a high incidence (71.4%) of dry mouth, which may be more related to environmental and psychological stressors.66 Nine Israeli patients were hospitalized during the Gulf War for acute intentional pyridostigmine overdoses.2 All patients recovered fully, including one patient who self-treated with atropine autoinjectors and presented with anticholinergic toxicity and another who suffered cardiac arrest, apparently from coingesting 4000 mg propranolol.
Vesicants are agents that cause blistering of skin and mucous membranes (Fig. 132–2).
Sulfur mustard is bis(2-chloroethyl) sulfide, a vesicant alkylating compound similar to nitrogen mustards used in chemotherapy. Nineteenth-century scientists described the compound as smelling like mustard, tasting like garlic, and causing blistering of the skin on contact. The Allies of World War I called it Hun Stoffe (also called “German Stuff”), abbreviated as HS and later as just H. Distilled, nearly pure mustard is designated HD. The French called it Yperite, after the site where it was first used, and the Germans called it LOST after the two chemists who suggested its use as a chemical weapon, Lommel and Steinkopf. It was also called “yellow cross” after the markings on German artillery shells filled with mustard.10,14,75 Sulfur mustard caused over one million casualties in World War I,21 and was later used by the Italians and Japanese in the 1930s, by Egypt in the 1960s, and by Iraq in the 1980s.46 About 100,000 Iranians from both military and civilian backgrounds were exposed to chemical warfare agents during the latter years of the Iran–Iraq war (1984–1988), many of whom are still suffering long-term effects.22 Nonbattlefield exposures have also occurred among Baltic Sea fishermen while recovering corroding shells dumped after WWII, and to persons unearthing or handling old chemical warfare ordinance.21,50,62,75
Sulfur mustard is a yellow to brown oily liquid with an odor resembling mustard, garlic, or horseradish. Mustard has relatively low volatility and high environmental persistence. Nonetheless, most historical mustard injuries occurred from vapor exposure, a danger that increases in warmer climates. Mustard vapor is 5.4 times denser than air. Mustard freezes at 57°F (13.9°C), so it is sometimes mixed with other substances, including chemical weapon agents like chloropicrin or Lewisite, to lower the freezing point and permit dispersion as a liquid.14,46,75
Sulfur mustard toxicity occurs through several mechanisms. First, mustard is an alkylating agent. Mustard spontaneously undergoes intramolecular cyclization to form a highly reactive sulfonium ion that alkylates sulfhydryl (–SH) and amino (–NH2) groups.10,14,46,75 The most important acute manifestation is indirect inhibition of glycolysis. Sulfur mustard rapidly alkylates and crosslinks purine bases in nucleic acids (Fig. 132–3). DNA repair mechanisms are activated, including the activation of the enzyme poly(ADP-ribose) polymerase,42 depleting NAD+, which, in turn, inhibits glycolysis, and ultimately leads to cellular necrosis from adenosine triphosphate depletion.10 Other mechanisms are probably involved, since the inhibition of glycolysis only partially correlates with the depletion of NAD+; sulfur mustard may also inhibit glycolysis directly through undetermined mechanisms.42 Mustard also depletes glutathione, leading to loss of protection against oxidant stress, dysregulation of calcium homeostasis, and further inactivation of sulfhydryl-containing enzymes.75 Sulfur mustard is also a weak cholinergic agonist.46,75
Mechanism of sulfur mustard toxicity: alkylation and DNA crosslinking.
The organs most commonly affected by mustard are the eyes, skin, and respiratory tract. During WWI, 80% to 90% of American mustard casualties had cutaneous lesions, 86% had ocular involvement, and 75% had airway injury. Iranian soldiers had more airway (95%) and ocular injuries (92%), and 83% had cutaneous lesions, probably because of the more extensive vaporization occurring in the warmer environment.10,75 Incapacitation may be severe in terms of number of lost man-days, time for lesions to heal, and increased risk of infection. In contrast, mortality is rather low. In WWI, only 2% to 3% of British mustard casualties and fewer than 2% of American casualties died. Fatality rates of 3% to 4% were reported from the Iran–Iraq War.10 Most deaths occur several days after exposure, either from respiratory failure, secondary bacterial pneumonia, or bone marrow suppression.
Dermal exposure produces dose-related injury. After a latent period of 4 to 12 hours, victims develop erythema that may progress to vesicles and/or bullae formation and skin necrosis. Warm, moist, and thin skin is at increased risk of mustard injury, in particular the perineum, scrotum, axillae, antecubital fossae, and neck. The vesicle fluid does not contain mustard because all chemical reactions are complete within a few minutes. If decontamination is not performed immediately after exposure, injury cannot be prevented. However, later decontamination may limit the severity of lesions and further spread of the agent. Skin exposure to vapor typically results in first- or second-degree burns, although liquid exposure may result in full-thickness burns.75 Mustard easily penetrates normal clothing and uniforms, and many soldiers received gluteal, perineal, and scrotal burns from sitting on contaminated objects.
Latency of several hours also occurs following ocular and respiratory tract exposures. Ocular effects include pain, miosis, photophobia, lacrimation, blurred vision, blepharospasm, and corneal damage. Permanent blindness is rare, with recovery generally occurring within a few weeks. Inhalation of mustard results in a chemical tracheobronchitis. Hoarseness, cough, sore throat, and chest pressure are common initial complaints. Bronchospasm and obstruction from sloughed membranes occur in more serious cases, but lung parenchymal damage occurs only in the most severe inhalational exposures. Productive cough associated with fever and leukocytosis is common 12 to 24 hours after exposure, and represents a sterile bronchitis or pneumonitis. Nausea and vomiting are common within the first few hours. High-dose exposures may also cause bone marrow suppression.10,46,75
Various long-term sequelae are associated with sulfur mustard. Factory workers chronically exposed to mustard have increased risk of respiratory tract carcinomas, although the carcinogenic risk from battlefield exposures is more controversial.21,22,74 Respiratory sequelae include chronic bronchitis, emphysema, tracheobronchomalacia, and bronchiolitis obliterans.22 Mustard victims may also develop a delayed and often recurrent keratitis.21,68 Chronic dermatologic complications include scarring, pigmentation changes, and chronic, neuropathic pain, and pruritus.21,68 Among approximately 34,000 Iranians with confirmed exposure to sulfur mustard during the war with Iraq, chronic pulmonary sequelae were noted in 42.5%, ocular lesions in 39.3%, and dermatologic lesions in 24.5%.35
Decontamination is essential in treating the sulfur mustard exposures, even among asymptomatic victims. Further treatment is largely supportive and symptomatic.10,46,75 Victims may become blinded because of a combination of blepharospasm and corneal edema, which is temporary and completely resolves in most cases.
Several xenobiotics have been investigated as treatments for sulfur mustard injury. Antiinflammatory and sulfhydryl-scavenging agents have shown benefit in animals as prophylactic therapy or if given immediately after exposure.75 N-acetyl cysteine appears to be a promising therapeutic agent in cell culture and animal studies, although most of the evidence for its use relates to inhalational aerosol exposures to mustard.8 Neutropenia from bone marrow suppression can be treated with granulocyte colony–stimulating factor.45
Lewisite (2-chlorovinyldichloroarsine) was developed as a less persistent alternative to avoid some shortcomings in the use of sulfur mustard in World War I. Lewisite was never used in combat because the first shipment was en route to Europe when the war ended, and it was intentionally destroyed at sea. British anti-Lewisite (BAL, dimercaprol) was developed as a specific antidotal agent and remains in use for chelation of arsenic and other metals.41,75
Pure Lewisite is an oily, colorless liquid. Impure preparations are colored from amber to blue-black to black and have the odor of geraniums. Lewisite is more volatile than mustard and is easily hydrolyzed by water and by alkaline aqueous solutions such as sodium hypochlorite. These properties increase safety for offensive battlefield use, but make maintaining a potent vapor concentration difficult.
Lewisite toxicity is similar to that of sulfur mustard, resulting in dermal and mucous membrane damage, with conjunctivitis, airway injury, and vesiculation. An important clinical distinction is that Lewisite is immediately painful, whereas initial contact with mustard is not. Other differences are faster onset of inflammatory response and healing of lesions from Lewisite, less secondary infection of Lewisite lesions, and less subsequent pigmentation changes.75 The mechanisms of Lewisite toxicity are not completely known, but appear to involve glutathione depletion and arsenical interaction with enzyme sulfhydryl groups. Nevertheless, Lewisite toxicity is qualitatively and quantitatively different from the arsenic it contains. Treatment consists of decontamination with copious water and/or dilute hypochlorite solution, supportive care, and BAL. BAL is given parenterally for systemic toxicity and is also used topically for dermal or ophthalmic injuries. Alternative metal chelators that may be used as Lewisite antidotes include dimercaptopropane sulfonate and succimer (2,3-dimercaptosuccinic acid).41
Although classified as a vesicant, phosgene oxime (dichloroformoxime, or CX) does not cause vesiculation of the skin. CX is more properly an urticant or “nettle” agent, in that it produces erythema, wheals, and urticaria likened to stinging nettles. Phosgene oxime produces immediate irritation of the skin and mucous membranes. CX has never been used in battle, and little is known about its mechanism or effects on humans.46,75