Chemical terrorism is the intentional use of toxic chemicals to inflict mass casualties and mayhem on an unsuspecting civilian population, including children. Such an incident could potentially overwhelm the capacity of regional emergency medical services and pose extraordinary medical management challenges to pediatricians. However, careful community planning, robust research and development (by academic, private, and governmental collaborative efforts), and rigorous medical education could mitigate such a catastrophe.
The risk of chemical terrorism is more tangible since the events of September 11, 2001, and the subsequent intentional spread of anthrax through the U.S. mail. However, the specter of purposeful toxic exposures predates the September 11 attack. The 20th century witnessed Iraqi military attacks with nerve agents on civilian villages in Iran in the 1980s, the release of the nerve agent sarin in the Tokyo subway system in 1995, a chlorine bomb scare at Disneyland in 1995, and the finding of ricin in U.S. Senate office buildings in 2004.
Chemical terrorism often refers to the use of military chemical weapons that have been illicitly obtained or manufactured de novo. However, additional concerns might include the intentional explosion of an industrial chemical factory, a tanker car, or a transport truck in proximity to a civilian residential community, school, or worksite. These events underscore the need for all pediatricians to expand their working knowledge of the approach to mass casualty incidents involving traditional military chemical weapons and other toxic chemicals that might be used as “weapons of opportunity.”
The medical consequences and epidemiology of a chemical terrorist attack mimic more conventional disasters but also reflect some distinct differences. Such an incident combines elements of both a traditional mass disaster (e.g., an earthquake) and a hazardous materials incident. Potential differences of a chemical terrorist attack compared with a “routine” hazardous materials incident include the following:
Casualties occur almost immediately, and the attack would likely be recognized rapidly. First responders are emergency medical services (EMS), police, fire, and paramedic personnel. Decontamination and initial care of small children on-scene pose enormous management issues for personnel wearing bulky personal protective gear. In addition, many children who have been exposed but not critically injured will be taken by parents to hospitals and pediatricians' offices without prior on-scene decontamination—thus posing similar challenges for and possibly personal risk to pediatric care providers themselves.
Children have inherent physiologic, developmental, and psychological differences from adults that may enhance susceptibility and worsen prognosis after a chemical agent exposure (also read the Chapter 1 section, Children Are Not Small Adults). Briefly, such physiologic differences include higher minute ventilation, increased skin permeability, relatively larger body surface area, less intravascular volume reserve in defense of hypovolemic shock, and shorter stature (which places children nearer to the greatest gas vapor density at ground level). Children who are pre-ambulatory or pre-verbal and those who have special needs are less able to evade danger or seek attention effectively. A chaotic atmosphere compounded by rescuers wearing unfamiliar garb may frighten children of all ages and potentially increase the posttraumatic response to stress. Those providing care for children are faced with additional complexities posed by developmental, age, and weight considerations beyond the general scope of the already enormous challenge.
Pediatric vulnerabilities become particularly significant when weapons of mass destruction are involved. A chemical agent will most likely be dispersed via an aerosol route or in combination with traditional warfare. Chemical exposures warrant expedient and thorough decontamination to limit continued primary and secondary exposures. Children's relatively large body surface area plays a key role in degree of contamination and in their ability to maintain thermal homeostasis after decontamination. Table 5.1 summarizes pediatric-specific vulnerabilities to chemical agents.
A listing of many of the most notable chemical agents of concern has been compiled by the Centers for Disease Control and Prevention (CDC). Go to http://www.bt.cdc.gov/agent/agentlistchem.asp. Toxic effects from chemical agents usually follow dermal or inhalational exposure and may develop via injury to the skin, eyes, and respiratory epithelium, as well as via systemic absorption. The intensity and route of exposure to chemical agents affect both the rapidity of onset (seconds to hours) and the severity of symptoms. For example, a mild exposure to sarin vapor results in lacrimation, rhinorrhea, miosis, and slightly blurry vision; an intense exposure leads to seizures, apnea, and rapid death within minutes.
Clinical syndromes and management after exposure to various chemical agents (nerve agents, vesicants, pulmonary agents, cyanide, and riot-control agents) are summarized in Table 5.2 and detailed in the following sections. For in-depth discussions of general principles of supportive care for victims of chemical warfare agents, go to: Osterhoudt, et al, 2005, and Erickson, 2004.
Understanding the epidemiology of acute mass exposure to a toxin is helpful in recognizing a covert chemical attack with unknown agents. Mass exposure to a toxin will likely manifest as an acute onset of illness (within seconds to minutes or within hours in the case of some of the vesicants and pulmonary agents). In more severe chemical incidents, numbers of people may collapse or die within minutes of exposure.
Chemical weapons can be categorized based on the predominant symptoms they cause:
For additional advice on more definitive diagnosis and management strategies, contact public health authorities or the regional poison control center (1-800-222-1222).
The initial decision that will need to be made immediately will likely be the distinction of cyanide from nerve agent attack because the antidotal therapies are quite different. In both cases, large numbers of victims may suddenly collapse, have seizures, or go into a coma, and many deaths occur rapidly. Nerve agent casualties are likely to be cyanotic and have miotic pupils with altered vision, copious oral and nasal secretions, and acute bronchospasm and bronchorrhea.
The initial protection of everyone in a community exposed to a hazardous chemical requires safe evacuation or local sheltering. Circumstances may vary considerably, but it is expected that local and Federal authorities will decide and quickly advise on evacuation or local sheltering and broadcast their advice quickly and widely in the public media.
For the CDC guidelines for evacuation, go to: http://www.bt.cdc.gov/planning/evacuationfacts.asp.
For the CDC guidelines for sheltering in place in a chemical emergency, go to: http://www.bt.cdc.gov/planning/shelteringfacts.asp.
The general treatment of contaminated victims begins with extrication, triage, resuscitation as needed, and decontamination performed by rescue workers or health care providers wearing appropriate personal protective equipment (PPE). Ideally, decontamination would be done at the scene to avoid the considerable challenges posed by the arrival of contaminated patients, including children, at health care facilities. However, in a large-scale terrorist incident, it is far more likely that some victims will arrive at hospitals or other health care facilities without having been previously decontaminated. In this context, significantly contaminated victims should be decontaminated before they are allowed into the emergency department (ED). Even if decontamination has been done in the field, hospitals are likely to repeat decontamination procedures to protect the facility from contamination (which would result in closure or having to go “off line”); this would also address the possibility of cross-contamination moving from the scene. Decontamination to limit secondary exposures is especially important in exposures to nerve agents and vesicants.
Appropriate PPE for ED staff involved in patient decontamination is an important consideration. The amount of chemical agent believed to contaminate patients who arrive at the ED after a chemical terrorist attack would essentially consist of that on their skin and clothing (i.e., far lower concentration of chemicals than rescue workers would face at the scene of exposure). Most authorities believe that ED staff wearing level C PPE would be adequately protected. Level C PPE consists of a non-encapsulated, chemically resistant body suit, gloves, boots, and a powered purifying air respirator (PAPR) mask containing a cartridge with both an organic-vapor filter for chemical gases and vapors and a high efficiency particulate air (HEPA) filter to trap aerosols of biological and chemical agents. Such PPE is much less cumbersome to work in than level A or B outfits (which use self-contained breathing apparatus) and is also less expensive.
Cardiopulmonary and airway support, including endotracheal intubation, and emergent intramuscular antidotal therapy are provided as necessary and appropriate for the specific exposure. Contaminated clothing should be removed as soon as possible. The contamination hazard is reduced by as much as 80-90% simply by removing clothing. This is accompanied or immediately followed by more definitive decontamination. For vapor-exposed victims, decontamination may be accomplished primarily by clothing removal and washing of hair. In contrast, for victims with liquid dermal exposure, more thorough decontamination is required. Their skin and clothing pose considerable risk to ED personnel. Clothing should be carefully removed and disposed of in double bags. Victims with ocular exposure require eye irrigation with copious amounts of saline or water. Skin and hair should be washed thoroughly, but gently, with soap and tepid water. In the past, some authorities had recommended 0.5% sodium hypochlorite (dilute bleach) for skin decontamination of nerve agents and vesicants. However, this may be a skin irritant, thus increasing permeability to the agent. In addition, its use is time-consuming and has not been proven superior to washing with copious soap and water or water alone. Furthermore, there is little experience with this approach in infants and young children. A difficult question that remains is whether EMS and ED staff wearing bulky PPE will be able to provide significant advanced life support to small children before decontamination.
Ambulatory, asymptomatic victims may be able to be discharged from the scene, while those with minimal symptoms may be directed toward local shelters (e.g., American Red Cross stations, local schools, or other sites designated by local or State health departments) after decontamination for medical observation. These shelters may also serve as sites for reuniting children with their families, keeping track of all victims, and communicating with law enforcement agencies.
The potential of a terrorist attack on industrial sources of hazardous chemicals (e.g., factories, railroad and vehicular tank cars, or storage depots) expands the list of potential “chemical weapons” considerably. In general, many of the relevant industrial chemicals might be expected to induce respiratory effects analogous to those of chlorine or phosgene (read the section on pulmonary agents later in this chapter) or dermatologic injury from irritant or caustic properties, as well as more systemic effects in severe exposures (Table 5.3). For an in-depth discussion of principles in managing such toxic injuries, see Osterhoudt, et al., 2005, and Erickson, 2004.
In the aftermath of September 11, 2001, many agencies are collaborating to ensure coordinated care of pediatric victims (Chapter 2, Systems Issues). All pediatricians are encouraged to participate in disaster management training. The need to stock appropriate antidotes, practice decontamination strategies, and learn the use of PPE is apparent. Although perhaps not every practicing pediatrician needs to be competent in all aspects of disaster response, all in the community should work together to optimize the overall capacity for providing disaster care to chemically exposed children.
Successful planning and response to events involving chemical terrorism require strong collaboration and integrated functioning of many agencies and facilities, both governmental and nongovernmental, including local treatment facilities, local and State health departments, and Federal agencies (CDC, FEMA, FBI, etc.).
Nerve agents are organophosphorous compounds similar to the organophosphate insecticides used in agriculture or industry but far more toxic. Four compounds are currently regarded as nerve agents: tabun, sarin, soman, and VX (“Venom X”). All of these agents are hazardous by ingestion, inhalation, or cutaneous absorption, the latter being particularly true for VX. The toxic effects of nerve agent vapors depend on the concentration of the agent inhaled and on the time exposed to the agent. The toxicity of nerve agent liquid depends on the time exposed and the bodily site of exposure. Nerve agents exist as liquids at standard temperatures and pressures. In gaseous form, they are denser than air and vary in volatility, with some (e.g., VX) being more persistent than others (e.g., sarin).
The Iran-Iraq War of the 1980s reportedly resulted in more than 100,000 casualties from chemical weapons. Iranian sources reported that the number of casualties caused by nerve agents was far greater than the number of casualties caused by mustard agent. Many nerve agent casualties that were only mildly to moderately affected were not counted.
A chemical warfare campaign by the Iraqi military on Kurdish civilians in the late 1980s caused thousands of deaths. The exact agents are not definitively known, but Iraq is known to have stockpiled tabun, sarin, and VX.
A Japanese religious cult that manufactured sarin deployed it in 1994 in attacks on a residential neighborhood of Matsumoto and again in 1995, in the Tokyo subway. Immediate mortality was low, but thousands of individuals arrived at emergency rooms. The lack of a decontamination process resulted in significant morbidity to health care personnel. The sarin was released by a relatively primitive method (punctured plastic bags allowing sarin vapor to escape); many experts believe a more sophisticated delivery system might have resulted in far higher mortality.
Nerve agent exposures in the United States have been individual cases associated with industrial exposures.
Nerve agents inhibit the action of acetylcholinesterase at cholinergic neural synapses, where acetylcholine then accumulates markedly. The resulting cholinergic syndrome is classically divided into central, nicotinic (neuromuscular junction and sympathetic ganglia), and muscarinic (smooth muscle and exocrine gland) effects.
Clinical manifestations vary with the type of exposure. Symptoms after a vapor exposure appear suddenly with a full range of clinical effects, or there may be a partial expression of the syndrome. Symptoms after a liquid exposure may start with local sweating and then progress.
Central nervous system (CNS) effects. Effects on the CNS include headache, seizures, coma, respiratory arrest, confusion, slurred speech, and respiratory depression. Although the seizures probably begin due to excess cholinergic stimulation, other effects (e.g., excitatory glutamate receptor stimulation and antagonism of inhibitory gamma-aminobutyric acid [GABA] receptors) may also play a role. Little experience with nerve agents is available to distinguish clinical effects in children from those in adults, although two cases of antichlolinesterase pesticide poisonings in children suggest a disproportionate degree of depressed sensorium and muscle weakness. Thus, children may manifest primarily central and/or neuromuscular effects after nerve agent exposure.
Autonomic nervous system effects. These include both nicotinic and muscarinic findings. Nicotinic effects on sympathetic activity can result in the following:
Muscarinic effects involve multiple systems:
Neuromuscular effects. At the neuromuscular junction, initial stimulation of cholinergic synaptic transmission is followed by paralysis. Thus, nicotinic effects include muscle fasciculations and twitching, followed by weakness progressing to flaccid paralysis and respiratory failure.
The clinical syndrome of organophosphate toxicity is summarized by various mnemonics, including “bag the puddles,”1 “sludge” syndrome, and “dumbbels.”
B = bronchoconstriction, bronchorrhea
A = apnea
G = graying/dimming of vision
P = pupillary constriction (miosis)
U = urination
D = diarrhea
D = diaphoresis
L = lacrimation
E = emesis
S = salivation, seizures
S = salivation, seizures
L = lacrimation
U = urination
D = diarrhea
G = graying/dimming of vision
E = emesis
D = diarrhea
U = urination
M = miosis
B = bronchoconstriction
B = bronchorrhea
E = emesis
L = lacrimation
S = salivation
The diagnosis of nerve agent toxicity is primarily based on clinical recognition and response to antidotal therapy. Measurements of acetylcholinesterase in plasma or red blood cells (RBCs) may confirm organophosphate poisoning, but correlation between cholinesterase levels and clinical toxicity is poor in some contexts; also, these analyses are rarely available on an emergent basis. RBC cholinesterase levels may help in monitoring recovery or in forensic investigations. In symptomatic patients, treatment is indicated without waiting for cholinesterase levels, while in exposed asymptomatic patients, antidotal therapy is not needed, even if cholinesterase is depressed.
If recognized early, this is a treatable and reversible syndrome. Triage, resuscitation, and decontamination should begin at the scene and at accepting health care facilities (go to Chapter 1). Individuals exposed to liquid should be observed for at least 18 hours.
Treatment focuses on airway and ventilatory support; aggressive use of antidotes, particularly atropine and pralidoxime (2-PAM); prompt control of seizures; and decontamination as necessary. Antidotal therapy is titrated according to clinical severity (Table 5.4).
Atropine, in relatively large doses, is used for its antimuscarinic effects, and pralidoxime chloride serves to reactivate acetylcholinesterase and thus enhance neuromuscular function. Atropine counters bronchospasm and increased bronchial secretions; bradycardia; gastrointestinal (GI) effects of nausea, vomiting, diarrhea, and cramps; and may lessen seizure activity. Severely affected nerve agent casualties in the military have received 20-200 mg of atropine. Atropine should be administered until respiratory status improves, because tachycardia is not an absolute end-point for atropinization. Atropine cannot reverse neuromuscular symptoms, and paralysis may persist without pralidoxime.
Pralidoxime cleaves the organophosphate away from the cholinesterase, thus regenerating the intact enzyme if aging has not occurred. This effect is noted most at the neuromuscular junction, with improved muscle strength. Prompt use of pralidoxime is recommended in all serious cases.
Both atropine and pralidoxime should be administered intravenously (IV) in severe cases (intraosseous access is likely equivalent to IV). However, animal studies suggest that hypoxia should be corrected, if possible, before IV atropine use, to prevent arrhythmias; otherwise intramuscular (IM) use might be preferable initially. Atropine has also been administered by the endotracheal or inhalational route in some contexts, and such use might have a beneficial effect. Experience with organophosphate pesticide poisoning in children suggests that continuous IV infusion of pralidoxime may be optimal. Nevertheless, the IM route is acceptable if IV access is not readily available. This may be of considerable relevance in a mass casualty incident involving children. In fact, most EMS programs in the United States now stock military IM auto-injector kits of atropine and 2-PAM. Similar kits with pediatric doses are currently not available in the United States. However, pediatric auto-injectors of atropine in 0.25 mg, 0.5 mg, and 1.0 mg sizes have recently been approved by the Food and Drug Administration (FDA). In dire circumstances, the adult 2-PAM auto-injector (600 mg) might be used in children older than 2-3 years or weighing more than 13 kg.
Seizures are primarily controlled with benzodiazepines. Diazepam is principally used by the U.S. military, but other benzodiazepines may be equally efficacious (e.g., midazolam or lorazepam). Midazolam is believed optimal for IM administration in the treatment of status epilepticus in general and so may be especially useful in nerve agent toxicity in children. Finally, routine administration of anticonvulsant doses of benzodiazepines has been recommended in severe cases even without observed convulsive activity because animal studies have indicated some amelioration of subsequent seizures and morphologic brain damage with such use.
Supportive care is critical to patient outcome and includes the following:
Isolation is required only for potentially exposed victims before they are definitively decontaminated. Health care workers should wear PPE to treat victims before decontamination is complete.
Cyanide has long been used for sinister purposes, including as an agent of murder, suicide, chemical warfare, and judicial execution. In addition, it may pose an occupational hazard, and it has been ingested (usually in a precursor form) by children. Its efficacy as an agent of chemical terrorism is considered somewhat limited by its volatility in open air and relatively low lethality compared with nerve agents. However, if cyanide were released in a crowded, closed room, the effects could be devastating. This was more than amply illustrated by its notoriety as the chemical weapon used by the Nazis in the concentration camp gas chambers. More than 900 people ingested potassium cyanide salt in the 1978 Jonestown mass suicide incident. Chemical warfare agents involving cyanide include the liquids hydrocyanic acid (HCN, the form used by the Nazis, as “Zyclon B”) and cyanogen chloride (deployed during World War I), which rapidly vaporize after detonation. Cyanogen chloride may cause some initial eye, nose, throat, and airway irritation, but otherwise its effects are the same as those of hydrocyanic acid and result from systemic cyanide toxicity.
Cyanide has a strong affinity for the ferric iron (Fe3+) of the heme ring and thus inhibits many heme-containing enzymes. Its primary effect in acute toxicity is inhibition of cytochrome a3, thereby interfering with normal mitochondrial oxidative metabolism in the electron transport chain, causing cellular anoxia and lactic acidosis. It may also interfere with other important enzymes, including succinic acid dehydrogenase and superoxide dismutase, which may underlie some of its chronic toxicity. In addition, cyanide is believed to be a direct neurotoxin contributing to an excitatory injury in the brain, probably mediated by glutamate stimulation of N-methyl D-aspartate receptors. The primary human enzyme, rhodanese, detoxifies cyanide by combining it with a sulfate moiety such as thiosulfate to form the relatively nontoxic thiocyanate ion, which is then excreted by the kidneys. Therefore, exposure to a potentially lethal dose of cyanide that occurs slowly though continually over time may be tolerated, making it relatively unique among the agents of chemical terrorism.
Clinical manifestations of cyanide toxicity vary considerably depending on dose, route of exposure, and acuteness of exposure but in general reflect the effects of cellular anoxia on organ systems. Thus, the most metabolically active tissues, the brain and heart, tend to be the most affected. With exposure to low concentrations of vapor, early findings include tachypnea and hyperpnea, tachycardia, flushing, dizziness, headache, diaphoresis, nausea, and vomiting. As exposure continues, symptoms may progress to those associated with exposures to high concentrations of vapor. The latter include rapid onset (within 15 seconds) of tachypnea and hyperpnea, followed by seizures (30 seconds), coma and apnea (2-4 minutes), and cardiac arrest (4-8 minutes). “Classical” signs of cyanide poisoning include severe dyspnea without cyanosis—or even with cherry-red skin (due to lack of peripheral oxygen use)—and a bitter almond odor to breath and body fluids. However, some patients do develop cyanosis (likely secondary to shock), and only about half the population is genetically capable of detecting the cyanide-induced bitter almond odor. Laboratory abnormalities in cyanide poisoning include metabolic acidosis with a high anion gap and increased serum lactate and an abnormally high mixed venous oxygen saturation (also due to decreased use of peripheral oxygen). Blood cyanide levels can be determined but not usually on an emergent basis.
In an aerosol attack using recognized military chemical weapons, if people are convulsing or dying within minutes of exposure, the weapon is likely to be either cyanide or a nerve agent. Although the symptoms of exposure to cyanide and nerve agents may be hard to distinguish, when there are high concentrations of cyanide, seizures begin within seconds and death within minutes, generally with little cyanosis or other findings. The course for lethal nerve agent toxicity is characteristically somewhat longer and accompanied by copious nasal secretions, miotic pupils, muscle fasciculations, and cyanosis before death.
Management of cyanide poisoning begins with removing the victim from the contaminated environment to fresh air. Dermal decontamination is rarely necessary because these agents are so volatile but in case of contact with liquid agent, wet clothing should be removed and underlying skin washed. Ingested cyanide may be partially bound by activated charcoal.
Basic supportive intensive care is critical, including providing 100% oxygen, mechanical ventilation as needed, and circulatory support with crystalloid and vasopressors; correcting metabolic acidosis with IV sodium bicarbonate; and controlling seizures with benzodiazepines. Symptomatic patients, especially those who have lost consciousness or have other severe manifestations, may benefit further from antidotal therapy, which is a multistep process.
First, a methemoglobin-forming agent is administered, typically inhaled amyl nitrite or IV sodium nitrite because methemoglobin has a high affinity for cyanide and disassociates it from cytochrome oxidase. However, nitrite administration can be hazardous because it may cause hypotension, and overproduction of methemoglobin may compromise oxygen-carrying capacity. Thus, nitrite is probably not indicated for mild symptoms or if the diagnosis of cyanide poisoning is uncertain. Furthermore, people with cyanide poisoning who may have concomitant hypoxic insult (e.g., most victims of smoke inhalation) probably are not good candidates for nitrite therapy. Optimal nitrite dosing, especially when given parenterally, depends on body weight and hemoglobin concentration, which is of particular importance in pediatric patients, who have a broad range of hemoglobin concentrations. In the pre-hospital setting, or whenever IV access is not possible, amyl nitrite may be used to begin nitrite therapy. Amyl nitrite is provided in glass pearls, which are used by crushing the pearl and then either allowing spontaneous inhalation or introducing the vapor into a ventilation circuit, for 30 seconds of each minute. As soon as IV access is established, sodium nitrite may be given. The recommended pediatric dosage, assuming a hemoglobin concentration of 12 g/dL, is 0.33 mL (of the standard 3% solution)/kg, given slowly IV over 5-10 minutes (with a maximal, or adult, dose of 10 mL). Dosing may be adjusted for patients with significant anemia, although this would not likely be known in emergent treatment of a poisoned child in critical condition.
The second step is providing a sulfur donor, typically sodium thiosulfate, which is used as substrate by the rhodanese enzyme for conversion to thiocyanate. Thiosulfate treatment itself is believed efficacious and relatively benign, and thus it may be used alone empirically in cases in which the diagnosis is uncertain. (This approach has also been recommended, for example, in the management of the situation described above of cyanide toxicity complicating smoke inhalation, with likely concomitant lung injury and carbon monoxide poisoning). The recommended pediatric dosage of thiosulfate is 1.65 mL (of the standard 25% solution)/kg, IV (with a maximal, or adult, dose of 50 mL).
Each agent may be given a second time at up to half the original dose as needed, or in the case of thiosulfate, even a full dose would be unlikely to pose inherent toxicity. Both these medications are packaged together in commercially available “cyanide antidote kits,” along with amyl nitrite pearls. Additionally, most hospital pharmacies stock 25% sodium thiosulfate solution in vials containing sufficient volume (50 mL) to treat even adult patients. This has been used routinely in the preparation of nitroprusside infusions, premixed with thiosulfate, so as to obviate nitroprusside-induced cyanide toxicity.
Several alternative therapies and experimental antidotes have been used in Europe (cobalt salts, hydroxocobalamin) or are in clinical trials (aldehydes, aminophenol derivatives) or animal studies (dihydroxyacetone, alpha-ketoglutarate). Hydroxocobalamin, in particular, has been cited as a potentially quite useful antidote in civilian terrorism scenarios because of its relative safety compared with nitrites. However, it currently is not commercially available in the United States in a pharmacologically appropriate concentration for antidotal efficacy.
1 Adapted from Rotenberg JS, Newmark J. Nerve agent attacks on children: diagnosis and management. Pediatrics 2003; 112:648-58.