Theodore J. Cieslak, Jonathan Newmark
In April of 2017, an attack on the town of Khan Shaykhun in Syria employed a poisonous “nerve agent” (likely Sarin) and resulted in the deaths of at least 92 civilians, many of them young children. The attack intentionally targeted civilian neighborhoods at the time children were getting ready for school—strong evidence that its purpose was terror, not warfare. Terrorist actions targeting children are not novel. Brought to the forefront of American consciousness by Timothy McVeigh's references to child fatalities as “collateral damage” during the Oklahoma City bombing in April 1995, the intentional targeting of children became firmly ensconced as a global reality with the attack upon a school in Beslan, Russia, in September 2004. The attack, which left 334 (including 186 children) dead, presaged additional attacks specifically directed against children at an Amish school in Pennsylvania in 2006, at a camp for teenagers in Utoya, Norway, in 2011, and at Sandy Hook Elementary School in Connecticut in 2012, among others.
Paralleling the targeting of children is an apparent trend toward the use of “unconventional” weapons of terror. In 1984, members of the Rajneeshee cult employed Salmonella typhi in a wave of intentional poisonings that affected 751 persons, including 142 teenage patrons of a popular pizza parlor. In 1995, the Aum Shinrikyo cult killed 12 and sickened thousands by intentionally releasing sarin nerve agent in the Tokyo subway system. A disgruntled scientist allegedly deployed anthrax spores via the U.S. mail in October 2001, killing 5 and injuring 17 in an attack upon a nation already reeling in the wake of the 9/11 attacks.
These developments remind us that terrorists can strike at any time, utilizing any number of unconventional weapons, including biologic and chemical agents. Children will not be spared in these attacks on civilians, and indeed schools and daycare sites may be the targets of these actions.
Terrorists may choose to use weapons of opportunity, agents that for some reason are readily available to some member of the terrorist group. The motives of terrorists often are obscure and difficult to predict. Prevention and response strategies should thus concentrate not on those agents most likely to be used but, rather, on those agents that, if used, would constitute the gravest potential threats to public health and security.
Biologic threat agents, including pathogens and toxins, have been divided by the Centers for Disease Control and Prevention into three categories, with category A including diseases caused by those six agents posing the greatest threat: anthrax, plague (see Chapter 230.3 ), tularemia (see Chapter 233 ), smallpox, botulism (see Chapter 237 ), and the viral hemorrhagic fevers (see Chapter 297 ).
Terrorists could also procure and release a vast array of potentially harmful chemicals. Tank cars full of flammable industrial gases and liquids, corrosive industrial acids and bases, poisonous compounds such as cyanides and nitrites, pesticides, dioxins, and explosives traverse our railways and roads daily. Four classes of “military-grade” chemicals with a history of use in warfare or manufactured specifically for use as weapons include the organophosphate-based nerve agents, vesicants, cyanides (misleadingly referred to as “blood agents”), and certain pulmonary irritants or “choking agents.”
Large-scale attacks on civilian targets will likely involve pediatric victims, and children may be more susceptible than adults to the effects of certain biologic and chemical agents (see Chapter 737 ). A thinner and less-keratinized epidermis makes dermally active agents, such as mustard or trichothecene mycotoxins, a greater risk to children than adults. A larger surface area per unit volume further increases the problem. A small relative blood volume makes children more susceptible to the volume losses associated with enteric infections such as cholera and to gastrointestinal intoxications such as might be seen with exposure to the staphylococcal enterotoxins. Children's high minute ventilation, compared with that of adults, increases the threat of agents delivered via the inhalational route. The fact that children live “closer to the ground” compounds this effect when heavier-than-air chemicals are involved. An immature blood-brain barrier may heighten the risk of central nervous system toxicity from nerve agents. Developmental considerations make it less likely that a child would readily flee an area of danger, thereby increasing exposure to these various adverse effects. Moreover, children are more likely to be terrified at the sight of responders in personal protective ensembles.
Children appear to have a unique susceptibility to certain potential agents that might be used by terrorists. Although adults generally suffer only a brief, self-limited incapacitating illness after infection with Venezuelan equine encephalitis virus, young children are more likely to experience seizures, permanent neurologic sequelae, and death. In the case of smallpox, waning herd immunity may disproportionately affect children. Vaccine-induced immunity to smallpox probably diminishes significantly after ages 3-10 yr. Although most adults are considered susceptible to smallpox, given that routine civilian immunization ceased in the early 1970s, older adults may have some residual protection from death, if not from the development of disease. Today's children are among the first to grow up in a world without any individual or herd immunity to smallpox.
Children also may experience unique disease manifestations not seen in adults. Suppurative parotitis is a common characteristic finding among children with melioidosis but is not generally seen in adults with Burkholderia pseudomallei infection (see Chapter 232.2 ). Seizures, often the presenting symptom of cyanide or nerve agent poisoning, may clinically be much harder to recognize in children than in adults, looking more like unresponsiveness or change in mental status than tonic-clonic phenomena.
Pediatricians are likely to experience unique problems in managing childhood victims of biologic or chemical attack. Many of the drugs useful in treating such casualties are unfamiliar to pediatricians or have relative contraindications in childhood. The fluoroquinolones and tetracyclines are commonly cited as agents of choice in the treatment and prophylaxis of anthrax, plague, tularemia, brucellosis, and Q fever. Both drug classes are often avoided in children, although the risk of morbidity and mortality from diseases induced by agents of bioterrorism far outweighs the minor risk associated with short-term use of these agents. Ciprofloxacin received, as its first licensed pediatric indication, FDA approval for use in the prophylaxis of anthrax after inhalational exposure during a terrorist attack. Doxycycline and levofloxacin are licensed specifically in children for the same indication, and levofloxacin is also licensed for postexposure prophylaxis of children against plague. Immunizations potentially useful in preventing biologic agent–induced diseases are often not approved for use in pediatric patients. The available anthrax vaccine is licensed only for those between 18 and 65 yr. The plague vaccine, currently out of production and probably ineffective against inhalational exposures, was approved only for individuals ages 18-61 yr. The smallpox vaccine, a live vaccine employing vaccinia virus, can cause fetal demise when given to pregnant women.
Many otherwise useful pharmaceutical agents are not available in pediatric dosing regimens. The military distributes nerve agent antidote kits consisting of prefilled autoinjectors designed for the rapid administration of atropine and pralidoxime. Many emergency departments and some ambulances stock these kits. The doses of agents contained in the nerve agent antidote kit are calculated for soldiers and thus are excessive of those appropriate for young children, and pediatric pralidoxime autoinjectors are not yet available. Atropine autoinjectors specifically formulated for children are approved by the FDA and are available. Even though these products exist, children smaller than 15 pounds are too small for safe use of the autoinjectors, and obtaining venous access via cutdown will not only be time-consuming but extremely difficult in a contaminated environment.
Although physical protective measures and devices (e.g., “gas masks”) are likely to be of little utility in a civilian terrorism setting, such commercially available devices are not often available in pediatric sizes. The Israeli experience during the first Gulf War suggests that frightened parents may improperly use such masks on their children, resulting in inadvertent suffocation.
In the event of a large-scale terrorist attack, there may be an insufficient number of pediatric hospital beds. In any large disaster, excess bed capacity might potentially be provided at civilian and veterans hospitals under the auspices of the National Disaster Medical System, but that system makes no specific provision for pediatric beds. The situation is even more dire regarding burn unit beds, which may be needed in an attack with vesicants like sulfur mustard.
Should a terrorist attack occur, clinicians may be called on to make prompt diagnoses and render rapid lifesaving treatments before the results of confirmatory diagnostic tests are available. Although each potential agent of terrorism produces its own unique clinical manifestations, it is useful to consider their effects in terms of a limited number of distinct clinical syndromes. This approach helps clinicians make prompt, rational decisions regarding empirical therapy. Casualties resulting from a terrorist attack would either experience symptoms immediately upon exposure to an agent (or within the first several hours after exposure) or, alternatively, would see their symptoms develop slowly over a period of days to weeks. In the former case, the sinister nature of the event is often obvious and the etiology more likely to be conventional or chemical in nature.
Biologic agents differ from conventional, chemical (see Chapter 737 ), and nuclear (see Chapter 736 ) weapons in that they have inherent incubation periods. Consequently, patients are likely to present distant in time and place from the point of an unannounced and unnoticed exposure to a biologic agent. Whereas traditional first responders, such as firefighters and paramedics, may be at the forefront of a conventional or chemical terrorism response, the primary care physician or emergency room is likely to constitute the first line of defense against the effects of a biologic agent.
Casualties can thus be categorized as either immediate or delayed in presentation. Within each of these categories, patients can be further classified as having primarily respiratory, neuromuscular, or dermatologic manifestations (Table 741.1 ). A limited number of agents may cause each particular syndrome, permitting institution of empiric therapy targeted at a short list of potential etiologies. The viral hemorrhagic fevers might manifest as fever and a bleeding diathesis; these agents are considered separately in Chapter 297 . In most cases, supportive care is the mainstay of hemorrhagic fever treatment.
Table 741.1
Diseases Caused by Agents of Chemical and Biologic Terrorism, Classified by Syndrome
| NEUROMUSCULAR SYMPTOMS PROMINENT | RESPIRATORY SYMPTOMS PROMINENT | DERMATOLOGIC FINDINGS PROMINENT | |
|---|---|---|---|
| Sudden onset or intermediate onset | Nerve agents |
Chlorine Phosgene Cyanide |
Mustard Lewisite |
| Delayed onset | Botulism |
Anthrax Plague Tularemia Ricin |
Smallpox |
The very rapid onset of neuromuscular symptoms after an exposure should lead the clinician to consider nerve agent intoxication. The nerve agents (tabun, sarin, soman, and VX ) are organophosphate analogs of common pesticides that act as potent inhibitors of the enzyme acetylcholinesterase. They are hazardous via ingestion, inhalation, or cutaneous absorption (see Chapter 77 ).
The inhibition of cholinesterase by these compounds results in the accumulation of acetylcholine at neural and neuromuscular junctions, causing excess stimulation. The resultant cholinergic syndrome involves central, nicotinic, and muscarinic effects. Central effects are both muscarinically and nicotinically mediated, and include altered mental status progressing rapidly to lethargy and coma, as well as ataxia, convulsions, and central respiratory depression. Studies on pesticide exposure suggest that children may be more prone to central neurologic dysfunction with organophosphate toxicity than adults. The most lethal effects are respiratory, which result not only from central effects but also from direct paralysis of the diaphragm and other respiratory muscles (nicotinic effects), as well as bronchospasm and bronchorrhea (muscarinic effects). Nicotinic effects include muscle fasciculations and twitching, followed by weakness, which can progress to flaccid paralysis as muscles fatigue. Importantly, flaccid paralysis is not present initially, as in a patient with botulinum toxin poisoning; in botulinum toxin poisoning, neurotransmitter cannot be released from the presynaptic terminal, whereas in nerve agent poisoning, excess neurotransmitter accumulates because acetylcholinesterase, the enzyme that turns off the transmitter, is inhibited. Muscarinic effects include miosis (the clinical hallmark of a patient who has suffered a non-life-threatening nerve agent challenge), visual blurring, profuse lacrimation, and watery rhinorrhea. Bronchospasm and increased bronchial secretions lead to cough, wheezing, dyspnea, and cyanosis. Cardiovascular manifestations include bradycardia, hypotension, and atrioventricular block. Flushing, sweating, salivation, nausea, vomiting, diarrhea, abdominal cramps, and urinary incontinence are also seen. In the absence of prompt intervention, death can quickly result from a combination of central effects and respiratory muscle paralysis.
The classic neuromuscular syndrome of extremely acute symptoms most commonly results from an aerosol or vapor challenge, the most likely route in a terrorist attack. But nerve agents are liquids at standard temperature and pressure, and do not cause immediate irritation to skin, so liquid nerve agent can be contagious person-to-person, pass through the skin, and cause the cholinergic crisis syndrome that way. This is often delayed by minutes to hours, depending upon dose and body site. In children, because the stratum corneum of the skin forms only gradually, skin transit time will be reduced. The most important clinical pearl is that miosis may be a late development. If the clinician suspects that the child may have been exposed to nerve agent via the skin route, she or he should immediately treat, even if miosis has not yet developed.
Cyanide poisoning is a major differential diagnosis of nerve agent poisoning in an attack scenario. Cyanide poisons cytochrome a3 in the mitochondrial electron transport chain and can cause an almost immediate and rather similar syndrome of loss of consciousness, immediate rapid breathing, status epilepticus, and rapid progression to cardiac arrest. Important clinical differential points include miosis, which is usually absent in cyanide poisoning, and the usual lack of cyanosis (ironically) due to the tissues’ inability to use oxygen from the blood, causing venous blood to retain oxygen and remain red. In a real emergency, it may be necessary to treat for both nerve agent and cyanide poisoning until the cause is definitively identified.
The delayed onset (hours to days after exposure) of neuromuscular symptoms is characteristic of botulism. Botulism occurs after exposure to 1 of 7 related neurotoxins produced by certain strains of Clostridium botulinum, a strictly anaerobic, spore-forming, Gram-positive bacillus commonly found in soil. Naturally occurring botulism (see Chapter 237 ) usually follows ingestion of preformed toxin (food poisoning) or results from intestinal toxin production (infantile botulism). An aerosol exposure would likely result in a case of clinical botulism indistinguishable from that caused by natural exposures.
Following exposure to botulinum toxin, clinical manifestations typically begin with bulbar palsies, causing patients to complain of ptosis, photophobia, and blurred vision resulting from difficulty in accommodation. Symptoms can progress to include dysarthria, dysphonia, and dysphagia, and finally, a descending symmetric paralysis. Sensation and sensorium are typically not affected. In the absence of intervention, death often results from respiratory muscle failure. The mechanism of action of botulinum toxin is almost the exact opposite of that of nerve agent. Seizures, loss of consciousness, and peripheral twitching and fasciculations, typical of nerve agent poisoning, are not seen in botulism.
The acute onset of respiratory symptoms shortly after exposure should prompt the clinician to consider a range of potential chemical agents. Of note, nerve agents, discussed previously, may affect respiration via massive bronchial hypersecretion, bronchospasm, and respiratory muscle paresis. However, the nerve agent casualty will likely have generalized muscle involvement and central nervous system manifestations. In contrast, the toxic inhalants chlorine and phosgene produce respiratory distress without neuromuscular involvement.
Chlorine is a dense, acrid, yellow-green gas that is heavier than air. After mild to moderate exposure, ocular and nasal irritation occurs, followed by cough, a choking sensation, bronchospasm, and substernal chest tightness. Pulmonary edema, mediated by hydrochloric acid and free oxygen radical generation, follows moderate to severe exposures within 30 min to several hours. Hypoxemia and hypovolemia secondary to pulmonary edema are the factors responsible for death when it occurs.
Phosgene, like chlorine, is a common industrial compound that was used as a weapon on the battlefields of World War I. Its odor has been described as similar to “new-mown hay.” Like chlorine, phosgene also is thought to result in the generation of hydrochloric acid, contributing particularly to upper airway, nasal, and conjunctival irritation. Acylation reactions caused by the effects of phosgene on the pulmonary alveolar-capillary membrane lead to pulmonary edema. Phosgene lung injury also may be mediated, in part, by an inflammatory reaction associated with leukotriene production. Patients with mild to moderate exposures to phosgene may be asymptomatic, a fact that may cause victims to remain in a contaminated area. Noncardiogenic pulmonary edema or “dry land drowning” occurs 4-24 hr after exposure and is dose dependent, with heavier exposures causing earlier symptoms. Dyspnea may precede radiologic findings. In severe exposures, pulmonary edema may be so marked as to result in hypovolemia and hypotension. As in the case of chlorine, death results from hypoxemia and asphyxia.
Cyanide is a cellular poison, with protean clinical manifestations. Initially, cyanide toxicity is most likely to manifest as tachypnea and hyperpnea, progressing rapidly to apnea in cases with significant exposure (see Chapter 77 ). The efficacy of cyanide as a chemical terrorism agent is limited by its volatility in open air and relatively low lethality in comparison with nerve agents. Released in a closed room, however, cyanide could have devastating effects, as evidenced by its use in the Nazi gas chambers during World War II. Cyanide inhibits cytochrome a3 , interfering with normal mitochondrial oxidative metabolism and leading to cellular anoxia and lactic acidosis. In addition to respiratory distress, early findings among cyanide victims include tachycardia, flushing, dizziness, headache, diaphoresis, nausea, and vomiting. With greater exposure, seizures, coma, apnea, and cardiac arrest may follow within minutes. An elevated anion gap metabolic acidosis is typically present, and decreased peripheral oxygen utilization leads to an elevated mixed venous oxygen saturation value.
A delayed onset of respiratory symptoms (days after exposure) is characteristic of several infectious diseases and 1 toxin that might be adapted for sinister purposes by terrorists. Among the most threatening and problematic of these are anthrax, plague, tularemia, and ricin, the latter having garnered considerable media attention in recent years.
Anthrax is caused by infection with the Gram-positive spore-forming rod Bacillus anthracis. Its ability to form a spore enables the anthrax bacillus to survive for long periods in the environment and enhances its potential as a weapon.
The vast majority of naturally occurring anthrax cases are cutaneous, acquired by close contact with the hides, wool, bone, and other by-products of infected ruminants (principally cattle, sheep, and goats). Cutaneous anthrax is amenable to therapy with a variety of antibiotics and is readily recognizable to experienced clinicians in endemic areas; consequently, it is rarely fatal. Although it is common in parts of Asia and sub-Saharan Africa, only two cases of cutaneous anthrax had occurred in the United States in the 9 yr that preceded the attacks of 2001 (when 11 cutaneous cases were seen). Gastrointestinal anthrax has been described only once in the United States, in a drum circle participant whose drum heads were made from imported animal hides. In general, however, it occurs after the ingestion of contaminated meat. In the past, inhalational anthrax, or woolsorters’ disease , was an occupational hazard of abattoir and textile workers. Now eliminated as a naturally occurring disease in the United States, it is this inhalational form of anthrax that poses the greatest terror threat. Following an inadvertent release in 1979 from a bioweapons facility at Sverdlovsk in the former Soviet Union, 66 of 77 (86%) known adult victims of inhalational anthrax died. In the 2001 attacks involving contaminated mail in the United States, 5 of 11 (46%) patients with inhalational anthrax died. Whether better intensive care modalities, changes in antibiotic therapy, or earlier recognition accounted for this improved mortality rate remains unknown.
Symptomatic inhalational anthrax typically begins 1-6 days after exposure, although incubation periods of up to several weeks have been reported. The disease begins as a flulike illness, characterized by fever, myalgia, headache, and cough. A brief intervening period of improvement sometimes follows, but rapid deterioration then ensues; high fever, dyspnea, cyanosis, and shock mark this second phase. Hemorrhagic meningitis occurs in up to 50% of cases. Chest radiographs obtained late in the course of illness may reveal a widened mediastinum or prominent mediastinal lymphadenopathy; pleural effusions also may be seen. Bacteremia is often so profound that Gram stains of peripheral blood may demonstrate the organism at this stage. Prompt treatment is imperative; death occurs in as many as 95% of inhalational anthrax cases if such treatment is begun more than 48 hr after the onset of symptoms.
Whereas inhalational anthrax is a disease primarily of mediastinal lymphatic tissue, exposure to aerosolized plague bacilli typically leads to a primary pneumonia. Endemic plague is usually transmitted via the bites of fleas and is discussed in Chapter 230.3 . The causative organism of all forms of human plague, Yersinia pestis, is a bipolar-staining, Gram-negative facultative intracellular bacillus. An ability to survive within the macrophage aids its dissemination to distant sites following inoculation or inhalation. “Buboes,” markedly swollen, tender regional lymph nodes in the distribution of a bite, are the hallmark feature of bubonic plague. Fever and malaise are typically present, and septicemia often develops as bacteria gain access to the circulation. Petechiae, purpura, and overwhelming disseminated intravascular coagulopathy commonly occur, and 80% of bubonic plague victims ultimately have positive blood culture results. Plague is extremely infective and lethal, as illustrated by the fact that the “Black Death” eliminated one third of the population of Europe during the Middle Ages.
Intentional aerosol dissemination of Y. pestis would likely result in a preponderance of pneumonic plague cases. Pneumonic plague may also arise secondarily after seeding of the lungs of septicemic patients. Symptoms include fever, chills, malaise, headache, and cough. Chest radiographs may reveal a patchy consolidation, and the classic clinical finding is blood-streaked sputum. Disseminated intravascular coagulation and overwhelming sepsis typically develop as the disease progresses. Untreated pneumonic plague has a fatality rate approaching 100%.
Tularemia is a highly infectious disease caused by the Gram-negative coccobacillus Francisella tularensis. Naturally occurring tularemia is discussed in Chapter 233 . The high degree of infectivity of F. tularensis (<10 organisms are thought to be necessary to produce infection via inhalation), as well as its survivability in the environment, contributes to its inclusion on the list of agents of concern. Several clinical forms of endemic tularemia are known, but inhalational exposure resulting from a terrorist attack would likely lead to a plague-like primary pneumonia or to typhoidal tularemia, manifesting as a variety of nonspecific symptoms, including fever, malaise, and abdominal pain.
Ricin is a protein toxin derived from the castor bean plant (Ricinus communis) that inhibits ribosomal protein synthesis. It is highly toxic in animal studies when inhaled, and may result in the delayed onset of respiratory distress, pulmonary edema, and acute respiratory failure. One case series of 8 persons from the 1940s described a febrile respiratory illness after inhalational exposure. If injected, it may cause a sepsis-like syndrome that may progress to multiorgan system failure; ingestion can lead to severe gastroenteritis. Ricin-containing letters were mailed to a U.S. Senate office building in 2004, and again to President Obama and New York City Mayor Bloomberg in 2013, although no persons were sickened in either attack.
The development of skin lesions within hours to days of exposure is characteristic of the chemical vesicants. These compounds, often referred to as blistering agents , are cellular poisons and include the alkylating agent mustard and the organic arsenical agent lewisite. Tissue injury to rapidly reproducing cells begins within minutes of contact with these agents. Clinical effects typically become evident several hours after exposure to mustard, whereas patients exposed to lewisite feel immediate pain. Both mustard and lewisite affect the eyes and respiratory tract, and their inadvertent ingestion may produce significant gastrointestinal symptoms. Mustard exposure may lead several days later to bone marrow suppression. With a large challenge, mustard may also cause an acute respiratory syndrome, particularly affecting the upper airway and presenting with laryngospasm and stridor.
The appearance of an exanthem days to weeks after exposure is likely to be a presenting feature of smallpox. Caused by infection with variola virus, a member of the orthopoxvirus family, smallpox has an incubation period of 7-17 days. This would likely permit the wide dispersal of asymptomatic exposed persons, thus contributing to the spread of an outbreak. During the incubation period, the virus replicates in the upper respiratory tract. A primary viremia ensues, during which time seeding of the liver and spleen occurs. A secondary viremia then develops, the skin is seeded, and the classic exanthem of smallpox appears.
Symptoms of smallpox begin abruptly during the phase of secondary viremia and include fever, rigors, vomiting, headache, backache, and extreme malaise. Within 2-4 days, macules appear on the face and extremities and then progress in synchronous fashion to papules, pustules, and finally scabs. As the scabs separate, survivors often are left with disfiguring, depigmented scars. The synchronous nature of the rash and its centrifugal distribution distinguish smallpox from chickenpox, which has a centripetal distribution. Historically, smallpox had a 30% mortality rate, with death typically resulting from visceral organ involvement.
In some cases, the terrorist nature of a chemical or biologic attack may be obvious—for example, a chemical attack in which victims succumb in close temporal and geographic proximity to a dispersal device or terrorists announce their attack. In other instances, the clinician may need to rely on epidemiologic clues to suspect an intentional release of chemical or biologic agents. The presence of large numbers of victims clustered in time and space should raise the index of suspicion, as should cases of unexpected death or unexpectedly severe disease. Diseases unusual in a given locale, in a given age group, or during a certain season likewise may warrant further investigation. Simultaneous outbreaks of a disease in noncontiguous areas should cause one to consider an intentional release (as in the 2001 mail-borne anthrax attacks), as should outbreaks of multiple diseases in the same area. Even a single case of a rare disorder such as anthrax or certain viral hemorrhagic fevers would be suspicious, and a single case of smallpox would almost certainly be the result of an intentional dissemination. Large numbers of dying animals might provide evidence of an unnatural aerosol release, as would evidence of disparate attack rates between those known to be indoors and outdoors at a given time.
In a mass casualty setting, diagnoses may be made largely on clinical grounds. The diagnosis of nerve agent intoxication is based primarily on clinical recognition and patient response to antidotal therapy. Several simple rapid detection devices developed for military use can detect the presence of nerve agents in the environment. Some of these are now commercially available and are stocked in certain emergency departments and public safety vehicles. Measurements of acetylcholinesterase in plasma or erythrocytes of nerve agent victims may be helpful in long-term prognostication, but the correlation between cholinesterase levels and clinical effects is often poor, and the test rarely is available on an emergency basis.
Botulism should be suspected clinically among patients presenting with a symmetric, descending, flaccid paralysis. Although the differential diagnosis of botulism includes other uncommon neurologic disorders, such as myasthenia gravis and the Guillain-Barré syndrome, the presence of multiple casualties with similar symptoms should aid in the determination of a botulism outbreak. Electromyography is useful in supporting the diagnosis.
Initially the diagnosis of cyanide poisoning also will likely be made on clinical grounds in the presence of the appropriate toxidrome. An unusually high anion gap metabolic acidosis with elevated serum lactate and an oxygen concentration greater than expected in mixed venous blood lend support to the clinical diagnosis. Elevated blood cyanide concentrations can confirm the clinical suspicion.
Of all the chemical and biological agents, the only ones for which immediate therapy without waiting for definitive diagnosis is potentially life-saving and mandatory are nerve agents and cyanide poisoning. If these are suspected, they should be treated before waiting for further diagnostic certainty, since they can kill so quickly.
Anthrax should be suspected upon finding Gram-positive bacilli in skin biopsy material (in the case of cutaneous disease), blood smears, pleural fluid, or spinal fluid. Chest radiographs demonstrating a widened mediastinum in the context of fever and constitutional signs and, in the absence of another obvious explanation (e.g., blunt trauma or postsurgical infection), should also lead one to consider the diagnosis. Confirmation can be obtained by blood culture.
A diagnosis of plague can be suspected on finding bipolar “safety-pin”–staining bacilli in Gram or Wayson stains of sputum or aspirated lymph node material; confirmation is obtained by culturing Y. pestis from blood, sputum, or lymph node aspirate. The organism grows on standard blood or MacConkey TRA agars, but it is often misidentified by automated systems. F. tularensis , the causative agent of tularemia, grows poorly on standard media; its growth is enhanced on media containing cysteine. Because of its extreme infectivity, however, many laboratories prefer to make a diagnosis via polymerase chain reaction or serologically using an enzyme-linked immunosorbent assay or serum agglutination assay.
Smallpox should be suspected on clinical grounds and can be confirmed by culture or electron microscopy of scabs or vesicular fluid, although the manipulation of clinical material from suspected smallpox victims should be attempted only at public health laboratories able to employ maximum biocontainment (Biosafety Level 4) precautions. Similar caution should be exercised with specimens from patients with various viral hemorrhagic fevers.
Preventive measures can be considered in both a preexposure and a postexposure context. Preexposure protection against a chemical or biologic attack may consist of physical, chemical, or immunologic measures. Physical protection against primary attack often involves gas masks and protective suits; such equipment is used by the military and by certain hazardous materials response teams, but it is unlikely to be available to civilians at the precise moment that a release occurs. Medical personnel need to understand the principles of physical protection as they apply to infection control and the spread of contamination.
Pneumonic plague is spread through respiratory droplets. Droplet precautions, including the use of simple surgical masks, are thus warranted for providers caring for patients with plague. Smallpox is transmitted by droplet nuclei. Airborne precautions, including (ideally) a high-efficiency particulate air filter mask, are thus warranted with smallpox victims. Patients with certain viral hemorrhagic fevers, such as those caused by filoviruses (Ebola, Marburg) and arenaviruses, should be managed using a combination of droplet and contact precautions, ideally in a specialized biocontainment unit. Most other biologic agent victims can be safely cared for with the use of standard precautions. In the case of chemical agents, residual mustard or nerve agent on the skin or clothing of victims might potentially pose a hazard to medical personnel. For such victims, whenever possible, clothing should be removed, and the patients decontaminated using copious amounts of water before extensive medical care is rendered. Most other chemical agents are volatile enough that spread of an agent among patients or from patient to caregiver is unlikely.
Preexposure chemical prophylaxis might be used on the basis of credible intelligence reports. Should officials deem that the threatened release of a specific biologic agent appears imminent, antibiotics might be distributed to a population prior to exposure. Opportunities to employ such a strategy are likely to be limited, although federal and state officials are examining various mechanisms for such employment. In military settings, pyridostigmine is FDA-approved as pretreatment against expected nerve agent attack. It is not approved for use in children, and it is not likely to be recommended in civilian settings.
Although licensed vaccines (preexposure immunologic measures) against anthrax and smallpox have been developed, widespread use of either vaccine is likely to be problematic, especially in children. The anthrax vaccine is licensed only for those persons age 18 yr and older, is given as a five-dose series over 18 mo, and requires annual booster doses. These considerations make civilian employment of the current anthrax vaccine on a large scale unlikely, although a new recombinant anthrax vaccine is in development and being studied as a three-dose series.
Significant obstacles to the widespread employment of smallpox vaccine also exist, although public health officials have contemplated the resumption of a smallpox vaccination campaign. Whereas in the past smallpox vaccine (prepared from vaccinia virus, an orthopoxvirus related to variola) was used safely and successfully in young infants, it has a relatively high rate of serious complications in certain patients. Fetal vaccinia and demise can occur when pregnant women are vaccinated. Vaccinia gangrenosa , an often fatal complication, can occur when immunocompromised persons are vaccinated. Eczema vaccinatum occurs in those with preexisting dermatoses (atopic dermatitis). Severe vaccine-related encephalitis was well known during the era of widespread vaccination; because it occurs only in primary vaccines, it would disproportionately affect pediatric patients. Autoinoculation can occur when the virus present at the site of vaccination is manually transferred to other areas of skin or to the eye. Young children would presumably be at greater risk for such inadvertent transmission. Myocarditis has been reported following vaccinations of military recruits.
To manage these complications, vaccinia immune globulin should be available when one is undertaking a vaccination campaign. Vaccinia immune globulin (0.6 mg/kg IM) may be given to vaccine recipients who experience severe complications or to significantly immunocompromised individuals exposed to smallpox and in whom vaccination would be unsafe. A compound, tecovirimat, has been used successfully under an Investigational New Drug permit to treat persons (including children) experiencing severe complications from vaccine. The current cell-culture–derived vaccine (ACAM2000), as well as vaccinia immune globulin and tecovirimat, can be obtained as needed upon consultation with officials at the Centers for Disease Control and Prevention. In addition to a potential role in preexposure prophylaxis, vaccination may be effective in postexposure prophylaxis if given within the 1st 4 days or so after exposure.
Anthrax vaccine might similarly be employed in a postexposure setting. Some authorities recommend three doses of this vaccine as an adjunct to postexposure chemoprophylaxis after documented exposure to aerosolized anthrax spores. Nonetheless, postexposure administration of oral antibiotics constitutes the mainstay of management for asymptomatic victims believed to have been exposed to anthrax as well as to other bacterial agents such as plague and tularemia. Table 741.2 lists appropriate prophylactic regimens for various biologic exposures.
Table 741.2
Critical Biologic Agents of Terrorism
| DISEASE | CLINICAL FINDINGS | INCUBATION PERIOD (DAYS) | ISOLATION PRECAUTIONS | INITIAL TREATMENT | PROPHYLAXIS |
|---|---|---|---|---|---|
|
Anthrax (inhalational) Patients who are clinically stable after 14 days can be switched to a single oral agent (as described in the prophylaxis section of this table) to complete a 60-day course* |
Febrile prodrome with rapid progression to mediastinal lymphadenitis and mediastinitis, sepsis, shock, and meningitis | 1-5 | Standard | See Table 741.3 | Ciprofloxacin 30 mg/kg/day PO divided q12h † (max 500 mg/dose) or Doxycycline 4.4 mg/kg/day PO divided q12h (max 100 mg/dose) or Clindamycin 30 mg/kg/day PO divided q8h (max 900 mg/dose) or Levofloxacin 16 mg/kg/day PO divided q12h (max 250 mg/dose) or Amoxicillin 75 mg/kg/day PO divided q8h ‡ (max 1 g/dose) or Penicillin VK 50-75 mg/kg/day divided q6-8h |
| Plague (pneumonic) | Febrile prodrome with rapid progression to fulminant pneumonia, hemoptysis, sepsis, disseminated intravascular coagulation | 2-3 | Droplet (for 1st 3 days of therapy) | Gentamicin 2.5 mg/kg IV q8h or doxycycline 2.2 mg/kg IV q12h or ciprofloxacin 15 mg/kg IV q12h | Doxycycline 2.2 mg/kg PO q12h or ciprofloxacin 20 mg/kg PO q12h |
| Tularemia |
Pneumonic: abrupt onset of fever with fulminant pneumonia Typhoidal: fever, malaise, abdominal pain |
2-10 | Standard | Same as for plague | Same as for plague |
| Smallpox | Febrile prodrome with synchronous, centrifugal, vesiculopustular exanthema | 7-17 | Airborne (+ contact) | Supportive care | Vaccination may be effective if given within the 1st several days after exposure |
| Botulism | Afebrile descending symmetric flaccid paralysis with cranial nerve palsies | 1-5 | Standard | Supportive care; antitoxin (see text) may halt the progression of symptoms but is unlikely to reverse them | None |
| Viral hemorrhagic fevers | Febrile prodrome with rapid progression to shock, purpura, and bleeding diatheses | 4-21 | Contact (consider airborne in cases of massive hemorrhage) | Supportive care; ribavirin may be beneficial in treating Lassa fever, and perhaps other arenaviral hemorrhagic fevers | Ribavirin has been shown to be efficacious in the postexposure prophylaxis of Lassa fever |
† Preferred drugs are shown in bold font.
‡ Penicillin and amoxicillin should only be used when the strain of Bacillus anthracis is known to be susceptible.
Tables 741.2 , 741.3 , and 741.4 provide recommended therapies for overt diseases caused by various chemical and biologic agents. It is likely that the clinician attending to victims will need to make therapeutic decisions before the results of confirmatory diagnostic tests are available and in situations in which the diagnosis is not known with certainty. In particular, decontamination by hospital personnel in appropriate personal protective equipment is required for patients exposed to chemical agents who have not been adequately decontaminated in the prehospital setting (see Table 741.4 ). In such cases, it is useful to note that many diseases and symptoms caused by chemical and biologic agents will resolve spontaneously, with only supportive care required. Most cases of chlorine or phosgene exposure can be successfully managed by providing meticulous attention to oxygenation and fluid balance. Mustard victims may require intensive multisystem support, but no specific antidote or therapy is available. Many viral diseases, such as smallpox, most viral hemorrhagic fevers, and the equine encephalitides, are also managed supportively.
Table 741.3
Treatment of Inhalational Anthrax in Children
| WHEN MENINGITIS HAS NOT BEEN RULED OUT* | WHEN MENINGITIS CAN BE RULED OUT |
|---|---|
|
Ciprofloxacin 30 mg/kg/day IV divided q8h † (max 400 mg/dose) or Levofloxacin 16 mg/kg/day IV divided q12h (max 250 mg/dose) or Moxifloxacin 12 mg/kg/day IV divided q12h (max 200 mg/dose; for children 3 mo-2 yr old); 10 mg/kg/day IV divided q12h (for children 2-5 yr old); 8 mg/kg/day IV divided q12h (for children 6-11 yr old); 400 mg IV qd (for children >12 yr old and >45 kg) |
Ciprofloxacin 30 mg/kg/day IV divided q8h (max 400 mg/dose) or Levofloxacin 20 mg/kg/day IV divided q12h (max 250 mg/dose) or Imipenem 100 mg/kg/day IV divided q6h (max 1 g/dose) or Vancomycin 60 mg/kg/day IV divided q8h or Penicillin G 400,000 U/kg/day IV divided q4h (max 4 MU/dose) or Ampicillin 200 mg/kg/day IV divided q6h (max 3 g/dose) |
|
2. A 2nd Bactericidal Antimicrobial: Meropenem 120 mg/kg/day IV divided q8h (max 2 g/dose) or Imipenem 100 mg/kg/day IV divided q6h (max 1 g/dose) or Doripenem 120 mg/kg/day IV divided q8h (max 1 g/dose) or Vancomycin 60 mg/kg/day IV divided q8h or Penicillin G 400,000 U/kg/day IV divided q4h ‡ (max 4 MU/dose) or |
|
|
2. A Protein Synthesis Inhibitor Clindamycin 40 mg/kg/day IV divided q8h (max 900 mg/dose) or Linezolid 30 mg/kg/d IV divided q8h (for children <12 yr old); 30 mg/kg/day IV divided q12h (for children >12 yr old; max 600 mg/dose) or Rifampin 20/mg/kg/day IV divided q12h (max 300 mg/dose) or Doxycycline 4.4 mg/kg/day IV loading dose (for children <45 kg; max 200 mg), followed by 4.4 mg/kg/day IV divided q12h; 200 mg IV loading dose, followed by 100 MG IV q12h (for children >45 kg) |
* Meningitis occurs in approximately 50% of patients with inhalational anthrax.
† Preferred drugs are shown in bold font.
‡ Penicillin and ampicillin should only be used when the strain of Bacillus anthracis is known to be susceptible.
Table 741.4
Critical Chemical Agents of Terrorism
| AGENT | TOXICITY | CLINICAL FINDINGS | ONSET | DECONTAMINATION* | MANAGEMENT | |
|---|---|---|---|---|---|---|
| NERVE AGENTS | ||||||
| Tabun, sarin, soman, VX | Anticholinesterase: muscarinic, nicotinic, central nervous system effects |
Vapor: miosis, rhinorrhea, dyspnea Liquid: diaphoresis, vomiting Both: coma, paralysis, seizures, apnea |
Seconds: vapor Minutes to hours: liquid |
Vapor: fresh air, remove clothes, wash hair Liquid: remove clothes, wash skin, hair with copious soap and water, ocular irrigation |
ABCs. Atropine: 0.05 mg/kg IV † , IM ‡ (min: 0.1 mg, max: 5 mg), repeat q2-5 min prn for marked secretions, bronchospasm Pralidoxime: 25 mg/kg IV, IM § (max: 1 g IV; 2 g IM), may repeat within 30-60 min prn, then again q1h for 1 or 2 doses prn for persistent weakness, high atropine requirement Diazepam: 0.3 mg/kg (max: 10 mg) IV; lorazepam: 0.1 mg/kg IV, IM (max: 4 mg); midazolam: 0.2 mg/kg (max: 10 mg) IM prn for seizures or severe exposure |
|
| VESICANTS | ||||||
| Mustard | Alkylation |
Skin: erythema, vesicles Eye: inflammation Respiratory tract: inflammation |
Hours |
Skin: soap and water Eyes: water (effective only if done within minutes of exposure) |
Symptomatic care | |
| Lewisite | Arsenical | Immediate pain |
Skin: soap and water Eyes: water (effective only if done within minutes of exposure) |
Possibly British antilewisite (BAL) 3 mg/kg IM q4-6h for systemic effects of lewisite in severe cases | ||
| PULMONARY AGENTS | ||||||
| Chlorine, phosgene | Liberate hydrochloric acid, alkylation |
Eye, nose, and throat irritation (especially chlorine) Respiratory: bronchospasm, pulmonary edema (especially phosgene) |
Minutes: eye, nose, and throat irritation, bronchospasm Hours: pulmonary edema |
Fresh air Skin: water |
Symptomatic care (see text) | |
| CYANIDE | ||||||
| Cytochrome oxidase | Tachypnea, coma, seizures, apnea | Seconds | Fresh air | ABCs, 100% oxygen | ||
| Inhibition: cellular anoxia, lactic acidosis | Skin: soap and water | Na bicarbonate prn metabolic acidosis; hydroxocobalamin 70 mg/kg IV (max: 5 g) or nitrite/thiosulfate, given as follows (see text): | ||||
| Na nitrite (3%): dose (mL/kg) (max: 10 mL) | Estimated hemoglobin concentration (g/dL) | |||||
| 0.27 | 10 | |||||
| 0.33 | 12 (estimated for average child) | |||||
| 0.39 | 14 | |||||
| followed by Na thiosulfate (25%): 1.65 mL/kg (max: 50 mL) | ||||||
* Decontamination, especially for patients with significant nerve agent or vesicant exposure, should be performed by healthcare providers garbed in adequate personal protective equipment. For emergency department staff, this equipment consists of a nonencapsulated, chemically resistant body suit, boots, and gloves with a full-face air-purifier mask/hood.
† Intraosseous route is likely equivalent to intravenous.
‡ Atropine might have some benefit via endotracheal tube or inhalation, as might aerosolized ipratropium. See also Table 741.5 .
§ Pralidoxime is reconstituted to 50 mg/mL (1 g in 20 mL water) for IV administration, and the total dose infused over 30 min, or may be given by continuous infusion (loading dose 25 mg/kg over 30 min, and then 10 mg/kg/hr). For IM use, it might be diluted to a concentration of 300 mg/mL (1 g added to 3 mL water—by analogy to the U.S. Army's Mark 1 autoinjector concentration), to effect a reasonable volume for injection. See also Table 741.5 .
ABCs, Airway, breathing, and circulatory support; max, maximum; min, minimum; prn, as needed.
Adapted from Henretig FH, Cieslak TJ, Eitzen EM: Biological and chemical terrorism. J Pediatr 141:311–326, 2002.
In addition to ensuring adequate oxygenation, ventilation, and hydration, the clinician may need to provide specific empiric therapies on an urgent basis. Patients suffering from the sudden onset of severe neuromuscular symptoms may have nerve agent intoxication and should be given atropine (0.05 mg/kg) promptly for its antimuscarinic effects. Although atropine relieves bronchospasm and bradycardia, reduces bronchial secretions, and ameliorates the gastrointestinal effects of nausea, vomiting, and diarrhea, it does not improve skeletal muscle paralysis. Pralidoxime (also known as 2-PAM ) cleaves the organophosphate moiety from cholinesterase and regenerates intact enzyme if “aging” has not occurred. The effect is most prominent at the neuromuscular junction and leads to improved muscle strength. Its prompt use (at a dose of 25 mg/kg) as an adjunct to atropine is recommended in all serious cases.
Ideally, both atropine and pralidoxime should be administered intravenously in severe cases, although the intraosseous route may be acceptable. Some experts recommend that atropine be given intramuscularly in the presence of hypoxia to avoid arrhythmias associated with intravenous administration. Many emergency management services stock military-style autoinjector kits consisting of atropine and 2-PAM for intramuscular injection. Pediatric atropine autoinjectors are licensed, although kits intended for adults (with 2 mg of atropine and 600 mg of pralidoxime) might be used in children >2-3 yr (Table 741.5 ). Autoinjectors cannot easily be used in the smallest infants.
Table 741.5
Pediatric Autoinjector Recommendations for Mass Casualties or Prehospital Care*
| ATROPINE AUTOINJECTOR THERAPY | |||
| APPROXIMATE AGE | APPROXIMATE WEIGHT (kg) | AUTOINJECTOR SIZE (mg) | |
| <6 mo | <7.5 | 0.25 | |
| 6 mo-4 yr | 7.5-18 | 0.5 | |
| 5-10 yr | 18-30 | 1.0 | |
| >10 yr | >30 | 2.0 | |
| PRALIDOXIME AUTOINJECTOR THERAPY | |||
| APPROXIMATE AGE (yr) | APPROXIMATE WEIGHT (kg) | NUMBER OF AUTOINJECTORS | PRALIDOXIME DOSE (mg/kg) |
| 3-7 | 13-25 | 1 | 24-46 |
| 8-14 | 26-50 | 2 | 24-46 |
| >14 | >50 | 3 | <35 |
* Consider adult pralidoxime autoinjector use for severely affected mass casualties when IV access or more precise mg/kg IM dosing is logistically impractical. The initial dose using atropine autoinjectors is 1 autoinjector of each recommended size. The initial dose using pralidoxime autoinjectors is the recommended number of (adult-intended, 600 mg) autoinjectors. These latter may also be injected into an empty sterile vile; the contents redrawn through a filter needle into a small syringe may then provide a ready source of concentrated (300 mg/mL) pralidoxime solution for IM injection to infants. Autoinjectors may become available that provide adult doses of both atropine and pralidoxime in 1 injector; these could be used in children ≥3 yr in lieu of 2 individual injectors and dosed as noted previously for pralidoxime alone.
Animal studies support the routine prophylactic administration of anticonvulsant doses of benzodiazepines, even in the absence of observable convulsive activity. At present, the approved benzodiazepine is diazepam, but FDA approval of midazolam, which shows superior activity against nerve agent-induced seizures in multiple animal models, is anticipated within the next few years.
Delayed neuromuscular symptoms in the setting of terrorism might be due to botulism. Supportive care, with meticulous attention to ventilatory support, is the mainstay of botulism treatment. Such support may be necessary for several months, making the management of a large-scale botulism outbreak especially problematic in terms of medical resources. A licensed heptavalent antitoxin (types A-G) is available through the Centers for Disease Control (1-800-232-4636). Administration of this antitoxin is unlikely to reverse disease in symptomatic patients but may prevent further progression. In addition, a pentavalent (containing antibody against toxin types A to E, but licensed only for treatment of type A or B intoxication) product, Botulism Immune Globulin Intravenous (Human), BabyBIG, is available through the California Department of Health Services (1-916-327-1400) specifically for the treatment of infant botulism.
The rapid onset of respiratory symptoms may signal an exposure to chlorine, phosgene, cyanide, or a number of other toxic industrial chemicals. Although the mainstay of therapy in virtually all of these exposures consists of removal to fresh air and intensive supportive care, cyanide intoxication often requires the administration of specific antidotes.
The classic cyanide antidote utilizes a nitrite along with sodium thiosulfate and is given in 2 stages. The methemoglobin-forming agent (e.g., sodium nitrite) is administered first, because methemoglobin has a high affinity for cyanide and causes it to dissociate from cytochrome oxidase. Nitrite dosing in children should be based on body weight to avoid excessive methemoglobin formation and nitrite-induced hypotension. For the same reasons, nitrites should be infused slowly over 5-10 min. A sulfur donor, such as sodium thiosulfate, is given next. This compound is used as a substrate by the hepatic enzyme rhodanese, which converts cyanide to thiocyanate, a less toxic compound excreted in the urine. Thiosulfate treatment itself is efficacious and relatively benign, and may be used alone for mild to moderate cases. Sodium nitrite and sodium thiosulfate are packaged together in standard antidote kits, along with amyl nitrite, a sodium nitrite substitute that can be inhaled in prehospital settings in which intravenous access is not available.
Another antidote available in the United States is hydroxocobalamin, which exchanges its hydroxy group for cyanide, forming harmless cyanocobalamin (vitamin B12 ), which is subsequently excreted by the kidneys. Hydroxocobalamin use is not complicated by the potential for nitrite-induced hypotension or methemoglobinemia, and it has low toxicity. The recommended dose is 5 g in adults or 70 mg/kg in children, administered IV over 15 min. A second dose (2.5-5 g in adults; 35-70 mg/kg in children) may be repeated in severely affected patients. Side effects include modest hypertension and reddening of skin, mucous membranes, and urine that may last several days. Although no human controlled trials are currently available to compare hydroxocobalamin with nitrite/thiosulfate-based therapies, many authorities believe that hydroxocobalamin's efficacy and safety profile favor it as the cyanide antidote of choice, especially for children in the mass casualty context. To use hydroxocobalamin, however, the solution must be mixed immediately before use, in the field if need be, so first responders need to be properly trained to employ it.
Animal research suggests a modest benefit of steroid therapy in mitigating lung injury after chlorine inhalation, and thus steroids may be considered for patients with chlorine exposure, especially as an adjunct to bronchodilators in those manifesting bronchospasm and/or a history of asthma. Further, symptomatic relief has also been reported following chlorine exposure with nebulized 3.75% sodium bicarbonate therapy, though the impact of this regimen on pulmonary damage is unknown. Animal models have also suggested a benefit from antiinflammatory agents, including ibuprofen and N -acetylcysteine, which appear to ameliorate phosgene-induced pulmonary edema, as well as the utilization of low tidal volume ventilation (protective ventilation), although the results of such interventions have not yet been reported in clinical trials.
In cases in which the delayed onset of respiratory symptoms may be the result of a terrorist attack, consideration should be given to the empirical administration of an antibiotic effective against anthrax, plague, and tularemia. Ciprofloxacin (10-15 mg/kg IV q12h), levofloxacin (8 mg/kg IV q12h), or doxycycline (2.2 mg/kg IV q12h) is a reasonable choice. Although naturally occurring strains of B. anthracis usually are quite sensitive to penicillin G, these agents are chosen because penicillin-resistant strains of B. anthracis exist. Moreover, ciprofloxacin and doxycycline are effective against almost all known strains of Y. pestis and F. tularensis. Concerns about inducible β-lactamases in B. anthracis have led experts to recommend 1 or 2 additional antibiotics in patients with inhalational anthrax. Rifampin, vancomycin, penicillin or ampicillin, clindamycin, imipenem, and clarithromycin are reasonable choices based on in vitro sensitivity data. Because B. anthracis relies on the production of 2 protein toxins, edema toxin and lethal toxin, for its virulence, drugs that act at the ribosome to disrupt protein synthesis (e.g., clindamycin, the macrolides) provide a theoretical advantage. Frequent meningeal involvement among inhalational anthrax victims makes agents with superior central nervous system penetration desirable. The treatment of anthrax is detailed in Table 741.3 .
Raxibacumab, a monoclonal antibody that inhibits anthrax antigen binding to cell receptors, thus preventing toxins from entering cells, is approved for the treatment of inhalation anthrax in combination with antibiotics, as is obiltoxaximab, which neutralizes anthrax toxins. The adult dose of raxibacumab is 40 mg/kg given IV over 2 hr and 15 min. The dose for children is weight based; ≤15 kg: 80 mg/kg; >15-50 kg: 60 mg/kg; >50 kg: 40 mg/kg. Premedication with diphenhydramine IV or PO is recommended 1 hr before the infusion.
In patients in whom a diagnosis of plague or tularemia is established, streptomycin (15 mg/kg IM q12h) has historically been considered the drug of choice. Because this drug is generally unavailable, many experts consider gentamicin (2.5 mg/kg IV/IM q8h) the preferred choice for therapy. In addition to ciprofloxacin, levofloxacin, or doxycycline, chloramphenicol (25 mg/kg IV q6h) should be employed in the 6% of pneumonic plague cases with concomitant meningitis. To be effective, therapy for pneumonic plague must be initiated within 24 hr of the onset of symptoms. There is little clinical experience with ricin-induced pulmonary injury. The mainstay of therapy is expected to be supportive care.
The management of vesicant-induced injury is similar to that for burn victims and is largely symptomatic (see Chapter 92 ). The major difference between thermal burns and vesicant burns is that vesicant casualties do not need the large volumes of fluid required by thermal burn victims, as their epidermis remains intact. These patients risk overhydration if treated using thermal burn protocols. Mustard victims will benefit from the application of soothing skin lotions such as calamine and the administration of analgesics. Early intubation of severely exposed patients is warranted to guard against edematous airway compromise. Oxygen and mechanical ventilation may be needed, and meticulous attention to hydration is of paramount importance. Ongoing research suggests a role for oral N -acetylcysteine in mitigating chronic pulmonary effects due to mustard injury. Lewisite victims can be managed in much the same manner as mustard victims. In addition, dimercaprol (British antilewisite) in peanut oil, given intramuscularly, may help ameliorate the systemic effects of lewisite.
The management of symptomatic smallpox victims also is largely supportive, with attention to pain control, hydration status, and respiratory sufficiency again of primary importance. The parenteral antiviral compound cidofovir, licensed for the treatment of cytomegalovirus retinitis in HIV-infected patients, has in vitro efficacy against variola and other orthopoxviruses. Its utility in treating smallpox victims is untested. Moreover, in the face of a large outbreak of disease, wide parenteral use of this drug would be problematic. Tecovirimat, mentioned previously, demonstrates excellent in vitro activity against orthopoxviruses, but its utility in treating patients with smallpox is likewise untested.
In all chemical casualties, but especially if a liquid agent such as VX or mustard is suspected, decontamination is crucial and should be considered a primary medical intervention. While this has been part of casualty doctrine in the civilian and military environments for decades, only recently has information become available to quantify its value. In recent unpublished work funded by the U.S. government and carried out by Public Health England and the University of Hertfordshire, disrobing eliminated 90% of contamination in normal volunteers, and following this with showering using water or soap and water eliminated 99% of contamination. This has huge implications for the hospital management of possibly contaminated casualties, including children, and hospitals must plan to execute the decontamination mission at all levels.
A useful planning tool for clinicians faced with an acute chemical emergency is the National Library of Medicine's website, Chemical Emergency Medical Management (http://chemm.nlm.nih.gov ), which contains a quick tool assisting the clinician in quick syndromic identification similar to that used in this chapter.