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InternalMed_Harrison. The clinical features of the viral hemorrhagic fevers vary depending on the particular agent (Table 261e-3). Initial signs and symptoms typically include fever, myalgia, prostration, and disseminated intravascular coagulation with thrombocytopenia and capillary hemorrhage. These findings are consistent with a cytokine-mediated systemic inflammatory syndrome. A variety of different maculopapular or erythematous rashes may be seen. Leukopenia, temperature-pulse dissociation, renal failure, and seizures may also be part of the clinical presentation.


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InternalMed_Harrison. Outbreaks of most of these diseases are sporadic and unpredictable. As a consequence, most studies of pathogenesis have been performed using laboratory animals. The diagnosis should be suspected in anyone with temperature >38.3°C for <3 weeks who also exhibits at least two of the following: hemorrhagic or purpuric rash, epistaxis, hematemesis, hemoptysis, or hematochezia in the absence of any other identifiable cause. In this setting, samples of blood should be sent after consultation to the CDC or the USAMRIID for serologic testing for antigen and antibody as well as reverse transcriptase polymerase chain reaction (RT-PCR) testing for hemorrhagic fever viruses. All samples should be handled with double-bagging. Given how little is known regarding the human-to-human transmission of these viruses, appropriate isolation measures would include full barrier precautions with negative-pressure rooms and use of powered air-purifying respirators (PAPRs).


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InternalMed_Harrison. Unprotected skin contact with cadavers has been implicated in the transmission of certain hemorrhagic fever viruses such as Ebola, so it is recommended that autopsies of suspected cases be performed using the strictest measures for protection and that burial or cremation be performed promptly without embalming. There are no approved and effective antiviral therapies for this class of viruses (Table 261e-3). Although there are anecdotal reports of the efficacy of ribavirin, interferon-α, or hyperimmune immunoglobulin, definitive data are lacking. The best data for ribavirin are in arenavirus (Lassa and New World) infections. In some in vitro systems, specific immunoglobulin has been reported to enhance infectivity, and thus these potential treatments must be approached with caution.


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InternalMed_Harrison. Vaccination and Prevention There are no licensed and effective vaccines for these agents. Studies are currently under way examining the potential role of DNA, recombinant viruses, and attenuated viruses as vaccines for several of these infections. Among the most promising at present are vaccines for Argentine, Ebola, Rift Valley, and Kyasanur Forest viruses. A series of monoclonal antibodies directed against the envelope glycoproteins of Ebola have demonstrated protection against infection in a postexposure setting in nonhuman primates and are being further developed for human use. See also Chap. 178.


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InternalMed_Harrison. Botulinum Toxin as a Bioweapon In a bioterrorist attack, botulinum toxin would likely be dispersed as an aerosol or as contamination of a food supply. Although contamination of a water supply is possible, it is likely that any toxin would be rapidly inactivated by the chlorine used to purify drinking water. Similarly, toxin can be inactivated by heating any food to >85°C for >5 min. Without external facilitation, the environmental decay rate is estimated at 1% per minute, and thus the time interval between weapon release and ingestion or inhalation needs to be rather short. The Japanese biologic warfare group, Unit 731, is reported to have conducted experiments on botulism poisoning in prisoners in the 1930s. The United States and the Soviet Union both acknowledged producing botulinum toxin, and there is some evidence that the Soviet Union attempted to create recombinant bacteria containing the gene for botulinum toxin. In records submitted to the United Nations, Iraq admitted to


InternalMed_Harrison

InternalMed_Harrison. toxin, and there is some evidence that the Soviet Union attempted to create recombinant bacteria containing the gene for botulinum toxin. In records submitted to the United Nations, Iraq admitted to having produced 19,000 L of concentrated toxin—enough toxin to kill the entire population of the world three times over. By many accounts, botulinum toxin was the primary focus of the pre-1991 Iraqi bioweapons program. In addition to these examples of state-supported research into the use of botulinum toxin as a bioweapon, the Aum Shinrikyo cult unsuccessfully attempted on at least three occasions to disperse botulinum toxin into the civilian population of Tokyo.


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InternalMed_Harrison. Microbiology and Clinical Features Unique among the category A agents for not being a live microorganism, botulinum toxin is one of the most potent toxins ever described and is thought by some to be the most poisonous substance in existence. It is estimated that 1 g of botulinum toxin would be sufficient to kill 1 million individuals if adequately dispersed. Botulinum toxin is produced by the gram-positive, spore-forming anaerobe C. botulinum (Chap. 178). Its natural habitat is soil. There are seven antigenically distinct forms of botulinum toxin, designated A–G. The majority of naturally occurring human cases are of types A, B, and E. Antitoxin directed toward one of these will have little to no activity against the others. The toxin is a 150-kDa zinc-containing protease that prevents the intracellular fusion of acetylcholine vesicles with the motor neuron membrane, thus preventing the release of acetylcholine. In the absence of acetylcholine-dependent triggering of muscle fibers, a


InternalMed_Harrison

InternalMed_Harrison. intracellular fusion of acetylcholine vesicles with the motor neuron membrane, thus preventing the release of acetylcholine. In the absence of acetylcholine-dependent triggering of muscle fibers, a flaccid paralysis develops. Although botulism does not spread from person to person, the ease of production of the toxin coupled with its high morbidity and 60–100% mortality make it a close to ideal bioweapon.


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InternalMed_Harrison. Botulism can result from the growth of C. botulinum infection in a wound or the intestine, the ingestion of contaminated food, or the inhalation of aerosolized toxin. The latter two forms are the most likely modes of transmission for bioterrorism. Once toxin is absorbed into the bloodstream, it binds to the neuronal cell membrane, enters the cell, and cleaves one of the proteins required for the intracellular binding of the synaptic vesicle to the cell membrane, thus preventing release of the neurotransmitter to the membrane of the adjacent muscle cell. Patients initially develop multiple cranial nerve palsies that are followed by a descending flaccid paralysis. The extent of the neuromuscular compromise is dependent on the level of toxemia. The majority of patients experience diplopia, dysphagia, dysarthria, dry mouth, ptosis, dilated pupils, fatigue, and extremity weakness. There are minimal true central nervous system effects, and patients rarely show significant alterations in


InternalMed_Harrison

InternalMed_Harrison. dysphagia, dysarthria, dry mouth, ptosis, dilated pupils, fatigue, and extremity weakness. There are minimal true central nervous system effects, and patients rarely show significant alterations in mental status. Severe cases can involve complete muscular collapse, loss of the gag reflex, and respiratory failure. Recovery requires the regeneration of new motor neuron synapses with the muscle cell, a process that can take weeks to months. In the absence of secondary infections, which may be common during the protracted recovery phase of this illness, patients remain afebrile. The diagnosis is suspected on clinical grounds and confirmed by a mouse bioassay or toxin immunoassay.


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InternalMed_Harrison. Treatment for botulism is mainly supportive and may require intubation, mechanical ventilation, and parenteral nutrition (Table 261e-3). If diagnosed early enough, administration of equine antitoxin may reduce the extent of nerve injury and decrease the severity of disease. At present, a heptavalent botulinum antitoxin (HBAT) is available through the CDC as an investigational agent for treatment of naturally occurring noninfant botulism. HBAT contains horse serum–derived antibody fragments to all seven known botulinum toxins (A–G). It is composed of <2% intact immunoglobulin and ≥90% Fab and F(ab′)2 immunoglobulin fragments. A single dose of antitoxin is usually adequate to neutralize any circulating toxin. Repeat dosing may be needed in a setting of continued toxin exposure. Given that this product is derived from horse serum, one needs to be vigilant for hypersensitivity reactions, including serum sickness and anaphylaxis following its administration. Once the damage to the nerve


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InternalMed_Harrison. this product is derived from horse serum, one needs to be vigilant for hypersensitivity reactions, including serum sickness and anaphylaxis following its administration. Once the damage to the nerve axon has been done, however, there is little possible in the way of specific therapy. At this point, vigilance for secondary complications such as infections during the protracted recovery phase is of the utmost importance. Due to their ability to worsen neuromuscular blockade, aminoglycosides and clindamycin should be avoided in the treatment of these infections.


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InternalMed_Harrison. Vaccination and Prevention A botulinum toxoid preparation has been used as a vaccine for laboratory workers at high risk of exposure and in certain military situations; however, it is not currently available in quantities that could be used for the general population. At present, early recognition of the clinical syndrome and use of appropriate equine antitoxin is the mainstay of prevention of full-blown disease in exposed individuals. The development of human monoclonal antibodies as a replacement for equine antitoxin antibodies is an area of active research interest.


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InternalMed_Harrison. The category B agents include those that are easy or moderately easy to disseminate and result in moderate morbidity and low mortality rates. A listing of the current category B agents is provided in Table 261e-2. As can be seen, it includes a wide array of microorganisms and products of microorganisms. Several of these agents have been used in bioterrorist attacks, although never with the impact of the category A agents described above. Among the more notorious of these was 261e-9 the contamination of salad bars in Oregon in 1984 with Salmonella typhimurium by the religious cult Rajneeshee. In this outbreak, which many consider to be the first bioterrorist attack against U.S. citizens, >750 individuals were poisoned and 40 were hospitalized in an effort to influence a local election. The intentional nature of this outbreak went unrecognized for more than a decade.


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InternalMed_Harrison. Category C agents are the third highest priority agents in the biodefense agenda. These agents include emerging pathogens to which little or no immunity exists in the general population, such as the severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) coronavirus or pandemic-potential strains of influenza that could be obtained from nature and deliberately disseminated. These agents are characterized as being relatively easy to produce and disseminate, having high morbidity and mortality rates, and having a significant public health impact. There is no running list of category C agents at the present time.


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InternalMed_Harrison. As noted above, a large number and diverse array of agents have the potential to be used in a bioterrorist attack. In contrast to the military situation with biowarfare, where the primary objective is to inflict mass casualties on a healthy and prepared militia, the objectives of bioterrorism are to harm civilians as well as to create fear and disruption among the civilian population. Although the military need only to prepare their troops to deal with the limited number of agents that pose a legitimate threat of biowarfare, the public health system needs to prepare the entire civilian population to deal with the multitude of agents and settings that could be used in a bioterrorism attack. This includes anticipating issues specific to the very young and the very old, the pregnant patient, and the immunocompromised individual. The challenges in this regard are enormous and immediate. Whereas military preparedness emphasizes vaccines toward a limited number of agents, civilian


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InternalMed_Harrison. patient, and the immunocompromised individual. The challenges in this regard are enormous and immediate. Whereas military preparedness emphasizes vaccines toward a limited number of agents, civilian preparedness needs to rely on rapid diagnosis and treatment of a wide array of conditions.


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InternalMed_Harrison. The medical profession must maintain a high index of suspicion that unusual clinical presentations or the clustering of cases of a rare disease may not be a chance occurrence but rather the first sign of a bioterrorist event. This is particularly true when such diseases occur in traditionally healthy populations, when surprisingly large numbers of rare conditions occur, and when diseases commonly seen in rural settings appear in urban populations. Given the importance of rapid diagnosis and early treatment for many of these conditions, it is essential that the medical care team report any suspected cases of bioterrorism immediately to local and state health authorities and/or to the CDC (888-246-2675). Enhancements made to the U.S. public health surveillance network after the anthrax attacks of 2001 have greatly facilitated the rapid sharing of information among public health agencies.


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InternalMed_Harrison. A series of efforts are in place to ensure the biomedical security of the civilian population of the United States. The Public Health Service has a more highly trained, fully deployable force. The Strategic National Stockpile (SNS) maintained by the CDC provides rapid access to quantities of pharmaceuticals, antidotes, vaccines, and other medical supplies that may be of value in the event of biologic or chemical terrorism. The SNS has two basic components. The first of these consists of “push packages” that can be deployed anywhere in the United States within 12 h. These push packages are a preassembled set of supplies, pharmaceuticals, and medical equipment ready for immediate delivery to the field. Given that an actual threat may not have been precisely identified at the time of stockpile deployment, they provide treatment for a variety of conditions. The contents of the push packs are constantly updated to ensure that they reflect current needs as determined by national security


InternalMed_Harrison

InternalMed_Harrison. deployment, they provide treatment for a variety of conditions. The contents of the push packs are constantly updated to ensure that they reflect current needs as determined by national security risk assessments; they include antibiotics for treatment of anthrax, plague, and tularemia as well as a cache of vaccine to deal with a smallpox threat. The second component of the SNS comprises inventories managed by specific vendors and consists of the provision of additional pharmaceuticals, supplies, and/ or products tailored to the specific attack.


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InternalMed_Harrison. The number of FDA-approved and licensed drugs and vaccines for category A and B agents is currently limited and not reflective of the pharmacy of today. In an effort to speed the licensure of additional drugs and vaccines for these diseases, the FDA has a rule for the licensure of such countermeasures against agents of bioterrorism when adequate and well-controlled clinical efficacy studies cannot be ethically conducted in humans. This is commonly referred to as the “Animal Rule.” Thus, for indications in which field trials of prophylaxis or therapy for a naturally occurring disease are not feasible, the FDA will rely on evidence solely from laboratory animal studies. For this rule to apply, it must be shown that (1) there are reasonably well-understood pathophysiologic mechanisms for the condition and its treatment; (2) the effect of the intervention is independently substantiated in at least two animal species, including species expected to react with a response predictive for


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InternalMed_Harrison. the condition and its treatment; (2) the effect of the intervention is independently substantiated in at least two animal species, including species expected to react with a response predictive for humans; (3) the animal study endpoint is clearly related to the desired benefit in humans; and (4) the data in animals allow selection of an effective dose in humans. As noted above, levofloxacin for treatment of plague and raxibacumab for treatment of inhalational anthrax have been licensed via this mechanism.


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InternalMed_Harrison. Finally, the Biomedical Advanced Research and Development Authority (BARDA) was established in 2006 within the U.S. Department of Health and Human Services to provide an integrated, systematic approach to the development and purchase of the necessary vaccines, drugs, therapies, and diagnostic tools for public health medical emergencies. As authorized by the All-Hazards Preparedness Reauthorization Act of 2013 in conjunction with the Project Bioshield Act of 2006 and the Pandemic and All Hazards Act of 2006, BARDA manages a series of initiatives designed to facilitate biodefense research within the federal government, create a stable source of funding for the purchase of countermeasures against agents of bioterrorism, and create a category of “emergency use authorization” to allow the FDA to approve the use of unlicensed countermeasures during times of extraordinary unmet needs, as might be present in the context of a bioterrorist attack.


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InternalMed_Harrison. Although the prospect of a deliberate attack on civilians with disease-producing agents may seem to be an act of incomprehensible evil, history shows us that it is something that has been done in the past and will likely be done again in the future. It is the responsibility of health care providers to be aware of this possibility, to be able to recognize early signs of a potential bioterrorist attack and alert the public health system, and to respond quickly to provide care to the individual patient. Among the websites with current information on microbial bioterrorism are www.bt.cdc.gov, www.niaid.nih.gov, and www.cidrap.umn.edu.


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InternalMed_Harrison. Chemical terrorism Charles G. Hurst, Jonathan Newmark, James A. Romano, Jr. The use of chemical warfare agents (CWAs) in modern warfare dates back to World War I (WWI). Sulfur mustard and nerve agents were used by Iraq against the Iranian military and Kurdish civilians. Most 262e recently the nerve agent Sarin, GB, was used by the Syrian military against their civilian population. Since the Japanese sarin attacks in 1994–1995 and the terrorist strikes of September 11, 2001, the alltoo-real possibility of chemical or biological terrorism against civilian populations anywhere in the world has attracted increased attention.


InternalMed_Harrison

InternalMed_Harrison. Military planners consider the WWI blistering agent sulfur mustard and the organophosphorus nerve agents as the most likely agents to be used on the battlefield. In a civilian or terrorist scenario, the choice widens considerably. For example, many of the CWAs of WWI, including chlorine, phosgene, and cyanide, are used today in large amounts in industry. They are produced in chemical plants, are stockpiled in large tanks, and travel up and down highways and railways in large tanker cars. The rupture of any of these stores by accident or on purpose could cause many injuries and deaths. In three attacks in February 2007, for example, insurgents in Iraq used chlorine gas released from tankers after explosions as a crude form of chemical weaponry; these attacks killed 12 people and intoxicated more than 140 others. Countless hazardous materials (HAZMATs) that are not used on the battlefield can be used as terrorist weapons. Some of them, including insecticides and ammonia, could wreak as


InternalMed_Harrison

InternalMed_Harrison. more than 140 others. Countless hazardous materials (HAZMATs) that are not used on the battlefield can be used as terrorist weapons. Some of them, including insecticides and ammonia, could wreak as much damage and injury as the weaponized chemical agents.


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InternalMed_Harrison. Many mistakenly believe that chemical attacks will always be so severe that little can be done except to bury the dead. History proves the opposite. Even in WWI, when IV fluids, endotracheal tubes, and antibiotics were unavailable, the mortality rate among U.S. forces on the battlefield from CWAs—chiefly sulfur mustard and the pulmonary intoxicants—was only 1.9%. That figure was far lower than the 7% mortality rate from conventional wounds. In the 1995 Tokyo subway sarin incident, among the 5500 patients who sought medical attention at hospitals, 80% were not actually symptomatic and only 12 died. Recent events should prompt not a fatalistic attitude but a realistic wish to understand the pathophysiology of the syndromes these agents cause, with a view to treating expeditiously all patients who present for care and an expectation of saving the vast majority. As we prepare to defend our civilian population from the effects of chemical terrorism, we also must consider the fact that


InternalMed_Harrison

InternalMed_Harrison. who present for care and an expectation of saving the vast majority. As we prepare to defend our civilian population from the effects of chemical terrorism, we also must consider the fact that terrorism itself can produce sequelae such as physiologic or neurologic effects that may resemble the effects of nonlethal exposures to CWAs. These effects are due to a general fear of chemicals, fear of decontamination, fear of protective ensembles, or other phobic reactions. The increased difficulty in differentiating between stress reactions and nerve agent–induced organic brain syndromes has been pointed out. Knowledge of the behavioral effects of CWAs and their medical countermeasures is imperative to ensure that military and civilian medical and mental health organizations can deal with possible incidents involving weapons of mass destruction.


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InternalMed_Harrison. For the reader’s benefit, the CWAs, their two-letter North Atlantic Treaty Organization (NATO) codes (which were established by a NATO international convention and convey no clinical implications), their unique physical features, and their initial effects are listed in Table 262e-1. Table 262e-2 provides guidelines for immediate treatment. The focus of this chapter is on the blister and nerve CWAs, which have been employed in battle and against civilians and have had a significant public health impact. VESICANTS: SULFUR MUSTARD Sulfur mustard has been a military threat since it first appeared on the battlefield in Belgium during WWI. In modern times, it remains a threat on the battlefield as well as a potential chemical terrorism aLetters in parentheses indicate NATO codes for designated agents. bFrostbite may occur from skin contact with liquid arsine, cyanogen chloride, or phosgene.


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InternalMed_Harrison. Source: State of New York, Department of Health, as modified by the Chemical Casualty Care Division, U.S. Army Medical Research Institute of Chemical Defense. weapon because of the simplicity of its manufacture and its extreme effectiveness. Sulfur mustard accounted for 70% of the 1.3 million chemical casualties in WWI. Occasional cases of sulfur mustard intoxication continue to occur in the United States among people exposed to WWIand WWII-era munitions. Mechanism Sulfur mustard constitutes both a vapor and a liquid threat to all exposed epithelial surfaces. The effects are delayed, aFor frostbite areas, DO NOT remove any adhering clothing. Wash area with plenty of warm water to release clothing. Source: State of New York, Department of Health.


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InternalMed_Harrison. appearing hours after exposure. The organs most commonly affected blister formation. Mustard also has mild cholinergic activity, which are the skin (with erythema and vesicles), the eyes (with manifestations may be responsible for effects such as early gastrointestinal and CNS ranging from mild conjunctivitis to severe eye damage), and the air-symptoms. Mustard reacts with tissue within minutes of entering the ways (with effects ranging from mild upper airway irritation to severe body. Its circulating half-life in unaltered form is extremely brief. bronchiolar damage). After exposure to large quantities of mustard, precursor cells of the bone marrow are damaged, with consequent pan-Clinical Features Topical effects of mustard occur in the skin, airways, cytopenia and secondary infection. The gastrointestinal mucosa may and eyes; the eyes are most sensitive and the airways next most sensibe damaged, and there are sometimes central nervous system (CNS) tive. Absorbed mustard may produce


InternalMed_Harrison

InternalMed_Harrison. gastrointestinal mucosa may and eyes; the eyes are most sensitive and the airways next most sensibe damaged, and there are sometimes central nervous system (CNS) tive. Absorbed mustard may produce effects in the bone marrow, gas-signs of unknown mechanism. No specific antidotes exist; manage-trointestinal tract, and CNS. Direct injury to the gastrointestinal tract ment is entirely supportive. Immediate decontamination of the liquid also may occur after ingestion of the compound through contaminais the only way to reduce damage. Complete decontamination in 2 min tion of water or food. stops clinical injury; decontamination at 5 min reduces skin injury by Erythema is the mildest and earliest form of mustard skin injury. It ~50%. Table 262e-2 lists approaches to decontamination after expo-resembles sunburn and is associated with pruritus, burning, or sting-sure to mustard and other CWAs. ing pain. Erythema begins to appear within 2 h to 2 days after vapor


InternalMed_Harrison

InternalMed_Harrison. Mustard dissolves slowly in aqueous media such as sweat, but, once exposure. Time of onset depends on severity of exposure, ambient dissolved, it rapidly forms cyclic ethylene sulfonium ions that are temperature and humidity, and type of skin. The most sensitive sites extremely reactive with cell proteins, cell membranes, and especially are warm moist locations and areas of thin delicate skin, such as the DNA in rapidly dividing cells. The ability of mustard to react with and perineum, external genitalia, axillae, antecubital fossae, and neck. alkylate DNA gives rise to the effects by which it has been character-Within the erythematous areas, small vesicles can develop, which ized as “radiomimeti”—i.e., similar to radiation injury. Mustard has may later coalesce to form bullae (Fig. 262e-1). The typical bulla is many biologic actions, but its actual mechanism of action is largely large, dome-shaped, flaccid, thin-walled, translucent, and surrounded unknown. Much of the biologic damage


InternalMed_Harrison

InternalMed_Harrison. The typical bulla is many biologic actions, but its actual mechanism of action is largely large, dome-shaped, flaccid, thin-walled, translucent, and surrounded unknown. Much of the biologic damage from mustard results from by erythema. The blister fluid, a transudate, is clear to straw-colored DNA alkylation and cross-linking in rapidly dividing cells: corneal and becomes yellow, tending to coagulate. The fluid does not contain epithelium, basal keratinocytes, bronchial mucosal epithelium, gastro-mustard and is not itself a vesicant. Lesions from high-dose liquid intestinal mucosal epithelium, and bone marrow precursor cells. This exposure may develop a central zone of coagulation necrosis with blisdamage may lead to cellular death and inflammatory reactions. In the ter formation at the periphery. These lesions take longer to heal and are skin, proteolytic digestion of anchoring filaments at the epidermal-more prone to secondary infection than are the uncomplicated lesions dermal


InternalMed_Harrison

InternalMed_Harrison. periphery. These lesions take longer to heal and are skin, proteolytic digestion of anchoring filaments at the epidermal-more prone to secondary infection than are the uncomplicated lesions dermal junction may be the major mechanism of action resulting in seen at lower exposure levels. Severe lesions may require skin grafting.


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InternalMed_Harrison. FIgURE 262e-1 Large bulla formation from mustard burn in a patient. Although the blisters in this case involved only 7% of the body surface area, the patient still required hospitalization in a burn intensive care unit. The primary airway lesion is necrosis of the mucosa with possible damage to underlying smooth muscle. The damage begins in the upper airways and descends to the lower airways in a dose-dependent manner. Usually the terminal airways and alveoli are affected only as a terminal event. Pulmonary edema is not usually present unless the damage is very severe, and then it becomes hemorrhagic.


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InternalMed_Harrison. The earliest effects of mustard—and perhaps the only effects of a low concentration—involve the nose, sinuses, and pharynx. There may be irritation or burning of the nares, epistaxis, sinus pain, and pharyngeal pain. As the concentration increases, laryngitis, voice changes, and nonproductive cough develop. Damage to the trachea and upper bronchi leads to a productive cough. Lower airway involvement causes dyspnea, severe cough, and increasing quantities of sputum. Terminally, there may be necrosis of the smaller airways with hemorrhagic edema into surrounding alveoli. Hemorrhagic pulmonary edema is rare. Necrosis of airway mucosa causes “pseudomembrane” formation. These membranes may obstruct the bronchi. During WWI, high-dose mustard exposure caused acute death via this mechanism in a small minority of cases (Fig. 262e-2).


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InternalMed_Harrison. The eyes are the organs most sensitive to mustard vapor injury. The latent period is shorter for eye injury than for skin injury and is also dependent on exposure concentration. After low-dose vapor exposure, irritation evidenced by reddening of the eyes may be the only effect. As the dose increases, the injury includes progressively severe conjunctivitis, photophobia, blepharospasm, pain, and corneal damage FIgURE 262e-2 Schematic diagram of pseudomembrane forma-tion as is seen in high-dose sulfur mustard vapor inhalation exposure. In World War I, severe inhalation exposure often caused death via obstruction of large airways. FIgURE 262e-3 World War I photograph of troops exposed to sulfur mustard vapor. The vast majority of these troops survived with no long-term damage to the eyes; however, they were rendered effectively blind for days or weeks.


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InternalMed_Harrison. (Fig. 262e-3). About 90% of eye injuries related to mustard heal in 2 weeks to 2 months without sequelae. Scarring between the iris and the lens may follow severe effects; this scarring may restrict pupillary movements and predispose victims to glaucoma. The most severe damage is caused by liquid mustard. Extensive eye exposure can be followed by severe corneal damage with possible perforation of the cornea and loss of the eye. In some individuals, latent chronic keratitis, sometimes associated with corneal ulcerations, has been described as early as 8 months and as late as 20 years after initial exposure.


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InternalMed_Harrison. The mucosa of the gastrointestinal tract is susceptible to mustard damage from either systemic absorption or ingestion of the agent. Mustard exposure in small amounts will cause nausea and vomiting lasting up to 24 h. The mechanism of the nausea and vomiting is not understood, but mustard does have a cholinergic-like effect. The CNS effects of mustard also remain poorly defined. Exposure to large amounts can cause seizures in animals. Reports from WWI and from the Iran–Iraq war described people exposed to small amounts of mustard acting sluggish, apathetic, and lethargic. These reports suggest that minor psychological problems could linger for ≥1 year.


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InternalMed_Harrison. The cause of death in the majority of mustard poisoning cases is sepsis and respiratory failure. Mechanical obstruction via pseudomembrane formation and agent-induced laryngospasm is important in the first 24 h, but only in cases of severe exposure. From the third through the fifth day after exposure, secondary pneumonia due to bacterial invasion of denuded necrotic mucosa can be expected. The third wave of death is caused by agent-induced bone marrow suppression, which peaks 7–21 days after exposure and causes death via sepsis. A patient severely ill from mustard poisoning requires the general supportive care provided for any severely ill patient as well as the specific care given to a burn patient. Liberal use of systemic analgesics, maintenance of fluid and electrolyte balance, provision of nutrition, administration of appropriate antibiotics, and other supportive measures are necessary (Table 262e-2).


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InternalMed_Harrison. The management of a patient exposed to mustard may range from simple (as in the provision of symptom-based care for a sunburn-like erythema) to complex (as in total management of a severely ill patient with burns, immunosuppression, and multi-system involvement). Before raw denuded areas of skin develop, especially with less severe exposures, topical cortisone creams or lotions may be of benefit. Some very basic research data point to the early use of anti-inflammatory preparations. Small blisters (<1–2 cm) should be left intact. Because larger bullae eventually will break, they should be unroofed carefully. Denuded areas should be irrigated three or four times daily with saline, other sterile solutions, or soapy water and then liberally covered with the topical antibiotic of choice, such as silver sulfadiazine, mafenide acetate, or triple antibiotic ointment to a thickness of 1–2 mm. Some physicians advocate sterile needle drainage of large blisters, with collapsing of the blister


InternalMed_Harrison

InternalMed_Harrison. as silver sulfadiazine, mafenide acetate, or triple antibiotic ointment to a thickness of 1–2 mm. Some physicians advocate sterile needle drainage of large blisters, with collapsing of the blister roof to form a sterile dressing. Mustard blister fluid does not contain sulfur mustard but rather consists only of sterile tissue fluid. Health care staff should not fear possible contamination. If an antibiotic cream is not available, sterile petrolatum will be useful. Modified Dakin’s solution (sodium hypochlorite, 0.5%) was used for field-expedient irrigation and antisepsis both in WWI and for Iranian casualties in the Iran–Iraq war (1984–1987). Large areas of vesication require hospitalization, IV therapy, and whirlpool bath irrigation.


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InternalMed_Harrison. Systemic analgesics should be used liberally, particularly before manipulation of the patient. Monitoring of fluids and electrolytes is important in any sick patient, but it must be recognized that fluid loss is not of the magnitude seen with thermal burns. Overly rigorous hydration seems to have precipitated pulmonary edema in a few Iranian casualties sent to European hospitals.


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InternalMed_Harrison. Conjunctival irritation from a low-vapor exposure responds to any of a number of available ophthalmic solutions after the eyes are irrigated thoroughly. A topical antibiotic applied several times a day reduces the incidence and severity of infection. Animal laboratory data reflect remarkable results with early application of commercially available topical antibiotic/glucocorticoid ophthalmologic ointments. An ophthalmologist should be consulted. Topical glucocorticoids are not of proven value, but their use during the first few hours or days may significantly reduce inflammation and subsequent damage. Further use should be relegated to an ophthalmologist. Petroleum jelly or a similar substance should be applied regularly to the edges of the eyelids to prevent them from sticking together. Topical analgesics, although of limited value, may be useful initially if blepharospasm is too severe to permit an adequate examination.


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InternalMed_Harrison. A productive cough and dyspnea accompanied by fever and leukocytosis occurring within 12–24 h are indicative of chemical pneumonitis. The clinician must resist the urge to use prophylactic antibiotics for this process. Infection often occurs on the third to fifth day and is signaled by increased fever, a pulmonary infiltrate, and increased sputum production with a change in color. Appropriate antibiotic therapy should await confirmation by Gram’s stain and, later, by culture and sensitivity assessment. Intubation may be necessary if laryngeal spasm or edema makes breathing difficult or becomes life-threatening. Intubation permits better ventilation and facilitates suctioning of necrotic and inflammatory debris. Early use of positive end-expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) may be beneficial. Pseudomembrane formation may require fiberoptic bronchoscopy for suctioning of necrotic debris.


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InternalMed_Harrison. Bronchodilators are of benefit for bronchospasm. If additional relief of bronchospasm is needed, glucocorticoids should be used. There is little evidence that the routine use of glucocorticoids is beneficial except for additional relief of bronchospasm.


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InternalMed_Harrison. Leukopenia begins around day 3 with major systemic absorption. Marrow suppression peaks at 7–14 days. In the Iran–Iraq war, a white blood cell count of ≤200/μL usually resulted in death of the patient. Sterilization of the gut by nonabsorbable antibiotics should be considered to reduce the possibility of sepsis from enteric organisms. Cellular replacement (bone marrow transplants or transfusions) may be successful. Granulocyte colony-stimulating factor produced a 50% reduction in the time required for bone marrow recovery in nonhuman primates exposed to sulfur mustard. Medication for nausea and vomiting may be necessary for gastrointestinal side effects. Lymphopenia precedes general leukopenia by a day or more and may be a useful clinical tip-off to impending leukopenia.


InternalMed_Harrison

InternalMed_Harrison. Excellent experimental assessments of the contributions of DNA alkylation, inflammation, activation of proteolytic enzymes, or lipid peroxidation to the mustard injury have been developed in the past 15–20 years. Some examples include (1) the demonstration of a reduction by up to 75% of inflammation and tissue damage in the mouse ear swelling test by vanilloid compounds and (2) the demonstration of 50–60% protection by N-acetylcysteine in the generation of free radicals within guinea pig lung exposed to mustard. In many cases, the demonstration of protection is dependent on the availability of sufficient amounts of drugs with adequate half-lives. Strategies to enhance bioavailability include attachment of polyethylene glycol to the antioxidant drug/enzyme and/or delivery of the drug/enzyme in a liposome.


InternalMed_Harrison

InternalMed_Harrison. The organophosphorus nerve agents are the deadliest of the CWAs. They work by inhibition of tissue synaptic acetylcholinesterase, creating an acute cholinergic crisis. Death ensues because of respiratory depression and can occur within seconds to minutes. The nerve agents tabun and sarin were first used on the battlefield by Iraq against Iran during the first Persian Gulf War (1984–1987). Estimates of casualties from these agents range from 20,000–100,000. In 1994 and 1995, the Japanese cult Aum Shinrikyo used sarin in two terrorist attacks in Matsumoto and Tokyo. Two U.S. soldiers were exposed to sarin while rendering safe an improvised explosive device in Iraq in 2004.


InternalMed_Harrison

InternalMed_Harrison. The “classic” nerve agents include tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX; VR, similar to VX, was manufactured in the former Soviet Union (Table 262e-1). All the nerve agents are organophosphorus compounds, which are liquid at standard temperature and pressure. The “G” agents evaporate at about the rate of water, except for cyclosarin, which is oily and thus probably will have evaporated within 24 h after deposition on the ground. Their high volatility thus makes a spill of any amount a serious vapor hazard. In the Tokyo subway attack in which sarin was used, 100% of the symptomatic patients inhaled sarin vapor that spilled out on the floor of the subway cars. The low vapor pressure of VX, an oily liquid, makes it much less of a vapor hazard but potentially a greater environmental hazard because it persists in the environment far longer.


InternalMed_Harrison

InternalMed_Harrison. Mechanism Acetylcholinesterase inhibition accounts for the major life-threatening effects of nerve agent poisoning. The efficacy of antidotal therapy in the reversal of this inhibition proves that this is the primary toxic action of these poisons. At cholinergic synapses, acetylcholinesterase, bound to the postsynaptic membrane, functions as a turn-off switch to regulate cholinergic transmission. Inhibition of acetylcholinesterases causes the released neurotransmitter, acetylcholine, to accumulate abnormally. End-organ overstimulation, which is recognized by clinicians as a cholinergic crisis, ensues (Fig. 262e-4). Clinical Features Clinical effects of nerve agent exposure are identical for vapor and liquid exposure routes if the dose is sufficiently large. The speed and order of symptom onset will differ (Table 262e-2).


InternalMed_Harrison

InternalMed_Harrison. Exposure of a patient to nerve agent vapor, by far the more likely route of exposure in both battlefield and terrorist scenarios, will cause cholinergic symptoms in the order in which the toxin encounters cholinergic synapses. The most exposed synapses on the human integument are in the pupillary muscles. Nerve agent vapor easily crosses the cornea, interacts with these synapses, and produces miosis, described by Tokyo subway victims as “the world going black.” Rarely, FIgURE 262e-4 Schematic diagram of the pathophysiology of nerve agent exposure. Nerve agent ( ) binds to the active site of acetylcholinesterase (AChE), which is shown as floating free in space but is in reality a postsynaptic membrane-bound enzyme. As a result, acetylcholine ( ), which normally is released from presynaptic membrane but then is degraded, accumulates, and this leads ( ) to organ overstimulation and cholinergic crisis.


InternalMed_Harrison

InternalMed_Harrison. this vapor also can cause eye pain and nausea. Exocrine glands in the nose, mouth, and pharynx are next exposed to the vapor, and cholinergic overload here causes increased secretions, rhinorrhea, excess salivation, and drooling. Toxin then interacts with exocrine glands in the upper airway, causing bronchorrhea, and with bronchial smooth muscle, causing bronchospasm. This combination of events can result in hypoxia. Once the victim has inhaled, vapor can passively cross the alveolar-capillary membrane, enter the bloodstream, and incidentally and asymptomatically inhibit circulating cholinesterases, particularly free butyrylcholinesterase and erythrocyte acetylcholinesterase, both of which can be assayed. Unfortunately, the results of this assay may not be easily interpretable without a baseline, since cholinesterase levels vary enormously between individuals and over time in an individual, healthy patient.


InternalMed_Harrison

InternalMed_Harrison. Usually the first organ system to become symptomatic from bloodborne nerve agent exposure is the gastrointestinal tract, where cholinergic overload causes abdominal cramping and pain, nausea, vomiting, and diarrhea. After the gastrointestinal tract becomes involved, nerve agents will affect the heart, distant exocrine glands, muscles, and brain. Because there are cholinergic synapses on both the vagal (parasympathetic) and sympathetic sides of the autonomic input to the heart, one cannot predict how heart rate and blood pressure will change once intoxication has occurred. Remote exocrine activity will include oversecretion in the salivary, nasal, respiratory, and sweat glands—the patient will be “wet all over.” Bloodborne nerve agents will overstimulate neuromuscular junctions in skeletal muscles, causing fasciculations followed by frank twitching. If the process goes on long enough, ATP in muscles will eventually be depleted and flaccid paralysis will ensue.


InternalMed_Harrison

InternalMed_Harrison. In the brain, since the cholinergic system is so widely distributed, bloodborne nerve agents will, in sufficient doses, cause rapid loss of consciousness, seizures, and central apnea leading to death within minutes. If respiration is supported, status epilepticus that does not respond to usual anticonvulsants may ensue (Chap. 445). If status epilepticus persists, neuronal death and permanent brain dysfunction may occur. Even in mild nerve-agent intoxication, patients may recover but may experience weeks of irritability, sleep disturbance, and nonspecific neurobehavioral manifestations. The time from exposure to development of the full-blown cholinergic crisis after nerve agent vapor inhalation can be minutes or even seconds, yet there is no depot effect. Since nerve agents have a short circulating half-life, if the patient is supported and, ideally, treated 262e-5 with antidotes, improvement should be rapid, without subsequent deterioration.


InternalMed_Harrison

InternalMed_Harrison. Liquid exposure to nerve agents results in different speeds and orders of symptom onset. A nerve agent on intact skin will partially evaporate and partially begin to travel through the skin, causing localized sweating and then, when it encounters neuromuscular junctions, localized fasciculations. Once in muscle, the agent will cross into the circulation and cause gastrointestinal discomfort, respiratory distress, heart rate changes, generalized fasciculations and twitching, loss of consciousness, seizures, and central apnea. The time course will be much longer than with vapor inhalation; even a large, lethal droplet can take up to 30 min to exert an effect, and a small, sublethal dose could progressively take effect over 18 h. Clinical worsening that occurs hours after treatment has started is far more likely with liquid than with vapor exposure. In addition, miosis, which is practically unavoidable with vapor exposure, is not always present with liquid exposure and may be the last


InternalMed_Harrison

InternalMed_Harrison. is far more likely with liquid than with vapor exposure. In addition, miosis, which is practically unavoidable with vapor exposure, is not always present with liquid exposure and may be the last manifestation to develop in this situation; such a delay is due to the relative insulation of the pupillary muscle from the systemic circulation.


InternalMed_Harrison

InternalMed_Harrison. Unless the cholinesterase is reactivated by specific therapy (oximes), its binding to the enzyme is essentially irreversible. Erythrocyte acetylcholinesterase activity recovers at ~1% per day. Plasma butyrylcholinesterase recovers more quickly and is a better guide to recovery of tissue enzyme activity. Acute nerve agent poisoning is treated by decontamination, respiratory support, and three antidotes: an anticholinergic, an oxime, and an anticonvulsant (Table 262e-3). In acute cases, all these forms of therapy may be given simultaneously.


InternalMed_Harrison

InternalMed_Harrison. Decontamination of a vapor is formally unnecessary; however, in the Tokyo subway attack, sarin vapor trapped in patients’ clothing caused miosis in 10% of emergency personnel. Removal of clothing would have prevented most of these instances. Expedient decontamination methods for CWAs are available. For soap and water decontamination, the skin surface and hair are washed in warm or tepid water at least three times, or the exposed individual showers for 2 min, washing with soap and rinsing. The rapid physical removal Elderly, frail Atropine (1 mg IM) and 2-PAM Cl (10 mg/kg IM or 5–10 mg/kg IV slowly) Atropine (2–4 mg IM) and 2-PAM Cl (25 mg/kg IM or 5–10 mg/kg IV slowly) Assisted ventilation after antidotes for severe Repeat atropine (2 mg IM, or 1 mg IM for infants) at 5to 10-min intervals until secretions have diminished and breathing is comfortable or airway resistance has returned to nearly normal.


InternalMed_Harrison

InternalMed_Harrison. Repeat atropine (2 mg IM, or 1 mg IM for infants) at 5to 10-min intervals until secretions have diminished and breathing is comfortable or airway resistance has returned to nearly normal. Diazepam for convulsions (0.2–0.5 mg IV for infants <5 years; 1 mg IV for children >5 years; 5 mg IV for adults). aMild/moderate effects include localized sweating, muscle fasciculations, nausea, vomiting, weakness, and dyspnea. bSevere effects include unconsciousness, convulsions, apnea, and flaccid paralysis. cIf the calculated dose exceeds the adult IM dose, adjust accordingly. Abbreviation: 2-PAM Cl, 2-pralidoxime (or Protopam®) chloride. Source: State of New York, Department of Health.


InternalMed_Harrison

InternalMed_Harrison. of a chemical agent is essential. Scrubbing of exposed skin with a stiff brush or bristles is discouraged, because skin damage may occur and may increase absorption of agent. “Gentle” liquid dish soap and copious amounts of water should be used, with mild to moderate friction applied with a single-use sponge or washcloth in the first and second washes. The third wash should be a rinse with copious amounts of warm or tepid water. Shampoo can be used to wash the hair. If only cold water is available, it should be used; decontamination should not be delayed while warm water is sought. Spot (local) decontamination with reactive skin decontamination lotion (RSDL), followed by a soap and water wash/shower, is the method preferred by the Department of Defense. RSDL is available for purchase by civilians and has been shown to be superior across a broad spectrum of nerve agents as well as sulfur mustard. RSDL is the only product approved by the U.S. Food and Drug Administration (FDA) for


InternalMed_Harrison

InternalMed_Harrison. by civilians and has been shown to be superior across a broad spectrum of nerve agents as well as sulfur mustard. RSDL is the only product approved by the U.S. Food and Drug Administration (FDA) for initial spot decontamination. An important caveat is that RSDL and 0.5% sodium hypochlorite (dilute bleach military field expedient) should not be used concurrently because of a potential exothermic reaction. In any event, decontamination must be accomplished before the patient enters the medical facility to avoid contaminating the facility and its staff. In patients with contaminated wounds, potentially contaminated clothing and other foreign material that may serve as a depot for the liquid agent should be extracted.


InternalMed_Harrison

InternalMed_Harrison. Death from nerve agent poisoning is almost always attributable to respiratory causes. Ventilation will be complicated by increased resistance and secretions. Atropine should be given before ventilation or as it begins, since it will make ventilation far easier.


InternalMed_Harrison

InternalMed_Harrison. ANTIDOTAL THERAPY Atropine In theory, any anticholinergic agent could be used to treat nerve agent poisoning. Worldwide, however, the choice is invariably atropine because of its wide temperature stability and rapid effectiveness when administered either IM or IV and because inadvertent administration of this drug usually causes little CNS dysfunction (Table 262e-3). Atropine rapidly reverses cholinergic overload at muscarinic synapses but has little effect at nicotinic synapses. The practical implication is that atropine can quickly treat the life-threatening respiratory effects of nerve agents but probably will not help with neuromuscular (and possibly sympathetic) effects. In the field, military personnel are given a combined autoinjector containing both 2.1 mg of atropine and oxime (2-pralidoxime chloride [2-PAM Cl])—a product licensed by the FDA under the trade name Duodote . Its miltary designation is the Antidote Treatment Nerve Agent Autoinjector (ATNAA) (Fig. 262e-5). Only


InternalMed_Harrison

InternalMed_Harrison. chloride [2-PAM Cl])—a product licensed by the FDA under the trade name Duodote . Its miltary designation is the Antidote Treatment Nerve Agent Autoinjector (ATNAA) (Fig. 262e-5). Only full—and not divided—autoinjector doses can be administered. The field loading dose is 2, 4, or 6 mg, with re-treatment every 5–10 min until the patient’s breathing improves and secretions diminish. The Iranian military initially used larger doses during the Iran–Iraq war, in which oximes were in short supply. When the patient reaches a level of medical care at which drugs can be given IV, this is the preferred route. In small children, the IV route may be the initial avenue for atropine therapy; however, pediatric autoinjectors of 0.5 mg and 1 mg are manufactured. There is no upper limit to atropine therapy (whether IM or IV), but the total average dose for a severely afflicted adult is usually 20–30 mg.


InternalMed_Harrison

InternalMed_Harrison. In a mildly afflicted patient with miosis and no other systemic symptoms, atropine or homatropine eyedrops may suffice for therapy. This treatment will result in ~24 h of mydriasis. Frank miosis or imperfect accommodation may persist for weeks or even months after all other signs and symptoms have resolved.


InternalMed_Harrison

InternalMed_Harrison. Oximes Oximes are nucleophiles that reactivate the cholinesterase whose active site has been occupied and bound to nerve agent (Table 262e-3). Therapy with oximes therefore restores normal enzyme function. Oxime therapy is limited by a second side reaction, called “aging,” in which a side chain on nerve agents falls off the complex at a characteristic rate. “Aged” complexes are negatively charged, and oximes cannot reactivate negatively charged complexes. The practical effect of this limitation differs from one nerve agent to another since each ages at a characteristic rate. For example, sarin ages in 3–5 h, tabun ages over a longer period (12–13 h), and VX ages much less rapidly (>48 h). All these intervals are so much longer than the patient’s expected life span and expected treatment time after acute nerve-agent toxicity that they are irrelevant. Soman, in contrast, ages in 2 min; thus, only a few minutes after exposure, oximes are useless in treating soman poisoning. The oxime


InternalMed_Harrison

InternalMed_Harrison. time after acute nerve-agent toxicity that they are irrelevant. Soman, in contrast, ages in 2 min; thus, only a few minutes after exposure, oximes are useless in treating soman poisoning. The oxime used varies by country; the United States has approved and fielded 2-PAM Cl. MARK 1 kits and Duodotes® (Fig. 262e-5A) both contain autoinjectors holding 600 mg of 2-PAM Cl. Initial field loading doses are 600, 1200, and 1800 mg. Since blood pressure may become elevated after administration of 45 mg/kg in adults, field use of 2-PAM Cl is restricted to 1800 mg/h IM. During the time when more oxime cannot be given, atropine alone is recommended. In the hospital setting, 2.5–25 mg/kg of 2-PAM Cl by the IV route has been found to reactivate 50% of inhibited cholinesterase. The usual recommendation is 1000 mg by slow IV drip over 20–30 min, with ≤2500 mg over a period of 1–1.5 h. Active research aims to field a more effective and broader-spectrum oxime than 2-PAM Cl.


InternalMed_Harrison

InternalMed_Harrison. Anticonvulsants Nerve agent–induced seizures do not respond to the usual anticonvulsants used for status epilepticus, including phenytoin, phenobarbital, carbamazepine, valproic acid, and lamotrigine (Chap. 445). The only anticonvulsants that have been shown to stop this form of status are the benzodiazepines. Diazepam is the only benzodiazepine approved for seizures in humans, although other FDA-approved benzodiazepines (notably midazolam) work well against nerve agent–induced seizures in animal models. Diazepam FIgURE 262e-5 Antidotes to nerve agents. A. The Antidote Treatment Nerve Agent Autoinjector (ATNAA) replaces the MARK I Kit. It is easier to self-administer and allows prompt distribution of the antidotes atropine and 2-pralidoxime chloride (2-PAM Cl). B. Diazepam 10-mg autoinjectors are carried by all U.S. military forces in a potential chemical battlefield and are being stockpiled by civilian first responders.


InternalMed_Harrison

InternalMed_Harrison. B. Diazepam 10-mg autoinjectors are carried by all U.S. military forces in a potential chemical battlefield and are being stockpiled by civilian first responders. therefore is manufactured in 10-mg injectors for IM use and given to


InternalMed_Harrison

InternalMed_Harrison. U.S. forces for this purpose (Fig. 262e-5B). Civilian agencies are stockpiling this field product (convulsive antidote for nerve agent, CANA), which generally has not been used in hospital practice. Extrapolation from animal studies indicates that adults will probably require 30–40 mg of diazepam given IM to stop nerve agent–induced status epilepticus. In the hospital or in a small child unable to receive the autoinjector, IV diazepam may be used at similar doses. The clinician may confuse seizures with the neuromuscular signs of nerve agent poisoning. In the hospital, early electroencephalography is advised to distinguish among nonconvulsive status epilepticus, actual seizures, and postictal paralysis. Animal studies have shown that the most effective benzodiazepine in this situation is midazolam, which is not FDA-approved for seizures. At the time of this writing, a new drug application for use of midazolam against seizures has been submitted to the FDA. The superiority of IM


InternalMed_Harrison

InternalMed_Harrison. is midazolam, which is not FDA-approved for seizures. At the time of this writing, a new drug application for use of midazolam against seizures has been submitted to the FDA. The superiority of IM midazolam to IV lorazepam in a large community trial of status epilepticus suggests that emergency personnel will soon incorporate autoinjectors into routine clinical practice and that these field products will thus become integrated into clinical medicine.


InternalMed_Harrison

InternalMed_Harrison. Peripheral neuropathy and the so-called intermediate syndrome, which are prominent long-term effects of insecticide poisoning, are not described in nerve agent survivors. Recent research has explored approaches leading to transient “immunity” and eventually to biologic products that will be protective against lethal nerve agents yet be devoid of side effects. A novel approach is to use enzymes to scavenge these highly toxic nerve agents before they attack their intended targets. The accumulated work has shown that if a scavenger is present at the time of nerve agent exposure, toxicant levels are rapidly reduced. This reduction is so rapid and profound that the need to administer a host of pharmacologically active drugs as antidotes is, according to laboratory studies, eliminated.


InternalMed_Harrison

InternalMed_Harrison. Cyanide (CN–) has become an agent of particular interest in terrorist scenarios because of its applicability to indoor targets. In recent years, for example, attacks with this agent have targeted the water supply of the U.S. Embassy in Italy. The 1993 World Trade Center bombing in New York may have been intended as a cyanide release as well.


InternalMed_Harrison

InternalMed_Harrison. Hydrogen cyanide and cyanogen chloride, the major forms of cyanide, are either true gases or liquids very close to their boiling points at standard room temperature. Hydrogen cyanide gas is lighter than air and does not remain concentrated outdoors for long; thus it is a poor military weapon but an effective weapon in an indoor space such as a train station or a sports arena. Cyanide is also water-soluble and poses a threat to the food and water supply from either accidents or malign intent. It is well absorbed from the gastrointestinal tract, through the skin, or via inhalation—the preferred terrorist route. Cyanide smells like bitter almonds, but 50% of persons lack the ability to smell it.


InternalMed_Harrison

InternalMed_Harrison. Unique among CWAs, cyanide is a normal constituent of the environment and actually is a required cofactor in many compounds important in metabolism, including vitamin B12. Cyanide is present in many plants, including tobacco; therefore, smokers, for instance, chronically carry cyanide at three times the usual level. Humans have evolved a detoxification mechanism for cyanide. Cyanide poisoning results if a large challenge of CN– overwhelms this mechanism, while treatment of cyanide poisoning exploits it.


InternalMed_Harrison

InternalMed_Harrison. Mechanism Cyanide directly poisons the last step in the mitochondrial electron transport chain, cytochrome a3, which results in a shutdown of cellular energy production. Tissues are poisoned in direct proportion to their metabolic rate, with the carotid baroreceptors and the brain—the most metabolically active tissues in the body—affected fastest and most severely. This poisoning results from cyanide’s high affinity for certain metals, notably Co and Fe+++. Cytochrome a3 contains Fe+++, to which CN− binds. Cyanide-poisoned tissues cannot extract oxygen from the blood; even though pulmonary oxygen exchange and cardiac function are preserved, cells die of hypoxia—i.e., 262e-7 of histotoxic rather than cardiopulmonary cause.


InternalMed_Harrison

InternalMed_Harrison. Clinical Features Hyperpnea occurs ~15 s after inhalation of a high concentration of cyanide and is followed within 15–30 s by the onset of convulsions and electrical status epilepticus. Respiratory activity stops 2–3 min later, and cardiac activity ceases several minutes after that. Exposure, especially via inhalation, to a large challenge of CN– can cause death in as little as 8 min. Smaller challenges will cause symptom spread over a longer period; very low doses may produce no effects at all because of the body’s ability to detoxify small amounts. Cyanogen chloride additionally produces mucous membrane irritation. Many but not all patients have a cherry-red appearance because their venous blood remains oxygenated.


InternalMed_Harrison

InternalMed_Harrison. Differential Diagnosis In a mass casualty incident caused by a chemical agent, the primary differential diagnosis of cyanide poisoning will be nerve agent poisoning. Cyanide-poisoned patients lack the prominent cholinergic signs seen in nerve agent poisoning, such as miosis and increased secretions. The cherry-red appearance often seen in cyanide poisoning is never seen in nerve agent poisoning. Cyanosis, confusingly, is not a prominent early sign in cyanide poisoning. Treatment of cyanide poisoning may require simply evacuation of the patient from the source of contamination. Decontamination of a true gas, other than clothing removal to avoid gas trapped in clothing air cells, is probably not a major concern. Oxygen, supplied via mask, nasal cannula, or endotracheal tube, has been shown to benefit patients, although the benefit is not explained by the known mechanism of action of CN–.


InternalMed_Harrison

InternalMed_Harrison. Oxygen, supplied via mask, nasal cannula, or endotracheal tube, has been shown to benefit patients, although the benefit is not explained by the known mechanism of action of CN–. Cyanide antidotes exploit the body’s innate detoxification mechanism, the hepatic enzyme rhodanese. They also exploit cyanide’s affinity for certain metal ions. Antidote recommendations are summarized in Table 262e-4.


InternalMed_Harrison

InternalMed_Harrison. The classic two-step cyanide antidote kit includes two IV solutions: sodium nitrite and sodium thiosulfate. It may also include amyl nitrite perles for inhalation. Nitrites are methemoglobin formers; when administered to a patient, nitrite converts a fraction of the body’s hemoglobin into methemoglobin by converting heme iron from Fe++ to Fe+++. CN– has a greater affinity for methemoglobin Fe+++ than for cytochrome a3. As a result, administration of nitrite creates a “sink” of cyanmethemoglobin; formation of methemoglobin pulls CN– off mitochondrial cytochrome a3, allowing cellular respiration to resume. Recent work suggests that nitrites may also work via a second mechanism involving the neurotransmitter nitrous oxide; if so, this mechanism may explain why cyanide-poisoned patients improve after nitrite administration faster than is explained by the known rate of methemoglobin formation.


InternalMed_Harrison

InternalMed_Harrison. Nitrite administration may save the patient acutely but creates an unstable pool of cyanmethemoglobin, the elimination of which requires a sulfur donor: sodium thiosulfate. Sodium thiosulfate donates sulfur to the reaction catalyzed by rhodanese; cyanide is converted to thiocyanate, a compound the body eliminates harmlessly in urine. Sodium thiosulfate alone may be administered to fire victims, whose oxygen-carrying capacity is already reduced and in whom the administration of nitrite may form so much methemoglobin as to render the blood unable to carry oxygen at all.


InternalMed_Harrison

InternalMed_Harrison. Hydroxocobalamin, or vitamin B12a, has recently been approved for use as an alternative cyanide antidote. Unlike sodium nitrite and sodium thiosulfate, it must be reconstituted at the scene. Hydroxocobalamin lacks the propensity of nitrites for hypotension, but many cases in which it has been beneficial have also required the use of sodium thiosulfate. Hydroxocobalamin causes an orange discoloration of the skin that is of no functional significance.


InternalMed_Harrison

InternalMed_Harrison. All of these antidotes require the placement of an IV line. Amyl nitrite is currently the only non-intravenous cyanide antidote available and has never been formally approved by the FDA. Amyl nitrite aVictims whose clothing or skin is contaminated with hydrogen cyanide liquid or solution can secondarily contaminate response personnel by direct contact or through off-gassing vapors. Dermal contact with cyanide-contaminated victims or with the gastric contents of victims who may have ingested cyanide-containing materials should be avoided. Victims exposed only to hydrogen cyanide gas do not pose contamination risks to rescuers. If the patient is a victim of recent smoke inhalation (and thus may have high carboxyhemoglobin levels), only sodium thiosulfate should be administered. bIf sodium nitrite is unavailable, administer amyl nitrite by inhalation from crushable ampoules. cAvailable in cyanide antidote kits, which can be purchased from various manufacturers.


InternalMed_Harrison

InternalMed_Harrison. Source: State of New York, Department of Health. perles in cyanide antidote kits can be crushed and inhaled by a Prognosis Cyanide casualties tend to recover much more quickly than patient who is still breathing. Amyl nitrite can also be given through casualties exposed to other chemical agents. Many patients with indusa respirator. trial cases have returned to work within the same shift. If a patient None of the cyanide antidotes is specifically approved for pedi-receives a large challenge and dies, death usually takes place within atric use. minutes of exposure.


InternalMed_Harrison

InternalMed_Harrison. None of the cyanide antidotes is specifically approved for pedi-receives a large challenge and dies, death usually takes place within atric use. minutes of exposure. radiation terrorism Christine E. Hill-Kayser, Eli Glatstein, Zelig A. Tochner The threat of a terror attack employing nuclear or radiation-related devices is unequivocal in the twenty-first century. Such an attack would certainly have the potential to cause unique and devastating 263e medical and psychological effects that would require prompt action by members of the medical community. This chapter outlines the most probable scenarios for an attack involving radiation as well as the medical principles for handling such threats.


InternalMed_Harrison

InternalMed_Harrison. Potential terrorist incidents with radiologic consequences may be considered in two major categories. The first is the use of radiologic dispersal devices. Such devices disseminate radioactive material purposefully and without nuclear detonation. An attack with a goal of radiologic dispersal could take place through use of conventional explosives with incorporated radionuclides (“dirty bombs”), one or more fixed nuclear facilities, or nuclear-powered surface vessels or submarines. Other means could include detonation of malfunctioning nuclear weapons with no nuclear yield (nuclear “duds”) and installation of radionuclides in food or water. The second and less probable scenario is the actual use of nuclear weapons. Each scenario poses its own specific medical threats, including “conventional” blast or thermal injury, introduction to a radiation field, and exposure to either external or internal contamination from a radioactive explosion.


InternalMed_Harrison

InternalMed_Harrison. Atomic isotopes with uneven numbers of protons and/or neutrons are typically unstable; such isotopes discharge particles or energy to matter as they move to stability, a process that is defined as radiation. Mass-containing particles, including alpha particles, electrons, and/ or neutrons, may be transferred during this process (alpha radiation, beta radiation, and neutron radiation, respectively); alternatively, the transfer may consist only of energy in the form of a gamma ray. Alpha (α) radiation consists of heavy, positively charged particles, each of which contains two protons and two neutrons. Alpha particles usually are emitted from isotopes that have an atomic number of ≥82, such as uranium and plutonium. Due to their large size, alpha particles have limited penetrating power. Fine obstacles such as cloth and human skin usually can stop these particles from penetrating into the body. Thus they represent a small risk from external exposure. If they are somehow internalized,


InternalMed_Harrison

InternalMed_Harrison. Fine obstacles such as cloth and human skin usually can stop these particles from penetrating into the body. Thus they represent a small risk from external exposure. If they are somehow internalized, however, alpha particles can cause significant damage to human cells that are in their immediate proximity.


InternalMed_Harrison

InternalMed_Harrison. Beta (β) radiation consists of electrons, which are small, light, negatively charged particles (about 1/2000 the mass of a neutron or proton). Electrons can travel only a short, finite distance in tissue, with the precise distance depending on their energy. Exposure to beta particles is common in many radiation accidents. Radioactive iodine released in nuclear plant accidents is the best-known form of beta radiation. Plastic layers and clothing can stop most beta particles, and their penetration is generally measured at a few millimeters. A large quantum of energy delivered via beta particles to the basal stratum of the skin can cause a burn that is similar to a thermal burn and is treated as such.


InternalMed_Harrison

InternalMed_Harrison. Gamma (γ) rays and x-rays (both photons) are similar. Gamma rays are uncharged electromagnetic radiation discharged from a nucleus as a wave of energy. X-rays are the product of abrupt mechanical deceleration of electrons striking a heavy target such as tungsten. Although they are generated by different sources, gamma rays and x-rays have similar properties; that is, they have no charge and no mass, just energy. They travel easily through matter and thus are sometimes referred to as penetrating radiation. Gamma rays and x-rays are the principal types of radiation that cause dangerous total-body exposure. Gamma rays and x-rays of the same energy will cause the same biologic effects, and these effects will require the same treatment.


InternalMed_Harrison

InternalMed_Harrison. Neutron (η) particles are heavy and uncharged and are often emitted during nuclear detonation. They possess a wide energy range; their ability to penetrate tissues is variable, depending on their energy. They 263e-1 are less likely to be present in most scenarios of radiation bioterrorism than are the other forms of radiation discussed above.


InternalMed_Harrison

InternalMed_Harrison. Radiation interactions with atoms can result in ionization and the formation of free radicals that damage tissue by disrupting chemical bonds and molecular structures in the cell, including DNA. Protons, electrons, and gamma rays cause cellular damage through ionization of DNA. Depending on energy and other factors, some fraction of this damage will be caused by a direct strike to the DNA molecule (direct ionization). The remainder will be caused by ionization of water molecules to create free radicals that, in turn, damage DNA (indirect ionization). Ionization of DNA resulting from neutrons is exclusively indirect. Radiation damage can lead to cell death; the cells that recover may be mutated and at higher risk for subsequent cancer evolution. Cell sensitivity increases as the replication rate increases and cell differentiation decreases.


InternalMed_Harrison

InternalMed_Harrison. The commonly used units of radiation are the rad and the gray (Gy). The rad (radiation absorbed dose) is energy deposited within living matter and is equal to 100 ergs/g of tissue. The traditional rad has been replaced by the Système Internationale (SI) unit of the gray; 100 rad = 1 Gy, while 1 Gy is equal to 1 joule/kg. The sievert (Sv) is the SI unit that refers to the equivalent radiation dose in biologic tissues. While 1 Sv is equal to 1 joule/kg, Sv and Gy are not interchangeable units: Sv refers to the biologic effect of the radiation, while Gy refers to the physical energy being transferred.


InternalMed_Harrison

InternalMed_Harrison. Whole-body exposure occurs when radiation energy is deposited throughout the entire body. During a whole-body exposure, alpha and beta particles have limited penetration and do not cause significant noncutaneous injury unless emission results from an internalized source. Whole-body exposure from gamma rays, x-rays, or neutrons, which can penetrate through the body (the degree of which depends on their energy), can result in damage to multiple tissues and organs. The damage is proportional to the radiation exposure of the specific organ or tissue.


InternalMed_Harrison

InternalMed_Harrison. External contamination is a result of fallout of radioactive particles that land on the body surface, clothing, skin, and hair. This is the dominant element to consider in the mass-casualty situation resulting from a radioactive terrorist strike. The common contaminants primarily emit alpha and beta radiation. Alpha particles do not penetrate beyond the skin and thus have minimal systemic effects. Beta emitters can cause significant cutaneous burns and scarring. Due to their ability to penetrate tissue, gamma emitters can cause not only local damage but also whole-body radiation exposures and injury. Medical treatment primarily entails decontamination of the body, including wounds and burns, to prevent internalization of radioactive contaminants. Removal of contaminated clothing reduces levels of contamination significantly and is a first step in the decontamination process. Generally, patients do not constitute a significant radiation hazard to health care providers, and lifesaving


InternalMed_Harrison

InternalMed_Harrison. levels of contamination significantly and is a first step in the decontamination process. Generally, patients do not constitute a significant radiation hazard to health care providers, and lifesaving treatment should not be delayed for fear of secondary contamination of the medical team. Although risk is relatively low, any damage to health care personnel will depend directly on the duration of exposure and will be inversely proportional to the square of the distance from any radioactive source. Gowns that can be easily removed offer protection.


InternalMed_Harrison

InternalMed_Harrison. Internal contamination occurs when radioactive material is inhaled or ingested or enters the body through open wounds or burns or via skin absorption. In principle, any externally contaminated casualty should be evaluated for internal contamination. Because of their chemical properties, some isotopes may exert toxic effects on specific target organs in addition to causing radiologic injury. The respiratory system is the main portal of entry for internal contamination, and the lung is the organ at greatest risk. Aerosol particles <5 μm in diameter can reach the alveoli, whereas larger particles will remain in the proximal airways. The tiny particles can be absorbed by the lymphatic system or the bloodstream. Bronchial lavage is often a helpful treatment in this situation. Radioactive material entering the gastrointestinal tract is absorbed according to its chemical structure and solubility.


InternalMed_Harrison

InternalMed_Harrison. The insoluble radionuclides may affect the lower gastrointestinal tract. Intact skin is normally an effective barrier to most radionuclides. Penetration through the skin usually takes place when wounds or burns have compromised the skin barrier. Therefore, any skin erosion should be cleaned and decontaminated promptly. Absorbed radioactive materials travel throughout the body. Liver, kidney, adipose tissue, thyroid, and bone and bone marrow tend to bind and retain radioactive material more than other tissues do. Medical treatment thus includes the prevention of absorption, the reduction of incorporation, and the enhancement of elimination (see below).


InternalMed_Harrison

InternalMed_Harrison. Localized exposure refers to close contact between a highly radioactive source and a part of the body, with consequent discrete damage to the skin and deeper tissues that resembles a thermal burn. Later signs include epilation, erythema, moist desquamation, ulceration, blistering, and necrosis in proportion to exposure. Alopecia, transient or permanent, is dose related and starts at cutaneous doses of >3 Gy. Overt tissue damage can take weeks or even months to develop; the healing process can also be very slow, lasting for months. Long-term cutaneous changes, including keratosis, fibrosis, and telangiectasis, may appear years after the exposure. Treatment is based on analgesia and infection prophylaxis. Nevertheless, severe burns often require grafting or even amputation. Long-term radiation effects are characterized by cell loss, cell death, and tissue atrophy.


InternalMed_Harrison

InternalMed_Harrison. Radiologic dispersal incidents are generally of two types, resulting from small, usually localized sources or from wide dispersals over large areas. The methods that could be utilized to formulate an attack using dispersal of radiation are incredibly diverse. Radioactive materials can take the form of solid state, aerosol, gas, or liquid. They can be put into food or water, released from vehicles, or spread by explosion. The principal route of exposure is usually direct contact between the victim’s skin and the radioactive particles, although internal contamination can occur if the material is inhaled or ingested. The radiation field is also a potential source of whole-body exposure. The psychosocial effects that accompany such an event are significant and are beyond the scope of this chapter. A list of radioactive materials, including information on their major properties and medical treatment, is given in Table 263e-1.


InternalMed_Harrison

InternalMed_Harrison. In a localized event, the amount and spread of the radioactive materials are usually limited and can be treated like a spill of hazardous material. Protective clothing prevents or minimizes the contamination of emergency responders. The use of explosives coupled with a large amount of radioactive materials can result in wide dispersion of radiation, which is of far greater concern. Other potential sources of radiation are nuclear reactors, spent nuclear fuel, and transport vehicles. Less probable but still possible is the use of a large source of penetrating radiation without explosion. It is expected that most exposures would be low-level and that the principal health and psychosocial effects would be similar to those in the former scenario but on a larger scale. Whenever an explosion is involved, conventional lifesaving treatment should be given first priority. Only then should decontamination and specific treatment be given for the radiation exposure.


InternalMed_Harrison

InternalMed_Harrison. Silent exposure represents a scenario in which a powerful radiologic source, often called a radiologic exposure device, could be hidden in a crowded place and spread radioactive materials without being recognized or reported. Recognition of the event and the source of exposure might take a long time. A major clue in this situation is the appearance of unusual clinical manifestations in many individuals; such manifestations are often nonspecific and include symptoms of acute radiation sickness (see “Acute Radiation Syndrome,” below) such as headache, fatigue, malaise, and opportunistic infections. Gastrointestinal phenomena such as diarrhea, nausea, vomiting, and anorexia may occur. Dermatologic symptoms (e.g., burns, ulceration, and epilation) and hematopoietic manifestations (e.g., bleeding tendency, thrombocytopenia, purpura, lymphopenia, and neutropenia) are also possible and are dose-related. Careful epidemiologic studies may be necessary to identify the source of such exposure.


InternalMed_Harrison

InternalMed_Harrison. The most likely scenario in a nuclear terror attack is the detonation of a single low-yield device. The estimated yield of such a device is anywhere between 0.01 and 10 kilotons of 2,4,6-trinitrotoluene (TNT). The expected effects of such an explosion are a combination of several components: ground shock, air blast, thermal radiation, initial nuclear radiation, crater formation, and radioactive fallout.


InternalMed_Harrison

InternalMed_Harrison. A nuclear detonation, like a conventional explosion, produces a shock wave that can further damage structures and cause many casualties. In addition, the detonation can produce an extremely hot fireball that can ignite materials and cause severe burns. The detonation releases an intense pulse of ionizing radiation consisting mainly of gamma rays and neutrons. The radiation produced in the first minute is termed initial radiation, whereas the ongoing radiation due to fallout is termed residual radiation. Both types of radiation can cause acute radiation sickness, and winds can carry fallout and contaminate large areas. The LD50/30 (i.e., the dose that causes a 50% mortality rate at 30 days) is ~4 Gy for whole-body exposure without medical support; with medical support, the LD ranges between 8 and 10 Gy. On top of its immediate effects, a massive blast forms a crater in the soil and usually produces ground shock that compounds the physical damage and the number of casualties. Inhalation


InternalMed_Harrison

InternalMed_Harrison. 8 and 10 Gy. On top of its immediate effects, a massive blast forms a crater in the soil and usually produces ground shock that compounds the physical damage and the number of casualties. Inhalation of large amounts of radioactive dust causes pneumonitis that can lead to pulmonary fibrosis. Use of a mask covering the mouth and nose can result in effective prevention. The intense flash of infrared and visible light can cause either temporary or permanent blindness. Cataracts can develop months to years later among survivors.


InternalMed_Harrison

InternalMed_Harrison. Acute radiation syndrome (ARS) refers to multisystem symptomatology resulting hours to weeks after radiation exposure. As discussed earlier, cell sensitivity to radiation damage increases as the cell replication rate increases and as cell differentiation decreases. Bone marrow and mucosal surfaces of the gastrointestinal tract, which have vast mitotic activity, are significantly more sensitive to radiation than are slowly dividing tissues such as bones and muscles. After exposure of all or most of the human body to ionizing radiation, ARS can develop. The clinical manifestations of ARS reflect the dose and type of radiation as well as the parts of the body exposed.


InternalMed_Harrison

InternalMed_Harrison. ARS manifests as three major groups of signs and symptoms: hematopoietic, gastrointestinal, and neurovascular. In addition, ARS exists in four stages: prodrome, latent phase, clinical illness, and recovery or death. The higher the radiation doses, the shorter and more severe each stage. The prodrome appears within minutes to 4 days after exposure, lasts from a few hours to a few days, and can include nausea, vomiting, anorexia, and diarrhea. At the end of the prodrome, ARS progresses to the latent phase. Minimal or no symptoms are present during the latent phase, which commonly lasts up to 2.5 weeks but can last up to 6 weeks. The duration depends on the radiation dose, the prior health of the patient, and coexisting illness or injury. After the latent phase, the exposed person manifests illness that may end in recovery or lead to death.


InternalMed_Harrison

InternalMed_Harrison. With exposure to low doses of <1 Gy, ARS is generally mild. At this dose, symptoms can be minimal or nonexistent, even if the entire body is exposed to penetrating radiation. The main feature of the clinical picture is transient depression of bone marrow (lymphopenia) that lasts up to 2–3 weeks and then improves. ARS is significantly more acute and severe with exposure to very high radiation doses (>30 Gy). At these doses, the prodrome appears in minutes and is followed by 5–6 hours of latency before cardiovascular collapse occurs secondary to irreversible damage to the microcirculation.


InternalMed_Harrison

InternalMed_Harrison. Exposure to intermediate radiation doses may result in variable ARS courses. The type and dose of radiation and the part of the body exposed determine not only the timing of the different stages of ARS but also the dominant clinical picture. At low radiation doses of 0.7–4 Gy, hematopoietic depression due to bone marrow suppression is the main constituent of illness. The patient may develop infection and bleeding secondary to low leukocyte and platelet counts, respectively. The bone marrow eventually recovers in almost all patients if Mode of Accumulation Isotope Name Symbol Common Usage t1/2 Biologic (days) Exposure Type Contamination in Body Treatment Manganese Mn-56 Reactors, research β, γ; 2.6 h; 5.7 External, internal N/A Liver N/A laboratories Cobalt Co-60 Medical radio-β, γ; 5.26 y; 9.5 External, internal Lungs Liver Gastric lavage, therapy devices, Strontium Sr-90 Fission product of β; 28 y; 18,000 Internal GI tract Bones (similar to Strontium, calcium, uranium


InternalMed_Harrison

InternalMed_Harrison. Strontium Sr-90 Fission product of β; 28 y; 18,000 Internal GI tract Bones (similar to Strontium, calcium, uranium Molybdenum Mo-99 Hospitals: scans β, γ; 66.7 h; 3 External, internal N/A Kidneys N/A Technetium Tc-99m Hospitals: scans β, γ; 6.049 h; 1 External, internal IV administration Kidneys, total Potassium per-body chlorate to reduce thyroid dose Cesium Cs-137 Medical radiother-β, γ; 30 y; 70 External, internal Lungs, GI tract, Renal excretion Ion-exchange resapy devices ins, Prussian blue potassium Gadolinium Gd-153 Hospitals β, γ; 242 d; 1000 External, internal N/A N/A N/A Iridium Ir-192 Commercial β, γ; 74 d; 50 External, internal N/A Spleen N/A radiography Radium Ra-226 Instrument illumina-α, β, γ; 1602 y; External, internal GI tract Bones MgSO4 lavage, tion, industrial appli-16,400 ammonium cations, old medical chloride, calcium equipment, former


InternalMed_Harrison

InternalMed_Harrison. Radium Ra-226 Instrument illumina-α, β, γ; 1602 y; External, internal GI tract Bones MgSO4 lavage, tion, industrial appli-16,400 ammonium cations, old medical chloride, calcium equipment, former Tritium H-3 Luminescent β; 12.5 y; 12 Internal Inhalation, GI Total body Dilution with gunsights, muzzle- tract, wounds controlled water velocity detectors, intake, diuretics nuclear weapons Iodine-131 Reactors, thyroid β, γ; 8.1 d; 138 Internal Inhalation, GI Thyroid Potassium/sodium ablators tract, wounds iodide, propylthiouracil, methimazole Uranium U-235 Depleted uranium, α, (α, β, γ); 7.1 × Internal GI tract Kidneys, bones NaHCO3, chelation natural uranium, 108 y; 15 with EDTA fuel rods, weapons-grade material Plutonium Pu-239 Produced from α; 2.2 × 104 y; 73,000 Internal Limited lung Lungs, bones, Chelation with uranium in reactors, absorption, high bone marrow, DTPA or EDTA nuclear weapons retention liver, gonads


InternalMed_Harrison

InternalMed_Harrison. Americium Am-241 Smoke detectors, α; 458 y; 73,000 Internal Inhalation, skin Lungs, liver, Chelation with nuclear weapons wounds bones, bone DTPA or EDTA (in form of fallout) Polonium Po-210 Calibration source α; 138.4 d; 60 Internal Inhalation, Spleen, kidneys Lavage, wounds Thorium Th-232 Calibration source α; 1.41 × 1010 y; Internal N/A N/A N/A 73,000 Phosphorus P-32 Research labo-β; 14.3 d; 1155 Internal Inhalation, GI Bones, bone mar-Lavage, aluminum ratories, medical tract, wounds row, rapidly repli-hydroxide, phosfacilities Abbreviations: DTPA, diethylenetriamine pentaacetic acid; EDTA, ethylenediamine tetraacetic acid; GI, gastrointestinal; h, hours; N/A, not available; y, years.


InternalMed_Harrison

InternalMed_Harrison. they are supported with transfusions and fluids; antibiotics are often simply do not recover. In addition to the gastrointestinal syndrome needed in addition. Patients with isolated hematopoietic manifesta-associated with very high-level exposures, patients may develop a neutions of ARS can almost always survive with proper supportive care. rovascular syndrome that includes vascular collapse, seizures, and con-After exposure to 6–8 Gy, a significantly more complicated clinical fusion; death occurs within a few days. The neurovascular syndrome picture may ensue. At these doses, the bone marrow does not always dominates after whole-body exposure to >20 Gy. In this variant, the recover and death may occur as a result. A gastrointestinal syndrome prodrome and latent phase both last only a few hours. may accompany the hematopoietic manifestations and further worsen the patient’s condition. Gastrointestinal injury due to compromise of the absorptive layer of the gut alters absorption of


InternalMed_Harrison

InternalMed_Harrison. few hours. may accompany the hematopoietic manifestations and further worsen the patient’s condition. Gastrointestinal injury due to compromise of the absorptive layer of the gut alters absorption of fluids, electrolytes, and nutrients. Such injury can lead to vomiting, diarrhea, gastrointestinal bleeding, sepsis, and electrolyte and fluid imbalance. Generally, The treatment of ARS is focused on maintaining homeostasis, thus these symptoms are also accompanied by a severe hematopoietic giving damaged organs a chance to recover. Aggressive support syndrome, with only a slim chance of bone marrow recovery. These is provided for every damaged system. Treatment for the hemafactors in constellation often lead to death. Whole-body exposure to topoietic system targets mainly neutropenia and infection, with >9–10 Gy is almost always fatal. Crucial elements of the bone marrow measures that may include transfusion of leukoreduced irradiated blood as needed and administration of hematopoietic


InternalMed_Harrison

InternalMed_Harrison. with >9–10 Gy is almost always fatal. Crucial elements of the bone marrow measures that may include transfusion of leukoreduced irradiated blood as needed and administration of hematopoietic growth factors. The value of bone marrow transplantation in this situation is questionable. None of the bone marrow transplantations that were performed among the victims of the nuclear reactor accident in Chernobyl proved successful. Bone marrow transplantation could be considered for casualties with whole-body exposure to 6–10 Gy when the hematopoietic syndrome is dominant and the bone marrow is less likely to recover with time, although the efficacy of this treatment has not been proved. Another major component of the treatment of ARS is the provision of partial or total parenteral nutrition to bypass the damaged gastrointestinal system. For blast and thermal injuries, standard therapy for trauma is given. Psychological support is essential in many cases. A treatment algorithm is outlined in


InternalMed_Harrison

InternalMed_Harrison. the damaged gastrointestinal system. For blast and thermal injuries, standard therapy for trauma is given. Psychological support is essential in many cases. A treatment algorithm is outlined in Fig. 263e-1.


InternalMed_Harrison

InternalMed_Harrison. Victims of radiation bioterrorism can suffer from conventional thermal or blast injuries, exposure to radiation, and contamination by radioactive materials. Many will have combinations of the above, which can cause higher morbidity and mortality rates than each exposure would alone. The number of casualties will be a major factor in determining the response of the medical system to an act of radiation bioterrorism. If only a few persons are affected, no significant changes and adaptations of the system are needed to treat the victims. If a terror attack results in dozens of casualties or more, however, an organized disaster plan at the local and state levels must be invoked to deal with the crisis properly. Useful U.S. planning documents that include many universal planning concepts can be found at http://www.remm .nlm.gov/remm_Preplanning.htm. Ideally, medical personnel will have had a prior assignment and training and be prepared to function in a scenario with which they are


InternalMed_Harrison

InternalMed_Harrison. can be found at http://www.remm .nlm.gov/remm_Preplanning.htm. Ideally, medical personnel will have had a prior assignment and training and be prepared to function in a scenario with which they are familiar. Stockpiles of specific equipment and medications should be obtained ahead of time and stored safely (see the Centers for Disease Control and Prevention Web site at http:// www.bt.cdc.gov/stockpile/). One of the goals of terrorist attackers is to overwhelm medical facilities and minimize the salvage of casualties. Initial management consists of primary triage and transportation of the wounded to medical facilities for treatment. The rationale behind triage is to sort patients into classes according to the severity of injury for the purpose of expediting clinical care and maximizing the use of the available clinical services and facilities. Triage requires determination of the level of emergency care needed. The higher the number and broader the range of casualties, the more complex


InternalMed_Harrison

InternalMed_Harrison. use of the available clinical services and facilities. Triage requires determination of the level of emergency care needed. The higher the number and broader the range of casualties, the more complex and difficult triage becomes. The mildly wounded and victims of contamination only can be sent to evacuation, registration (with disaster response teams), and decontamination/treatment centers. Figure 263e-2 illustrates an evacuation scheme after a radiologic event causing multiple casualties. The goal of such an algorithm is to treat all possible victims of exposure and minor injury outside of the hospital setting. This approach prevents hospitals from being directly overwhelmed and enhances treatment for persons who are severely wounded. Emergency treatment should be administered initially for conventional injuries such as wounds, trauma, and thermal or chemical burns. Individuals with such injuries should be stabilized, if possible, and immediately transported to a medical facility.


InternalMed_Harrison

InternalMed_Harrison. for conventional injuries such as wounds, trauma, and thermal or chemical burns. Individuals with such injuries should be stabilized, if possible, and immediately transported to a medical facility. Removing clothing and wrapping the victim in clean blankets or nylon sheets reduce both the exposure of the patient and the contamination risk to the staff. Less severely injured victims should undergo preliminary decontamination before or during evacuation to a hospital.


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InternalMed_Harrison. FIGURE 263e-1 General guidelines for treatment of radiation casualties. CBC, complete blood count. One must remember that radionuclide contamination of the skin commonly is not an acute life-threatening situation for the patient or for the personnel who care for the patient. Only powerful gamma emitters are likely to cause real damage from contamination. It is important to emphasize that exposure to a radiation field alone does not necessarily create any contamination. The exposed person, if not contaminated, is not radioactive and does not directly emit any radiation.


InternalMed_Harrison

InternalMed_Harrison. To protect the staff, protective gear (gowns, gloves, masks, and caps) should be used. Protective masks with filters and chemically protective overgarments provide excellent protection from contamination. Waterproof shoe covers are also important. Remaining in the contaminated area and dealing with lifesaving procedures should take place according to the “ALARA” principle: as low as reasonably achievable. It is better to send many people to do the job for short exposure times than to send a few people for longer periods.