key: cord-021917-z9wpjr0d authors: Stephens, R. Scott; Wiener, Charles M.; Rubinson, Lewis title: Bioterrorism and the Intensive Care Unit date: 2009-05-15 journal: Clinical Critical Care Medicine DOI: 10.1016/b978-0-323-02844-8.50069-x sha: doc_id: 21917 cord_uid: z9wpjr0d nan • No country is fully prepared to avert illness when large portions of the population are covertly exposed to a serious bioweapons agent; a moderate or large-scale intentional release of a serious pathogen will likely cause lifethreatening illness in a large portion of exposed people. • Intensivists will play a key role in the medical response to a bioterrorism event due to the clinical conditions caused by serious bioweapons pathogens, such as severe sepsis, septic shock, hypoxemic respiratory failure, and ventilatory failure. • Compared with conventional disasters, bioterrorist attacks may not be readily recognized; thus, accurate clinical diagnoses and management on the basis of clinical suspicion are critical not only for appropriate care of individual patients but also for instituting an epidemiological investigation. • Victims of a bioterrorist attack who require intensive care unit-level care may be more contagious than those who are less sick. • Health care workers, accustomed to putting the welfare of patients ahead of their own in emergency situations, must be prepared for the proper use of personal protective equipment and trained in specific plans for the response to an infective or bioterrorism event. tive prophylactic countermeasures exist, a large portion of exposed people will likely develop life-threatening illness. Although intensivists working in developed countries generally have little experience treating specific illnesses caused by serious bioweapon pathogens, these diseases result in clinical conditions that commonly require treatment in intensive care units (ICUs) (e.g., severe sepsis and septic shock, hypoxemic respiratory failure, and ventilatory failure). Therefore, intensivists will play a key role in the medical response to a bioterrorism event. Usual critical care practices will likely require modification for any event resulting in more than a few critically ill victims, and critical care specialists should participate in planning for such situations. Capabilities to provide medical care, especially critical care, services to large numbers of contagious patients are very limited in most countries. Local hospitals will be expected to care for seriously ill victims of a bioterrorist (BT) attack, and the ability to care for large numbers of critically ill patients will likely be a major determinant of the medical impact of such events. Although the current risk of a large-scale BT event is uncertain, a number of groups throughout the world during past decades have deliberately exposed civilians to biologic agents. Fortunately, none of these prior events produced a large number of casualties because of the nonlethal nature of the pathogens released (e.g., Salmonella typhimurium in Oregon in 1984), the lack of technical expertise to successfully disseminate lethal pathogens (Aum Shinrikyo in Japan in 1994), or relatively limited exposure (the anthrax cases of 2001 in the United States). These limited exposures should not result in predictions of the numbers of potential casualties being reduced; rather, they simply reveal that an increasing number of groups throughout the world are willing to use biologic agents. The scope and effect of prior events could have been much greater if a contagious agent were used or if a lethal pathogen were widely disseminated. Despite the increased attention to biodefense, the risk of subsequent BT events may paradoxically be increasing. Rapid advancements in science are making synthetic and novel biologic agents more accessible and technologies to disseminate agents may no longer be restricted to only a few nations. To reduce the medical effect of a BT event, the major determinants of morbidity and mortality must be understood ( Fig. 64 .1). The number of deaths from a BT event depends in part on the lethality and infectivity of the released agent, in addition to how effectively and widespread it is delivered. Many biologic agents could theoretically be used as weapons, but some are An intentional release of a biologic agent within a civilian population, exposing hundreds or thousands of people to a serious pathogen, is increasingly recognized as a plausible terrorism event. Unlike most mass casualty incidents, releases of bioweapons agents may be covert, thus providing additional security and public health challenges to the medical response beyond the generic burden of scores of casualties. An optimal medical response to a bioweapon attack will require all or most of the following: early diagnosis, rapid case finding, large-scale distribution of countermeasures for postexposure prophylaxis or early treatment, immediate isolation of contagious victims, and enhanced capacity for providing medical care to seriously and critically ill victims. No country is fully prepared to avert illness when thousands of people are covertly exposed to a serious bioweapons agent. Hence, after a moderate or large-scale intentional release of a serious pathogen, even one for which effec-more lethal, more available, and more easily disseminated (Table 64 .1). The agent's characteristics alone will not, however, determine the overall impact of the BT event. Population characteristics (i.e., vulnerabilities) will also affect the impact of a BT event ( Fig. 64.1 ). Many agencies, professions, and community members must be involved in preparing and responding to a BT event. To optimally respond, hospital and public health cooperation, planning, and preparedness need to occur before the disaster. The integration and coordination of all these responders is very important, and detailed operational descriptions are beyond the scope of this chapter (see Box 64.1). Instead, this chapter is intended to be an introduction to the medical response issues for a BT event, specifically the critical care medical response. The Centers for Disease Control and Prevention (CDC) has compiled a list of potential agents of bioterrorism and divided these into three categories, A-C (see Table 64 .1). Category A agents are those believed to pose the greatest threat in terms of potential lethality, ability for widespread dissemination, ability for subsequent human-to-human transmission, and disruptive impact on the community and the public health system. These agents include Variola major (smallpox), Bacillus anthracis (anthrax), Yersinia pestis (plague), Clostridium botulinum (botulism), Francisella tularensis (tularemia), and viral hemorrhagic fevers (VHFs). This section provides a brief summary of the pathogenesis and diagnosis of each category A agent and also reviews current recommendations for treatment. Bacillus anthracis is acquired from contact with infected animals or animal products and causes three forms of disease: cutaneous, inhalational, and gastrointestinal. Approximately 2000 cases of cutaneous anthrax occur annually worldwide. Inhalational anthrax has not occurred naturally within the United States since 1976; any case must therefore be considered a possible sentinel case of a bioterrorist event. Gastrointestinal anthrax is uncommon in developed countries and is not discussed here. Cutaneous and inhalational anthrax are the forms expected following an aerosol release of spores, with the latter being the most lethal. A 1993 estimate by the U.S. Congressional Office of Technology Assessment predicted that an aerosolized release of 100 kg of "weaponized" anthrax over a populated city would cause 130,000 to 3 million deaths, similar to the mortality of a thermonuclear detonation. Inhalational anthrax results from spore particles 1 to 5 mm in diameter entering the alveolar spaces and being transported by macrophages to mediastinal lymph nodes. After an incubation period that ranges from 2 days to 7 www.acponline.org/bioterro www.upmc-biosecurity.org www.shea-online.org www.cdc.gov weeks (median of 4 days during the 2001 cases and up to 60 days after the release of spores in Sverdlovsk in 1979), germination occurs, with the vegetative bacilli producing two toxinslethal toxin and edema toxin. Initial symptoms of inhalational anthrax are nonspecific: fevers, chills, drenching sweats, nonproductive cough, dyspnea, nausea, vomiting, and fatigue. Hemorrhagic thoracic lymphadenitis and mediastinitis develop, and hemorrhagic pleural effusions with compressive atelactasis are common. Hemorrhagic meningitis may also occur. Patients may rapidly develop hemodynamic collapse, which typically has been refractory to treatment if it develops prior to antimicrobial administration. Diagnosis is predicated on a high index of suspicion. In the 2001 attacks, all patients with inhalational anthrax had an abnormal chest radiograph or thoracic computed tomography scan. Mediastinal widening due to lymphadenopathy and large bilateral pleural effusions were the most common features (Figs. 64.2 and 64.3). These findings in the setting of a previously healthy patient with the abrupt development of sepsis should raise suspicion of anthrax infection. Sputum Gram stain and culture are rarely positive. Blood cultures may yield a diagnosis but require hours to days to grow the organism. As in many infections, blood cultures lose diagnostic utility if obtained after antibiotic administration. Hemorrhagic meningitis was common (50% of patients) during the Sverdlovsk incident but was only confirmed in 1 of 11 patients in 2001. Patients suffering from inhalational anthrax are likely to require ICU care but do not require respiratory isolation. Antibiotics must be started as soon as possible without waiting for diagnostic confirmation. Treatment recommendations are summarized in Table 64 .2. For adults, combination antimicrobial therapy with intravenous ciprofloxacin and one or two other agents is recommended. Given the potential for meningitis, agents with good central nervous system penetration, such as rifampin, penicillin, or chloramphenicol, are recommended. Clindamycin has been administered for the theoretical benefit of reducing toxin production by the vegetative bacilli, although this has been done in too few instances to critically evaluate its effectiveness. A change to oral therapy is acceptable once the patient is stable. Therapy should continue for 60 days. The concomitant use of an anthrax vaccine in a modified dosing regimen (three doses within the first month) may be limited by availability. There is anecdotal evidence that drainage of pleural effusions carries some benefit. Whether the benefit is simply reduction of pleural fluid volume to improve oxygenation or actually helps to reduce toxin burden remains uncertain. During the 2001 outbreak, pleural drainage was accomplished via serial thoracenteses and tube thoracostomy. Optimal management may require tube thoracostomy due to the hemorrhagic nature of the fluid. Historically, inhalational anthrax had a mortality rate of approximately 90%. In the 2001 attacks, modern critical care interventions and use of multiple antimicrobial agents reduced mortality to 45%. Cutaneous anthrax results after the inoculation of skin with anthrax spores. These patients are unlikely to require ICU-level care if they are treated promptly. Two exceptions are the possibilities of airway compromise due to a neck lesion with resulting edema or postoperative management of a compartment syndrome. Local edema is the first feature of the condition, with the subsequent appearance of a macule or papule that rapidly ulcerates and develops into a painless black eschar ( Fig. 64.4 ). Systemic disease, including lymphadenopathy and lymphangitis, can follow. In the absence of antibiotic therapy, mortality has been reported to be as high as 20%; death is rare if adequate treatment is instituted. Between 1347 and the early 1350s, Y. pestis, the causative agent of plague, swept through Europe, eventually killing 20 to 30 million people-one-third of the population. Plague continues to occur naturally as an insect-borne illness, infecting approxi-Bioterrorism and the Intensive Care Unit mately 1700 people annually worldwide. In the United States, most cases occur in the rural states of the Southwest. Plague occurs in three forms: bubonic, septicemic, and pneumonic. Naturally occurring bubonic plague occurs when infected fleas bite a human and typically results in enlarged lymph nodes (bubo) and severe sepsis. A smaller percentage of patients may develop sepsis without bubo formation, and this is termed primary septicemic plague. Rarely, patients with bubonic or septicemic plague develop pneumonia, and this is termed secondary pneumonic plague. Patients with pneumonic plague can transmit disease through respiratory droplets. Those who contract pneumonic plague from person-to-person transmission are considered to have primary pneumonic plague and do not develop buboes. Both primary and secondary pneumonic plague are transmissible from person to person. The intentional release of aerosolized plague would result in primary pneumonic plague, a condition that is rare in naturally occurring plague. World Health Organization (WHO) estimates from 1970 predict that 50 kg of Y. pestis released over an urban area with 5 million inhabitants would cause pneumonic plague in 150,000, with 36,000 fatalities. Exposure is followed 1 to 6 days later by fever, dyspnea, and cough with bloody, watery, or purulent sputum. Gastrointestinal symptoms also occur. Cervical buboes are rare. Pneumonia progresses rapidly with unilateral or bilateral infiltrates or consolidation. Severe sepsis and septic shock develop with leukocytosis, multisystem organ failure, and disseminated intravascular coagulation. In the absence of therapy, irreversible shock and death occur 2 to 6 days after exposure. A bioterrorist attack with aerosolized plague would likely present as an outbreak of severe pneumonia and sepsis. Diagnosis depends on standard microbiologic studies, with confirmatory tests available only at select laboratories. Hence, unless epidemiologic clues alert health care workers that these patients do not have community-acquired pneumonia, the first group of patients will likely be cared for with the hospital's usual infection control policies for this condition. Unless droplet precautions are commonly used and strictly adhered to, a number of health care workers and addi- tional patients may be exposed to plague early in the outbreak. Therapeutic recommendations for pneumonic plague appear in Table 64 .2. Streptomycin and gentamicin are the first-line agents. Doxycycline, ciprofloxacin, and chloramphenicol are alternative choices. In the event of a mass casualty situation, or for postexposure prophylaxis, doxycycline or ciprofloxacin are the preferred agents for adults. Francisella tularensis is an extremely infectious pathogen; exposure to as few as 10 organisms can cause tularemia. Naturally occurring throughout North America, Europe, and Asia, tularemia is transmitted to humans via arthropod bites, contact with small mammals or contaminated food, and inhalation. Tularemia can take many clinical forms (Box 64.2). Disease manifestations depend on virulence, dose, and site of infection. The disease can begin in the skin, starting as a papule and resulting in an ulcer, and also involve regional lymph nodes (ulceroglandular). If contaminated water is ingested or contaminated droplets are inhaled, pharyngeal ulcers with cervical lymphadenitis can occur (oropharyngeal). The eyes can be the initial portal of entry leading to chemosis and lymphadenitis (oculoglandular). Sometimes, lymphadenitis may occur without ulceration (glandular). Inhalational tularemia may also occur naturally due to aerosolization of contaminated materials. This clinical scenario is the most likely after an intentional release, since aerosol release would be the most likely method of dissemination. WHO estimated that 50 kg of aerosolized F. tularensis in a city of 5 million would affect 250,000 people and cause 19,000 deaths. After an incubation period of 1 to 21 days, abrupt fever develops, accompanied by influenza-like symptoms (headache, chills, rigors, myalgias, coryza, and pharyngitis). Bronchiolitis, pleuropneumonitis, and hilar lymphadenitis would be expected, although inhalational tularemia can often present as a systemic disease without respiratory features. Progressive weakness, fever, chills, malaise, and anorexia rapidly incapacitate victims. Hematogenous spread can lead to pleuropneumonia, sepsis, and meningitis. Sepsis due to tularemia may manifest as severe sepsis or septic shock. Mortality without antibiotic therapy can be as high as 30% to 60% for pneumonic and septic tularemia. Current antimicrobial therapy results in a mortality rate of less than 2%. Rapid diagnostic testing for tularemia is not widely available. The constellation of atypical pneumonia, pleuritis, and hilar lymphadenopathy in association with the previously described symptoms should raise suspicion for tularemia. In the wake of a bioterrorist attack, until a number of patients present, initial diagnosis may be delayed. Most diagnoses are made serologically with a fourfold rise between acute and convalescent antibody titers. Antibodies are slow to develop: Titers will usually be negative at 1 week, positive at 2 weeks, and peak in 4 to 8 weeks. Laboratories need to be specifically notified if tularemia is suspected, both to improve diagnostic accuracy and to protect laboratory workers. Polymerase chain reaction (PCR) and antigen detection are rapid and available at reference laboratories in the United States through the Laboratory Response Network. If the reference lab is alerted when specimens are sent, an answer can be given within hours. Treatment recommendations for tularemia are presented in Table 64 .2. In the event of a contained casualty situation, streptomycin is the preferred drug, with gentamicin as a first-line alternate. Doxycycline, chloramphenicol, and ciprofloxacin are acceptable alternates. For mass casualties and for postexposure prophylaxis, oral doxycycline and ciprofloxacin are the recommended agents. Treatment with aminoglycosides or fluoroquinolones should last 10 days; tetracyclines and chloramphenicol require a 14-day course. Botulinum toxin, produced by the bacteria C. botulinum and a few other Clostridium species, is the most potent known neurotoxin. Botulinum toxin inactivates proteins necessary for the release of acetylcholine into the neuromuscular junction. The toxin could be disseminated as an aerosolized agent or as a food contaminant. Fewer than 200 naturally occurring cases of botulism occur annually in the United States. The use of botulinum toxin by terrorists would result in inhalational botulism or foodborne botulism, depending on the mode of dispersal. The neurologic signs are identical regardless of whether the toxin enters the body via the lungs or the digestive tract. Intestinal botulism may be preceded by gastrointestinal complaints. Symptoms appear approximately 12 to 72 hours after exposure. Botulism presents as an acute, symmetric, descending flaccid paralysis. There is no associated fever, and the bulbar musculature is always affected first. Presenting complaints and findings are related to cranial nerve palsies and include diplopia, dysarthria, dysphonia, and dysphagia. Hypotonia and generalized weakness ensue. Loss of airway protection may necessitate intubation, and respiratory muscle paralysis may require mechanical ventilation. The course is variable and may require months of mechanical ventilation. During small outbreaks with sufficient medical resources, serial measurement of vital capacity can help identify patients with respiratory muscle weakness. Elevation of PaCO 2 is a late finding, and positive pressure ventilation should be instituted prior to frank ventilatory failure. Notably, cognitive function is not affected; patients are completely awake and alert. A fever should raise suspicion of secondary infection or an alternative diagnosis. The diagnosis of botulinum intoxication is clinical and is classically described as the triad of symmetric cranial neuropathies with descending paralysis, clear sensorium, and lack of fever. Other diagnoses to consider are listed in Box 64.3. In developed nations, the occurrence of a number of temporally related cases of acute paralysis points to botulinum intoxication. The edrophonium or "Tensilon" test may be transiently positive in botulism, although it still may be helpful in distinguishing it from myasthenia gravis. CSF is generally normal in botulism. An electromyogram demonstrating an incremental Glandular Ulceroglandular Oculoglandular Oropharyngeal Pneumonic Septic response with repetitive stimulation at 50 Hz may suggest botulism when the conduction velocity and sensory nerves are normal. Culture of stool or gastric contents (for foodborne exposure) may yield Clostridium. Confirmation usually requires the mouse bioassay (mice are exposed to samples and those given polyvalent and specific antitoxin survive) but takes several days. Samples for the mouse bioassay must be collected prior to the patient's receiving antitoxin. A clinician who suspects botulism must immediately notify local public health authorities to aid with epidemiologic and diagnostic investigations. Most laboratory testing cannot be performed at hospitals. Laboratories must be notified of suspicion regarding botulism, since samples can be potentially harmful to laboratory personnel. Specific therapy consists of treatment with equine antitoxin (see Table 64 .2), which will not reverse extant paralysis but may prevent progression. It must therefore be administered as early as possible. In mass casualty situations, when the antitoxin supply may be limited, patients with weakness but not yet requiring mechanical ventilation may be the most appropriate for antitoxin therapy. Supportive therapy is essential, with a specific focus on mechanical ventilation and efforts to prevent complicating events (e.g., ventilator-associated pneumonia, venous thromboembolism, and decubitus ulcers). Nonventilated patients should be placed in the reverse Trendelenberg position at 20 to 25 degrees to optimize respiratory muscle function and minimize the possibility of aspiration Aminoglycosides and clindamycin should be avoided because of the potential for exacerbating the neuromuscular blockade. Mortality for foodborne botulism averages 6%. The last naturally occurring case of smallpox was identified in 1977, and the last case (due to a laboratory accident) was in 1978. Despite worldwide eradication, smallpox continues to concern biodefense experts due to uncertainties about available stocks of the virus. Despite the mortality rate of smallpox (30%) being considerably lower than those of other bioweapons agents, its potential for harm is still very high because those who survive may be severely deformed or blinded and no proven specific therapy exists once exposed people become symptomatic. In addition, with cessation of worldwide vaccination, entire populations and especially younger persons are susceptible to infection. The agent of smallpox, the Variola virus, belongs to the orthopoxvirus family. These viruses are quite stable in the environment, and hence an aerosol may be widely dispersed. Any case of smallpox would be an emergency and must be considered to be the result of a deliberate act. The typical incubation period for smallpox is 7 to 17 days, with an average of 12 to 14 days for the majority of patients. Initial symptoms include fever, rigors, backache, and headache. Vomiting and delirium may develop in this prodromal phase. Two or 3 days later, a nonspecific erythematous rash begins. The rash first appears in the mouth and throat, with red spots appearing on the buccal and pharyngeal surfaces. The usual dictum is that a person is not contagious until the rash begins. In most patients, the macular lesions become papular followed by vesicles. The lesions then become pustular, which umbilicate and are deeply seated in the dermis. The crops of lesions appear at the same time and are all at the same stage on the affected part of the body (Fig. 64 .5). They usually begin and are more concentrated on the face and limbs rather than the trunk. This is in contrast to primary varicella, in which lesions on any given part of the body are in different stages of development (some macular, some vesicular, and some crusting) and in which the rash begins on the trunk and moves outward. After 8 to 10 days, scabs form at the sites of the pustules. In survivors, these become depressed depigmented scars. Smallpox lesions also occur on the palms and soles, which rarely occurs with chickenpox. The previous description is seen in more than 90% of smallpox cases, but there are less common forms of smallpox as well. Hemorrhagic smallpox is uniformly fatal (it tends to affect pregnant women more frequently), and it typically has a shorter incubation period and does not lead to the classic rash. Instead, death follows development of a hemorrhagic rash. In the malignant or flat form of smallpox, the disease begins classically but does not progress to pustules. Instead, the rash is confluent and may desquamate. Also, Variola minor is a less severe form of smallpox. Suspicion of smallpox must initially be based on clinical findings; the possibility of this disease must be considered in any patient displaying fever and a characteristic centrifugal and uniform rash. Definitive diagnosis requires specialized diagnostic techniques. Electron microscopy can determine whether the virus is an orthopox, and confirmatory PCR techniques require primers specific to Variola. Laboratory confirmation will likely be required for the sentinel cases of an outbreak. After initial cases are confirmed, additional case identification can be based on clinically consistent criteria. Miller-Fisher variant of Guillan-Barré syndrome Myasthenia gravis Tick paralysis Atropine poisoning Paralytic shellfish/puffer fish poisoning If an exposure to smallpox is suspected but the patient is asymptomatic, administration of the Vaccinia virus within a few days from exposure can prevent or greatly diminish the severity of the illness. Once the disease develops, however, specific therapeutic options are limited (see Table 64 .2). There is evidence that cidofovir may have activity against the Variola virus, although the evidence is based on alternative orthopox disease models and in vitro assays. Supportive care for critically ill patients may limit mortality, but since the last case occurred more than 25 years ago, it is uncertain what effect modern critical care will have on outcomes. Mortality is expected to be approximately 30%, with far greater rates of disfigurement or disability. Secondary transmission is most likely to occur through close contact with symptomatic patients (e.g., droplet and contact transmission), although fomite and airborne transmission have been documented. Patients with a cough may be more likely to transmit droplet nuclei (i.e., airborne transmission), and those with atypical disease courses (e.g., hemorrhagic and malignant) may be more difficult to identify, so unprotected exposure of health care workers may be more likely. The viral hemorrhagic fevers believed to be possible agents of BT are listed in Box 64.4. The filoviruses and arenaviruses are transmissible from person to person. Although the limited information available suggests that transmission is primarily via infected body fluids, mucosal transmission has been documented in experimental animals and airborne or droplet transmission has been suggested in several outbreaks. Clinical manifestations will vary with the particular virus. In general, the VHFs have an incubation period ranging from 2 to 21 days (commonly, 5-10 days). Initial symptoms are nonspecific and may last up to 1 week. Fever, malaise, headache, myal-gias, arthralgias, nausea, and gastrointestinal complaints are prominent. A rash may be present. On exam, patients are typically febrile, relatively bradycardic, hypotensive, and tachypnic. As the disease progresses, hemorrhagic manifestations, such as petechiae, mucosal bleeding, hematuria, hematemesis, and melena, may appear. Eventually, disseminated intravascular coagulation, multiorgan system failure, and shock may develop. Mortality rates vary greatly, but in the case of Ebola virus they may be as high as 90%. Confirmatory diagnosis of VHFs must be made at specialized laboratories. The diagnosis must be suspected in any patient presenting with acute fever, severe illness, and hemorrhagic manifestations. Any patient who presents with a VHF who does not have a travel, contact, or exposure history consistent with the known natural occurrence of these illnesses must be considered as the possible victim of a BT attack. Unfortunately, VHFs have a high lethality and supportive therapy is the only treatment (see Table 64 .2). There is evidence that ribavirin may have some effect against Arenaviridae and Bunyaviridae. No therapies have been shown to be effective against the filoviruses or flaviviruses. Additionally, there is no recommended agent or vaccine for postexposure prophylaxis to any of the VHFs. Many of the operational functions for the response to bioterrorism events are similar to those for other disasters (intentional or natural), such as requiring coordination and communication among a number of government agencies, professions, citizens, and community stakeholders for the response. However, bioterrorism events pose specific challenges for the medical response that may be serious enough that if not addressed may shut down hospitals and leave many victims without adequate options for health care (Table 64 .3). Recognizing that a conventional disaster has occurred is usually immediate, and these events are limited both geographically and temporally. Casualties have traumatic injuries, and a large portion of the survivors are taken to the nearest health care facility. Within hours to a few days, the number of expected casualties is usually known. Immediate death rates may be high, especially with structural collapse, but typically only a small Bioterrorism and the Intensive Care Unit fraction of survivors are critically ill (injury severity score > 15). Enclosed space explosions may lead to higher proportions of survivors with critical injuries, but the absolute number of critically ill patients is usually less than 100. After the initial chaotic response period, medical staff and equipment are usually not in short supply. If local hospitals are overwhelmed, additional staff and resources can be transported to the disaster area, or patients can be evacuated to unaffected areas. The recovery plans for the affected health care facilities are usually initiated within the same day or a few days following a conventional disaster. Unlike conventional disasters, a release of a bioweapons agent may go undetected. In such situations, exposed people would present for medical care after the incubation period has passed. Since people travel extensively in developed countries, and most incubation periods are days to weeks, patients are likely to present to a number of hospitals rather than to the facility located closest to the release. Having patients distributed to a number of hospitals may lead to delayed recognition that a BT event has occurred. In addition, most diseases resulting from serious bioweapons agents initially cause symptoms and signs that are commonly seen every day in hospital emergency departments and outpatient clinics. There may be no pathognomonic signs that a bioterrorist event occurred in the sentinel patients initially presenting with respiratory failure or hemodynamic collapse. No diagnostic tests are available to help clinicians rapidly diagnose most diseases, so a BT event may go unnoticed until scores of ill victims arrive at hospitals. The presentation of multiple previously healthy patients with unusual and severe symptoms should prompt suspicion. Because of the specialized diagnostic techniques required for these organisms, and the biosafety precautions that are frequently beyond the capabilities of most hospital-based clinical laboratories, confirmatory diagnostic testing for the category A agents in the United States is handled at laboratories of the National Laboratory Response Network, which includes local and state labs as well as federal facilities, such as the U.S. Army Medical Research Institute of Infectious Diseases and the CDC. There will necessarily be a delay in final diagnosis because samples for confirmatory testing must be sent to off-site laboratories. This increases the importance of accurate clinical diagnoses and proceeding with management on the basis of clinical suspicion. Prompt diagnosis is critical not only for appropriate care of individual patients but also for instituting an epidemiological investigation. The community or nationwide response hinges on the results of this rapid investigation. Once the source, agent, and location of a BT attack have been deduced, other clinicians can be notified, resources can be mobilized, and the at-risk population can receive postexposure prophylaxis. The difficulties of recognizing initial exposures to a BT attack have profound implications for hospital functionality, particularly if the pathogen is contagious. Health care workers (HCWs) and other patients without adequate infection control protections may be exposed to contagious patients. During an outbreak of severe acute respiratory syndrome (SARS), unprotected exposure of HCWs and hospitalized patients to patients with SARS was thought to be the major risk to a hospital remaining open. Most victims of serious bioweapons attacks (e.g., anthrax, plague, smallpox, botulism toxin, tularemia, and VHFs) will develop illness that is rapidly progressive (ultimately requiring mechanical ventilation, hemodynamic support, or other aggressive therapeutic interventions) if they do not receive early medical intervention or if no disease-specific medical countermeasures exist. These critically ill patients will also likely require extended critical care for survival. Few hospitals can provide even usual critical care services for an additional 100 critically ill BT victims, especially if the pathogen is contagious. In the aftermath of a BT event, it may be very difficult to ascertain the extent of the exposure. Incubation periods have a range, so the first cases may simply represent the tails of the Gaussian distribution, and many more patients may require care in the following days. Some ill patients may go unrecognized as cases, and patients may arrive at hospitals in a larger geographical area than is typical after a conventional disaster. The initially affected area may be quickly overwhelmed because of shortages of critical care resources. The unaffected regions may choose to wait to offer help until the size of the event becomes better delineated so that they do not send staff and resources away until they are certain they were unaffected. Furthermore, if the pathogen is contagious, resources in affected areas may be more rapidly overwhelmed and unaffected regions may be even less likely to provide help. BT attacks resulting in a disproportion of critically ill victims to available ICU beds are plausible. If such an event occurred today, many critically ill patients would have to forgo potentially life-sustaining critical care interventions. Hospitals can plan to give traditional standards of critical care to the few who are fortunate to arrive early during the event, or they can modify critical care so that more patients have access to some of the most important critical care interventions (e.g., mechanical ventilation). Methods to decide who should get critical care (e.g., triage algorithms), what critical care interventions should be provided, who should provide critical care, and where critical care should be provided need to be addressed before a BT event. Through such planning, hospitals may "gracefully degrade" services rather than ceasing to function when overwhelmed. All efforts must be made to provide disease-specific therapies to victims of bioterrorism. Unfortunately, not all of the serious bioweapons agents have effective treatments, and for those with treatments there is concern about development of antimicrobialresistant strains. Systems must be in place for testing new treatments during an outbreak so that effective treatments can be rapidly communicated to other clinicians and ineffective or harmful treatments can be rapidly withdrawn. Methodological issues, ethical concerns, skeleton protocol development, and information technology systems capable of making data rapidly available for analysis should all be developed and made functional before a disaster. Patients seriously ill due to a bioweapons agent, regardless of whether a specific therapy exists, will likely require extensive supportive care, including interventions traditionally provided in ICUs. For small-scale events with few critically ill patients, traditional ICU care will likely be provided. For larger events, deci- sions regarding which supportive care practices to continue and which to forgo will depend on the number of patients relative to the available resources. Supportive care that is deemed most important can be better maintained if advanced planning and preparedness are undertaken. ICU physicians should alert their hospitals to the potential need for rapid acquisition of additional mechanical ventilators, noninvasive respiratory aids, oxygen, palliative medications, and specialized staff in the event of a BT attack. Perhaps the most critical aspect of caring for victims of a biologic attack or an emerging infective disease in an ICU is the prevention of secondary transmission. In the SARS outbreak of 2003, 77% of cases in Canada resulted from in-hospital exposure. In Taiwan, the percentage of hospital-acquired cases was 94%. These data include other patients in the hospital who contracted the disease as well as health care workers who suffered occupational exposures. Category A biologic agents that are transmissible from person to person are listed in Box 64.5. Effective infection control measures are paramount in preventing the spread of disease through the hospital and, by extension, into the community. Infection control is particularly important in the ICU, in which a "perfect storm" for the rapid spread of an infection exists. Victims of a bioterrorist attack who require ICU-level care may be more contagious than those who are less sick due to higher levels of viremia or bacteremia. Invasive procedures with their attendant risks of splashing or aerosolization of blood, respiratory secretions, or other bodily fluids are more commonly performed on critically ill patients. Staff members in an ICU are often called on to rapidly complete a number of tasks in stressful conditions, a situation conducive to errors in infection-control practices. Since critically ill patients require a high level of frequent care, cumulative exposure to staff may be higher than in other areas of the hospital. Finally, other patients in the ICU are immunocompromised by virtue of their own critical illnesses, notwithstanding the disproportionate number of ICU patients who are immunosuppressed secondary to organ transplantation, oncologic conditions, or infection with the human immunodeficiency virus (HIV). One of the mainstays of management of a chemical incident is rapid and effective decontamination of victims. Decontamination serves both to limit the total dose of chemical agent received by the victims and to protect health care workers from remnant chemicals on patient skin or clothing. Patients will not present for medical care after release of a biologic agent until the incubation period passes. Decontamination is not necessary for these patients, since they are not likely to be grossly conta-minated at the time of presentation. For an overt attack, if the patient is grossly contaminated and there is concern about secondary aerosolization, it becomes reasonable to decontaminate the patient. Since T2 mycotoxin can be transdermally absorbed, decontamination of patients grossly contaminated with this agent is also warranted. If possible, symptomatic victims of a communicable bioterrorism agent should be placed in a private room to prevent exposure to other patients. In the case of smallpox or a viral hemorrhagic fever, rooms should be under negative pressure and equipped with high-efficiency particulate air (HEPA) filtration. The exhaust air from these rooms should be expelled directly to the outside, and the ventilation system should not be shared with other areas of the hospital. Documented cases of smallpox transmission have occurred through ventilation systems. Although the number of airborne infection isolation (AII) rooms in most hospitals is few, there are engineering modifications to increase modified AII capacity during an outbreak. Planning for these modifications before an event is critical. Assuming a large outbreak of disease, patients should be grouped together not only with respect to location but also with respect to nursing staff, physicians, and equipment. If no diagnostic test exists, care must be taken to minimize exposure of uninfected patients with similar signs or symptoms who may be inadvertently housed in the same location. Although friends and family undoubtedly bring much comfort and support to critically ill patients, in the face of an infectious disease they become both potential victims and potential vectors. Visitors of victims of bioterrorism with contagious agents, or victims of an emerging infectious disease, must be kept to an absolute minimum. They must be instructed and supervised in the use of proper protective equipment and notified that they must seek treatment immediately if they develop symptoms. In extreme circumstances, it may be necessary to completely preclude friends and family from visiting patients. Health care providers are accustomed to putting the welfare of the patient ahead of their own; patient care, particularly in emergency situations, is often carried out without adequate protective equipment. This cannot be allowed in the case of extremely contagious agents, even in an emergency or "code" situation. A health care provider who has contact with a patient without suitable protective gear risks not only his or her own health but also the health of other patients, coworkers, visitors, and their own families. Individual patient care issues must be secondary to adequate infection control practices, lest an epidemic of smallpox, SARS, plague, or viral hemorrhagic fever spread unchecked. The CDC has developed categories of precaution that are to be applied to patients with potentially communicable diseases (Box 64.6). These categories have been described at length elsewhere but are summarized in the following sections, along with their applicability to the category A biological agents. Standard precautions should be applied to all patients and include measures designed to prevent transmission of blood- Smallpox Viral hemorrhagic fevers Pneumonic plague Cutaneous anthrax borne illnesses such as HIV and hepatitis B/C. Most interactions with patients do not require any protective equipment, but gloves, gown, and face shield should be used for any activity that could potentially result in an exposure to blood or bodily fluids. Of the category A agents, anthrax, tularemia, and botulinum toxin require only standard precautions because these diseases are not transmissible from person to person. Cutaneous anthrax should perhaps be treated with contact precautions because transmission has been suggested following contact with the lesions of this type of anthrax. Contact precautions are applicable to diseases that can be spread by touching the patient directly or indirectly by coming into contact with contaminated objects. Common examples include scabies, herpes, Clostridium difficile, and methicillin-resistant Staphylococcus aureus. Contact precautions must be used, if applicable, during all patient interactions, regardless of whether body fluid contact is expected. Protective equipment consists of gloves and gown, and a face shield is mandatory if splashing or spraying of body fluids is possible. Patients with smallpox and VHFs must be placed in contact precautions. Patient care equipment must also be dedicated to these patients and not used on patients not suffering from these diseases. Droplet precautions apply to diseases that are transmissible by large-particle droplets, defined as those greater than 5 mm. Due to the size of the droplets, transmission is highest over short distances (<1 m) and does not occur through ventilation systems. Necessary equipment includes a face shield or surgical mask with eye protection, gown, and gloves. Pneumonic plague requires droplet precautions. Airborne precautions are required for diseases that are spread via droplet nuclei, which are less than 5 mm. Tuberculosis is the most familiar of airborne infectious agents, but of the category A agents, both smallpox and VHFs fit into this category. Droplet nuclei may travel through ventilation systems, underscoring the importance of placing patients with these diseases in negativepressure rooms with HEPA filters and exhaust of air to the outside. Required equipment includes gown, gloves, and adequate respiratory protection. Either an N95 respirator (specifications are described elsewhere) with eye protection or a powered air purifying respirator (PAPR) is acceptable. A misconception exists that once a patient is intubated and mechanically ventilated, both large droplets and droplet nuclei are no longer expelled into the air. This is true only if the ven-tilator expiratory circuit is fitted with a filter that meets HEPA guidelines. Unfortunately, many of the filters and heat/moisture exchanging filters commonly used do not meet HEPA criteria. This poses dangers to health care personnel, visitors, and other patients not only for bioterrorist agents but also for tuberculosis, SARS, and other emerging infections. Hospitals would be well advised to stockpile HEPA-grade filters for ventilator expiratory circuits. Correct hand washing is an essential component of hospital infection control in all circumstances. This is perhaps even more true in the circumstances of an outbreak of an emerging infectious disease or possible agent of bioterrorism. Hands must be washed after each patient contact even when protective gloves are used because a surprisingly high percentage of protective gloves contain microscopic holes, and holes may develop during the activities of routine patient care. Failure to thoroughly wash hands following patient contact places other patients and health care workers at risk. There has been an increase in the use of waterless alcohol rubs in ICUs rather than soap and water. Although these gels are generally effective against bacteria and viruses, they have been shown to be ineffective against bacterial spores such as anthrax. Soap and water, antimicrobial or not, are effective at removing anthrax spores from hands. Accordingly, we recommend the use of antimicrobial soap and water for the washing of hands after patient contact. Complete recommendations for postexposure prophylaxis are given in Table 64 .1. In the case of anthrax and tularemia, postexposure prophylaxis with vaccination has not been proven effective. There is no need for prophylactic antibiotic therapy for health care workers unless they were potentially exposed in the initial attack. Vaccination does not confer protection against pneumonic plague. Health care workers caring for patients with pneumonic plague should, however, receive prophylaxis with 7 days of oral doxycycline. If symptoms such as fever develop, they should be aggressively treated with parenteral antibiotics. Health care workers caring for patients with smallpox should be vaccinated as soon as possible because vaccination within 4 days of exposure can prevent or limit the severity of subsequent illness. Immediate isolation must follow the development of fever after exposure to smallpox. No postexposure prophylaxis exists for VHFs. Although decontamination of victims of a biological attack is rarely necessary, the rooms in which they are treated can become contaminated with infectious organisms, particularly if sprays of bodily fluids or respiratory aerosols are produced. Virions of smallpox, in particular, can persist in linens for extended periods of time; documented cases exist in which laundry workers contracted smallpox from handling contaminated bedding and clothing. The causal agents of VHFs may also be transmitted via contaminated linens. Commercial hospital disinfectants and household bleach at a 1:10 dilution are effective at eliminating surface contamination with anthrax, smallpox, Ebola and Marburg viruses, tularemia, and plague. Linens from infected patients should be incinerated, autoclaved, or The bodies of deceased patients with smallpox, plague, or VHFs continue to pose an infectious risk. Autopsies or postmortem examinations should be avoided if possible. The bodies of victims of smallpox should be cremated. People who have died of a VHF should preferably be cremated, although prompt burial without embalmment is a secondary option. Proper use of personal protective equipment is essential in order to protect staff from infectious disease. The equipment required depends on the particular disease, as described previously. Effort must be made to ensure that adequate supplies of equipment exist, and requirements will likely be far greater than expected. Calculations estimating the amount of equipment necessary for one nurse caring for four patients with a communicable disease are striking and sobering. During an 8-hour shift, one nurse would likely require 64 sets of personal protective equipment: 64 pairs of gloves; 64 gowns; 64 surgical masks, N95 masks, or PAPR hoods; and 64 face shields. Providing for the needs of physicians, respiratory therapists, and other ancillary personnel increases this equipment need markedly. Beyond the availability of adequate stocks of equipment, health care workers must be adequately trained in their uses. N95 respirators require fit testing annually. The equipment must be used as designed, including donning and removing it correctly. Removing equipment in the proper order is particularly important: The gloves must be removed first to avoid contamination of the face or clothing when removing the gown, mask, and eye shield. Unfortunately, this correct sequence is not widely appreciated by health care workers. Given the complexity of caring for victims of a BT attack or an emerging infectious disease, early planning for such an incident must be carried out at the institutional and ICU levels. How will a hospital, or an ICU, care for a potentially massive influx of patients with communicable disease or specific requirements? Plans will differ in their specifics depending on each hospital and each ICU's architecture and capabilities. General principles include the following: Patients should be grouped according to infection, not necessarily by need. These patients should then be isolated from the remaining hospital population and staff. Dedicated physicians, nurses, ancillary personnel, and equipment should be used so as to prevent exposure to other patients and keep the numbers of exposed health care workers to a minimum. The scale of a bioterrorist attack could potentially be enormous. As described previously, many of the category A agents could produce the same lethality as a nuclear explosion. The number of casualties could rapidly overwhelm any one hospital or even all of the hospitals in a community. Staff safety must be paramount; if staff members believe themselves to be at risk, large numbers of nurses, physicians, and others may not show up to work, crippling or even forcing the closure of a hospital. Although all risk cannot be avoided, all possible provisions must be made. All staff members must be trained in the proper use of personal protective equipment. Beyond that, training should be provided in specific plans for the response to an infective or BT incident. Physicians and nurses in particular should be educated with regard to possible agents of BT and presented with disease-specific issues. Contingency plans must be made in advance for postexposure prophylaxis, either with antibiotics or vaccinations, as indicated. Given the critical and limited time windows to initiate effective prophylaxis, plans for distribution of medication or vaccine must be thought through in advance and not made in an ad hoc manner. A large-scale bioterrorist incident could rapidly exhaust the resources of individual hospitals or even whole communities in a number of respects. The demand for personal protective equipment will be enormous. Beyond that, there will be a need for pharmaceuticals of all types. Antibiotics will be essential, but so will medications regularly employed in the ICU setting: vasopressors, sedatives, narcotics, and others. Mechanical ventilators may be at a premium for patients with acute respiratory distress syndrome, pneumonia, or ventilatory failure secondary to botulism. Although in the United States, and likely in other countries, the federal government has assembled stockpiles of antibiotics, smallpox vaccine, and mechanical ventilators, it will take time for these to be deployed, and they may not contain all essentials. The prospect of bioterrorism is not an abstract one. It has been attempted before, and it will certainly be attempted again. That it has not happened is not reason for complacency. Adequate response to a bioterrorist incident is possible, but it requires careful and thoughtful preparation. Also, the preparation is hardly specific to the potential agents of bioterrorism. The principles of providing safe and effective care to victims of a BT incident are wholly applicable to the management of patients suffering from naturally acquired emerging infectious diseases. The age of bioterrorism is also that of SARS, coronavirus, avian influenza, Ebola virus, and, significantly, global travel. The potential for patients to present acutely ill with rare, unknown, and infectious diseases, whether naturally acquired or unleashed by criminals, has never been higher. Planning and preparation are essential. Botulinum toxin as a biological weapon. Medical and public health management Hemorrhagic fever viruses as biological weapons. Medical and public health management Tularemia as a biological weapon. Medical and public health management The challenge of hospital infection control during a response to bioterrorist attacks Smallpox as a biological weapon. Medical and public health management Plague as a biological weapon. Medical and public health management Updated recommendations for management