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Nuclear and Radiological Events

Richard J. Hatchett, Joseph M. Kaminski, and Ronald E. Goans

OVERVIEW

Large-scale Radiation Events: An Evolving Risk

Mass exposure to radiation does not occur frequently but when it does such events present significant logistical, operational, and medical challenges that may be compounded by the lack of famil- iarity most first responders and other medical personnel have with the manifestations and management of radiation injury. Because of the proliferation of nuclear states, the occurrence of at least one well-documented case of smuggling of nuclear technology, the widespread availability of radioactive materials, and continuing concerns about the risk of nuclear or radiolog- ical terrorism, the risk of deliberate mass exposures to radia- tion has likely increased in recent years. Additionally, there is an ever-present risk of mass radiation exposures, such as occurred after the Chernobyl accident and the 137Cs dispersion event in Goiânia, Brazil.1,2 The recent efforts of the United States and other nations to improve their capabilities to prevent or inter- dict nuclear smuggling, to enlarge the armamentarium of radi- ation countermeasures, and to disseminate information about the management of radiation casualties suggest the seriousness with which the threat of deliberate attack is regarded.3 Numer- ous authors have summarized the publicly available information related to this threat, and the interested reader is referred to these sources for more detailed accounts.4–7

SCENARIOS OF CONCERN

Mass exposures to radiation may be accidental or deliberate in origin. Heretofore, all such incidents have been the result of acci- dents, with the notable exceptions of the exposures occurring as a result of the atomic bombings in Hiroshima and Nagasaki and the exposure of more than a hundred people to 210Po in the wake of the Litvinenko poisoning.8 The causes of accidental exposures have varied dramatically, as might be expected, ranging from criticality events (or “excursions,” in which transient fission occurs) to the dispersion of radioactive materials (whether on a small or large scale) to the misadministration of radiation therapy. Selected incidents that are representative of the types of

accidental exposures that may be encountered will be discussed in detail later in this chapter. Presented here are the general features of such accidents. Many of the deliberate exposures that could occur as a consequence of acts of terrorism are comparable in scope and effect to some of the accidents. Therefore it is useful to summarize the nature of such threats. The threat of nuclear ter- rorism, however, is unique. The detonation of a moderate-sized (10- to 15-kT) device in a densely populated urban area would essentially reproduce the effects of the bombings of Hiroshima and Nagasaki and result in thousands or tens of thousands of fatalities.

Criticality Accidents

Criticality accidents (“excursions”) have occurred during the assembly or disassembly of nuclear weapons, the processing of solutions containing fissionable materials, and as a result of acci- dents within nuclear reactors.9–11 Criticality accidents are typi- cally associated with significant mixed-field exposures (i.e., neu- tron and gamma radiation) but are not associated with blast or thermal injury. In and of themselves, criticality accidents do not result in contamination of the environment or geographically extensive exposures and pose a threat mainly to workers in the immediate vicinity of the causative nuclear materials. Victims of some criticality accidents have received exceptionally high doses (>40 Gy), and these cases have been associated with highly accel- erated mortality, with death occurring 1–7 days postexposure.9

Since 1945, approximately 60 such accidents have occurred, not all of which have resulted in significant human exposures.9 Met- tler and colleagues cite 18 known deaths from acute radiation syndrome caused by such accidents over this period.12 Several of these accidents will be summarized at the end of the chapter.

Nuclear Power Plant Accidents

At the time of this writing, the explosion and subsequent fire in a graphite-moderated reactor at the Chernobyl nuclear power station on April 26, 1986 remains the most significant radiation accident in history in terms of the amount of radioactivity released, the area affected, and the number of people exposed.

477

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Approximately 50 MCi of radioactivity (representing <4% of the reactor’s total radionuclide inventory) were released into the environment before the fire in the reactor was extinguished on May 6, 1986, resulting in serious contamination of local regions and trace contamination throughout Eastern and Western Europe. The primary contributors to the released radioactivity were radiocesiums and radioiodines. Within ten days of the accident, elevated levels of radioactivity were detected as far away as Israel, Kuwait, China, Japan and the United States.13

Following is a summary of the salient features of the accident; the acute and long-term health effects of the accident have received comprehensive assessment elsewhere.1,13

The accident and subsequent release of radioactivity at Chernobyl were directly related to the design of the reactor, which had a water-cooled graphite core. In such reactors, graphite is used to moderate the chain reaction initiated by the decay of 235U, slowing the emitted neutrons and increasing their propen- sity to strike other 235U nuclei. Graphite is a very efficient mod- erator and offers two advantages over water, which can also be used as a moderator: first, it is such an efficient moderator that it can sustain fission in naturally occurring, unprocessed uranium (water-moderated reactors require enrichment of 235U from its natural 0.7% up to at least 3%); second, graphite-moderated reactors produce more weapons-grade plutonium than water- moderated reactors, and the plutonium is easier to recover. Water has one major advantage over graphite as a moderator: reac- tors using water as a moderator have a built-in fail-safe mecha- nism. Whereas graphite-moderated reactors use water as a crit- ical coolant to slow down and control the chain reaction, such that a failure in the water-cooling system can lead to an escala- tion of fission (as occurred at Chernobyl), the water in a water- moderated reactor directly facilitates the fission itself. Any change in conditions within the reactor resulting in increased fission and heat causes the water to boil, reducing its availability to serve as a neutron moderator, slowing down the chain reaction and reducing the temperature. Water-moderated reactors thus have a natural negative-feedback mechanism built into their design that functions independently of any human operator.14 Types of reactors and regulations governing reactors vary by coun- try. For example, by regulation, all nuclear reactors operating in the United States use water as a moderator. Other regulations mandate broader shutdown margins, more robust containment structures, and more stringent procedural controls than were operative at Chernobyl.15 These layered safety mechanisms are the basis of the common assertion that a Chernobyl-like accident could not occur in the United States.

Two other significant nuclear power plant accidents have resulted in the release of radioactivity into the environment. The first, a fire in the graphite-moderated, air-cooled Windscale facil- ity in Cumbria, England in October 1957, resulted in the release of approximately 20,000 Ci of radioactive material, primarily 131I, 137Cs, and 210Po, into the surrounding countryside, although no acute injuries were attributed to the accident.16 The U.S. Nuclear Regulatory Commission attributed the partial meltdown of the water-moderated Three Mile Island 2 reactor in March 1979 to a sequence of equipment malfunctions, design-related prob- lems, and human errors. Although approximately one half of the core melted in the accident, the meltdown did not result in a breach of the containment system and the amount of radiation released had trivial medical and health consequences, with the average dose to populations in the area being approximately 1 mrem and the maximum doses estimated at less than 100 mrem

(a computed tomography [CT] scan, by comparison, can result in an effective dose of up to 1 rem).17

The potential for the accidental release of spent nuclear fuel from its temporary storage facilities has led to plans for the establishment of a centralized geological repository. Currently within the United States, more than 50,000 tons of high-level nuclear waste and spent fuel is stored in pools or dry casks at 72 sites in 33 states.18 Three quarters of these locations are within 50 miles of major population centers and more than 160 million people live within 75 miles of a nuclear waste storage facility.19

Radionuclide Exposures

As described previously, nuclear power plant accidents leading to the release of radioactive materials could cause widespread environmental contamination with a variety of radionuclides. There are also numerous nonnuclear scenarios that could lead to the dispersion of radionuclides and the internal or external exposure of affected populations. Three such scenarios were the exposures that occurred in Lilo, Georgia; Goiânia, Brazil; and along the Techa River in Russia.

The accident in Lilo, Georgia involved orphan (abandoned) radiation sources that had been left behind at a civil defense training site by the Soviet Army when Georgia gained its inde- pendence in 1991. Between July 1996 and October 1997, 11 young military recruits presented for evaluation with nausea, headache, weakness, and skin lesions that evolved to ulceration and necrosis requiring prolonged medical care. Because they received medical care in a variety of facilities, there was a significant delay in the recognition of the links between the cases and the location of the lost radiation sources. Ultimately, investigators discovered multi- ple 137Cs, 60Co, and 226Ra sources during radiation surveys of the training facility. Apparently the Georgian recruits found some of these sources and at least one was placed into the pocket of a soldier’s winter jacket, which evidently was shared among sev- eral recruits who subsequently developed symptoms of radiation sickness.20

More widespread dispersion of radioactive material occurred as a result of an accident involving another orphan source in Goiânia, Brazil in 1987. On September 13 of that year, two ped- dlers removed a medical teletherapy source containing 50.9 TBq (1,375 Ci) of 137Cs from an abandoned radiotherapy clinic. They removed the rotating assembly of the shielding head of the device and subsequently ruptured the source canister itself before sell- ing the assembly containing the damaged source to the owner of a junkyard. This individual, noticing the blue glow emanating from the device, brought it home, where the CsCl salt it con- tained became widely dispersed. In addition, this new owner of the device showed it to multiple people in the local commu- nity because a glowing object like this was considered special in Brazilian society. Sixteen days passed before health authorities recognized that a radiation exposure had occurred, during which time a significant number of homes, public places, and vehicles became contaminated. Recognition of the accident generated sig- nificant public anxiety and ultimately almost 113,000 people, of a local population of almost 1 million, presented for health screen- ing; 249 showed evidence of contamination and 49 required med- ical treatment. Four persons died as a result of the accident.21

During the period 1949–1956, exposures along the Techa River in the former Soviet Union occurred as a result of the continuous discharge of radiochemical waste, primarily 90Sr and 137Cs, into the river from the Mayak weapons processing facility,

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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with the most significant exposures (≤2 Gy/year for some indi- viduals) occurring prior to 1952. Nearly 30,000 people were exposed, with the average effective equivalent dose assessed to be 320 mSv in the Chelyabinsk region and approximately 70 mSv in the Kurgan region. Inhabitants of villages along the upper Techa River were relocated over several years beginning in 1951, and affected populations have been followed medically since that time, now forming (with the atomic bomb survivors in Hiroshima and Nagasaki) one of the most important cohorts for the study of radiation carcinogenesis.22

These incidents varied tremendously in the duration and magnitude of the exposures that occurred and provide valuable data about the possible scenarios that could result from the acci- dental or deliberate release of radionuclides into the environment in the future.

Radiotherapy and Industrial Radiography Accidents

Accidents may occur if procedural safeguards against excess exposure during legitimate uses of radiation sources fail. Dozens of radiotherapy accidents, some involving hundreds of patients, have occurred in the last several decades, with some of these incidents resulting in iatrogenic deaths. One incident, for exam- ple, caused by an error in maintenance of a linear accelerator in a radiotherapy clinic in Zaragoza, Spain, resulted in significant exposure of 27 patients with 15 deaths. Another notable accident, in Costa Rica, attributed to the miscalibration of a 60Co telether- apy device, resulted in the overexposure of at least 114 patients and 17 deaths.23 Accidents at commercial irradiator facilities have occurred sporadically, typically involving one or at most a few individuals and have occasionally resulted in fatalities.24

Terrorist Threat Scenarios

Authorities have frequently expressed concern that motivated terrorists could use radioactive materials in attacks on civilian populations. Radiation sources are comparatively accessible and many of the scenarios of concern would not require a great deal of technical sophistication on the part of the perpetrators.

Radiological Terrorism A frequently discussed scenario is the detonation or deploy-

ment of a so-called radiological dispersal device. Such dispersion could be overt, as would be the case with the detonation of a “dirty bomb” (an improvised explosive device containing radioactive material), or covert, as would be the case if radioactive materi- als were dispersed surreptitiously, perhaps through ventilation systems or through food and water supplies. Some experts have argued that the public health threat from “dirty bombs” is mainly related to the conventional explosives they contain, and that the medical and health effects of any radioactive materials dispersed by a “dirty bomb” would be minimal. Such experts have clas- sified “dirty bombs” as “weapons of mass disruption” rather than “weapons of mass destruction.” Other authorities have dis- agreed, believing that such weapons, if properly constructed and delivered, would pose a significant radiation risk to affected civil- ian populations.25 In any case, timely and appropriate crisis and emergency risk communication will be an important factor in minimizing the public health impact of a dirty bomb.

The surreptitious placement of a radiation source in envi- ronments where people are likely to have prolonged expo- sures (such as on airplanes or subways or in movie theaters)

could result in the exposure of a significant number of peo- ple before the hidden source (a radiological exposure device or RED) is recovered. In an unusual demonstration, Chechen rebels surreptitiously placed a 137Cs radiation source in a park in Moscow in 1995, then notified authorities. No one was harmed in this incident, which nevertheless remains one of the most well-known acts of radiological terrorism.26

Nuclear Terrorism The most ominous scenario involves the detonation of an

improvised nuclear device. Although it is unlikely that a terror- ist group would ever have the wherewithal to establish a ura- nium enrichment program (such programs being phenomenally expensive and requiring a great deal of specialized equipment and technical expertise), it is not impossible that terrorists could acquire fissionable materials in quantities sufficient to fashion a crude nuclear device (a so-called improvised nuclear device). It is also theoretically possible that terrorists could obtain a device from a sympathetic, corrupt, or incompetent regime that pos- sessed such weapons. The possibility that such illicit transfers might occur in the period immediately following the collapse of the Soviet Union inspired the U.S. Nunn–Lugar Coopera- tive Threat Reduction Program, which has helped secure and deactivate thousands of nuclear warheads since its inception in 1991.27 More recently, the activities and Islamist sympathies of A.Q. Kahn, the “father” of Pakistan’s nuclear weapons pro- gram, raised concerns about the possibility of al-Qaeda’s obtain- ing a nuclear device.28 In terms of casualties and economic costs, the detonation of a nuclear weapon in an urban environ- ment would dwarf the events of September 11, 2001. Although the likelihood of such an event is undoubtedly remote, the potential consequences have led many elected officials to regard nuclear terrorism as the single greatest threat to U.S. national security.29

Nuclear Detonation Effects

This section summarizes the prompt and delayed effects of fis- sion explosions in the range of energy yields (10–15 kT) expected from an improvised nuclear device. Almost uniformly, nuclear security experts believe that the need for specialized and strictly controlled nuclear materials and highly sophisticated, industrial- level engineering capabilities preclude terrorists from obtaining, constructing, or using high-yield (megaton-range) thermonu- clear devices and consequently the effects of these devices are not discussed here.

General Considerations The yield of a nuclear detonation is described in terms of

the mass of conventional high explosives (TNT) required to produce comparable effects. The detonation of a 1-kT device generates 1012 calories, releasing neutrons and gamma radia- tion from the fissioning nuclei and heating the other weapon components to tens of millions of degrees.30 This intense heat causes any matter in the immediate vicinity of the detonation to emit radiation, mainly in the form x-rays, which heat the surrounding air. These x-rays produce an expanding sphere of heated gas, which in turn heats and vaporizes materials, releas- ing additional radiation, for a considerable distance from the detonation point. The shock wave produced by the detonation topples or severely damages buildings, shatters windows, turns loose objects into projectiles, and causes profound trauma to

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Figure 30.1. Flat-plain damage patterns from a ground-level nuclear detonation (viewed from above). See color plate.

persons in its path. Simultaneously, radioactive fission prod- ucts and neutron-activated debris are propelled upward into the atmosphere by the explosion. This material ultimately deposits downwind of the detonation as radioactive fallout.

A nuclear detonation will produce two kinds of casualties: victims with “prompt” injuries, reflecting the immediate blast, thermal, and radiation effects of the detonation, and victims with radiation injuries occurring as a result of exposure to fallout. Although the prompt and fallout effect areas partially overlap, in general they demonstrate significant spatial separation (Fig- ure 30.1).

Exposures to fallout after a nuclear detonation will vary according to distance, meteorological conditions, and the avail- able shelter. If the graphic depicted in Figure 30.1 represented a 10-kT ground detonation, fallout would arrive at a location 2.5-km downwind after approximately 1 minute. Approximate dose rates that might be measured 2.5 km downwind at different time intervals after the detonation are provided in Table 30.1.31

As Table 30.1 demonstrates, dose rates decline rapidly over time as fission products with short half-lives decay, so the impor- tance of obtaining shelter cannot be overstated. Underground shelters can substantially reduce doses from fallout, but if base- ment shelters are not available sheltering away from the ground in the upper floors of buildings (assuming windows are closed and intact and heating and ventilation systems are turned off) can also provide enhanced protection when compared with ground- level shelters. The quality of a shelter’s building materials influ- ences the degree of protection it affords, with stone office build- ings, for example, providing more shelter than a wood frame house.

Table 30.1: Estimated Dose Rates at Different Time Intervals at Point 2.5 km Downwind from a 10-kT Nuclear Detonation

Time Outdoor Exposure Postdetonation Rate From Fallout

1 min 300 Gy/min

15 min 0.25 Gy/min

120 min 0.03 Gy/min

480 min 0.001 Gy/min

Prompt Effects Prompt effects are those occurring as a direct result (and

within the first minutes) of the detonation. They encompass radiation, blast, and thermal effects, which are described briefly herein.

RADIATION EFFECTS

Prompt radiation includes neutrons and gamma rays emitted as a direct result of fission, alpha and beta particles and gamma radiation emitted by unstable fission products, and radiation emitted by neutron-activated debris swept up into the fallout cloud from the immediate vicinity of the detonation. Prompt radiation doses decline according to the inverse square law, but are sufficient to produce signs and symptoms of acute radiation syndrome at distances up to approximately 1.5 km from a 10-kT detonation. Within this radius, terrain and building structures may provide shielding from the thermal radiation but will not greatly attenuate the neutron and gamma radiation.

BLAST EFFECTS

The blast wave accounts for approximately 50% of the energy released by a nuclear detonation. Consequently, blast effects make the greatest single contribution to the immediate dam- age caused by the detonation. The blast wave moves outward from the point of detonation at supersonic velocity, generating winds of up to several hundred kilometers per hour. Injury and lethality due to blast effects are very difficult to predict because of the varied and complex mechanisms whereby the shock wave can interact with structures and people. Modeling suggests that many or most casualties receiving a prompt radiation dose exceeding a few hundred centiGray will probably die from blast effects.

THERMAL EFFECTS

Thermal radiation (heat) accounts for approximately 35% of the energy released by air bursts such as those at Hiroshima and Nagasaki (this percentage will be reduced if the detonation occurs at ground level). Thermal radiation will produce primary and secondary burn injuries, with primary burns caused by direct exposure to the thermal pulse, and secondary burns occurring as a result of the incendiary effects of the thermal radiation on inflammables. In certain environments, firestorms may ensue as a result of the coalescence of individual fires. Modeling suggests that burns will be severe at distances of up to 1 km for a 1-kT burst and up to 3–4 km for a 10-kT detonation. Within these

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Table 30.2: Yield of Fission Products

Element Percentage Yield

Strontium-90 5.8

Cesium-137 6.2

Xenon-135 6.5

Rubidium 7

Cerium 9.3

Molybdenum 11.3

Zirconium 12.5

Barium 12.6

Iodine 21.7

Yttrium 24

zones, burn lethality will be enhanced in victims experiencing blast and radiation effects.

Fallout Ground bursts aerosolize more radioactive debris, with a

wider range of particle sizes, than air bursts with the particles of larger size tending to precipitate sooner. Ground bursts thus produce more (and more concentrated) fallout than air bursts. Such fallout poses an extreme radiological hazard to downwind populations. The deposition of fallout will be heavily influenced by weather patterns and may not be uniform, with some areas (“hotspots”) receiving greater amounts than others as a result of local meteorological conditions.

FALLOUT COMPOSITION

Fission of nuclear weapons materials may generate more than 300 isotopes of 36 different elements, with each isotope having a unique specific activity and half-life (precise fission yields are dependent on the fissioning isotope and the energy of the neu- trons causing fission).30 In addition to these fission products, the fallout cloud produced by a ground burst will carry a substantial amount of neutron-activated debris. Table 30.2 provides esti- mates of fission yields for some of the more prevalent elements produced by the fission of 235U by slow neutrons (the combined yield exceeds 100% because each fission results in two prod- ucts).32 Elements listed by name only are represented by multiple isotopes. Due to the differential radioactive decay as the fallout cloud travels downwind, the isotopic composition of deposited fallout will change from location to location and over time.

Most of the isotopes occurring in fission products emit beta particles and a high percentage of the beta emitters also emit gamma radiation. Beta particles emitted by the fallout can pro- duce cutaneous burns when fallout particles remain in contact with skin for extended periods. Beta burns were the most promi- nent clinical manifestation in Marshall Islanders after exposure to fallout in the early 1950s, for example. Because beta particles are not penetrating, however, beta exposure will not contribute significantly to bone marrow doses and thus will not produce many of the systemic features of radiation exposure. Gamma rays, which are penetrating, will constitute by far the greatest contributor to bone marrow dose from fallout. Few if any of the fission products are alpha emitters, but alpha emitters will be rep- resented in fallout in the form of unfissioned 235U or 239Pu. That

Table 30.3: Fallout Doses in First Hour

Range (km) 1 kT detonation (Sv) 10 kT detonation (Sv)

1 4,100 32,000

2 58 930

4 14 79

8 3.3 13

10 1.9 7.3

20 0.12 0.64

40 minimal minimal

being said, the radioactivity of the fission products is far greater in aggregate than the activity of the dispersed fissile material and constitutes a much greater threat to downwind populations. Neutron radiation is not a component of fallout.

Among the isotopes in fallout of greatest concern are 90Sr, which has a long half life, concentrates in bones and teeth, and emits a high-energy beta particle; 137Cs, which has a long half-life, emits gamma rays, and behaves biologically like potassium (and thus, if consumed by grazing animals, can be passed up the food chain in contaminated meat or milk products); and the iodine isotopes, which have moderate half-lives (e.g., 8 days for 131I) and are avidly taken up by the thyroid, producing a significant cancer risk in younger individuals.

DYNAMIC DOSE RATES DUE TO FISSION PRODUCT DECAY

Doses and dose rates due to fallout reflect its patterns of deposition and thus are heavily influenced by meteorological conditions and other factors. The behavior, and to some extent the composition, of fallout produced by a ground burst in an urban environment affected by microclimate features is difficult to model precisely. Table 30.3 gives approximate predicted radia- tion doses received by fully exposed individuals directly under the fallout plume at various distances from the point of detonation for the first hour following a 1- or 10-kT surface detonation.31 It is clear from the calculated doses, rough approximations that they are, that the initial dose rates produced by fallout are extremely high (the low doses at large distances will increase as the major part of the fallout plume passes over). Early evacuation and/or sheltering, if feasible, are thus among the most important and effective strategies for reducing exposure.

Fortunately, most of the radioactive isotopes in fallout decay rapidly. Table 30.4 shows the rate of fallout decay, expressed as a

Table 30.4: Fallout Decay172

Time after Percentage of Dose Detonation (h) Rate at 1 h

1 100

2 43

4 19

6 11

8 8

10 6

12 5

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Figure 30.2. Estimated cumulative 24-hour fallout dose from HOTSPOT model.

percentage of the dose rate at 1 hour, during the first 12 hours following detonation.30

Because of the high early dose rates, however, the cumulative doses observed in exposed populations can still be quite elevated. Figure 30.2 shows estimated cumulative doses at different dis- tances for fully and continually exposed populations for the first 24 hours following a detonation.31 Such dose estimates have to be considered merely illustrative because individuals almost cer- tainly will move in and out of shelters and through areas with different degrees of fallout deposition during this time period.

BENEFITS OF SHIELDING

The most effective way to reduce exposure to fallout is evacu- ation, but for a variety of reasons this may be difficult to accom- plish within the appropriate timeframe. Sheltering in place may be more feasible and can provide substantial protection against exposure. Table 30.5 shows the estimated dose reduction factors for different types of shelter.30

CURRENT STATE OF THE ART

Basics of Radiation Biology

Ionizing radiation may be electromagnetic (gamma rays or x- rays) or particulate (alpha particles, beta particles, and neutrons) in origin. Both electromagnetic and particulate forms of ionizing radiation can contribute to the radiation injury sustained after accidental or deliberate exposures. Depending on the nature of the precipitating event, the radiation exposure for a given individual may be classified as localized or whole body and may, where the dispersion of fallout or other radioactive materials is

Table 30.5: Shelter Dose Reduction Factors173

Type of Shelter Dose Reduction Factor

0.3 m underground 0.0002

Frame house 0.3–0.6

Basement 0.05–0.1

Upper stories of apartment 0.01

Shelter with 0.6 m earth cover 0.005–0.02

involved, result in internal or external deposition of radioactive materials.

The acute radiation syndrome (ARS) encompasses a set of complex pathophysiological processes precipitated by exposure to high doses of radiation. The latency, severity, and duration of the various manifestations of ARS are a function of the organ sys- tem affected, the radiation dose and dose rate, and the “quality” (particulate or electromagnetic) of the precipitating exposure. Much of the immediate damage at the cellular level caused by radiation is nonspecific and mediated through the generation of free radicals and peroxides. Nonspecific lipid peroxidation, DNA damage, and protein oxidation lead to alterations of gene transcription and mRNA translation as part of the cellular stress response, ultimately resulting in changes in the tissue microenvi- ronment promoting inflammation and precipitating cell death. Inflammation and cell death, in turn, result in tissue and organ damage which in patients receiving sufficiently high doses of radiation can trigger a cascade of events leading to multiorgan failure and death. It is clear from both animal experiments and accidental high-dose exposures in humans that the kinetics of lymphocyte, neutrophil, and platelet depletion – and the time course of ARS symptoms in general – are accelerated at higher doses.

Knowledge of the acute effects of ionizing radiation on human subjects has been derived from

1) Animal studies 2) Studies of Japanese populations exposed to radiation from

atomic weapons 3) Studies of normal tissue injury in patients receiving radiation

therapy, typically for cancer 4) Accidents involving radiation workers, radiotherapy pa-

tients, and (rarely) civilian populations

The value of the first source of data is limited by inherent uncer- tainties about interspecies extrapolations. Studies of Japanese atomic bomb survivors have helped quantify the risk of sec- ondary malignancies and other late effects of radiation exposure, but this population has provided less insight into ARS because few detailed clinical or laboratory data were collected immedi- ately after the attacks. Radiation oncologists have gained exten- sive experience managing side effects in radiotherapy patients, but such patients are typically treated with fractionated and

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Figure 30.3. Effect of fission–neutron dose fraction on LD50 in mice. Data provided by the Armed Forces Radiobiology Research Institute.

highly focal therapy (minimizing systemic effects), are often heavily prophylaxed prior to treatment, and may experience symptoms or side effects related to their primary diseases or other concurrent therapy, so it has been difficult to use this clinical experience to develop protocols for the management of ARS. The most reliable information about ARS is derived from victims of radiation accidents. Not surprisingly, accidental expo- sures have been highly variable, ranging from the inhalation of alpha emitters in plutonium production and processing facilities to exposure to mixed gamma/neutron fields produced by criti- cality accidents. The most nearly contemporary large cohort of patients with ARS consisted of Chernobyl emergency workers who received high-dose exposures during the initial response to the accident These workers were subjected to the combined effect of radiation from several sources: 1) short-term exter- nal gamma/beta radiation from the gas emission cloud (in the case of persons in the immediate area of the accident zone at the time of the explosion); 2) external gamma/beta radiation of decreasing intensity, from fragments of the damaged reactor core scattered over the site; 3) inhalation of gases and aerosol dust particles containing a mixture of radionuclides reflecting the radionuclide inventory of the reactor core at the time of the accident; and 4) deposition of these particles on the skin and mucous membranes.33 Few of the accidents that have occurred have been good surrogates for the types of exposures that would be encountered following the detonation of a nuclear device or the deposition of fallout. A notable exception was the accidental exposure of inhabitants of the Marshall Islands to fallout from the detonation of a nuclear device in 1954. Exposures prior to evac- uation were estimated to be less than 2 Gy in the most severely exposed, with beta burns and mild depression of blood counts being the predominant acute effects.34

Estimates of the gamma dose lethal to 50% of persons exposed within 60 days of irradiation (the LD50/60) range from approximately 350 cGy for unsupported adults to 600–700 cGy in persons receiving optimal supportive care, antimicrobials, and transfusion support.35 In medically austere environments, or in the presence of combined injuries, the LD50/60 will likely decrease substantially. For example, it has been estimated that the LD50 for victims of the atomic bombings was approximately 220 cGy.36

Determinants of Biological Effects

Dose Rate The rate and degree of fractionation with which a radia-

tion dose is delivered is an important determinant of the overall biological effects and this fact is exploited by radiation oncolo- gists who seek to maximize tumor kill while minimizing normal tissue effects by administering the prescribed radiation to tar- get tissues in a series of small doses delivered daily over several weeks. In terms of lethality, studies in small animals have demon- strated that for continuous exposures the gamma/x-ray LD50/30

declines as dose rates increase.37 For example, Neal found that the LD50/30 in mice declined from 1100 cGy to 790 cGy as the dose rate increased from 2.5 cGy/minute to 706 cGy/minute.38 These findings are generally consistent with observations in humans, although it has not been possible to test this hypothesis system- atically.39

Radiation Quality The quality of radiation received is an important determi-

nant of the biological effects observed for a given dose. Neutron radiation, for example, consists of unbound neutrons and is more penetrating than alpha or beta radiation but less penetrat- ing than gamma radiation. Because neutrons are comparatively heavy particles with a moderate degree of penetration, neutron radiation has a high relative biological effectiveness (RBE). The RBE in canines for an exposure with a mixed radiation field hav- ing a neutron/gamma ratio of 5.4:1 is approximately 1.7 (i.e., the ratio of the LD50/30 with gamma radiation alone to the LD50/30

of the mixed field is 1.7:1).40 Consistent with the higher RBE observed for neutrons, increasing the neutron/gamma ratio at a fixed exposure has been shown to accelerate and prolong the suppression of white blood cell counts.41 The effect of increasing fractions of fission neutrons on survival in rodents is illustrated in Figure 30.3.42,43

Alpha particles, which consist of two protons and two neu- trons (and thus are identical to the nucleus of a helium atom), are charged and relatively heavy. They interact intensely with atoms in materials they encounter, dissipating their energy over a very short range, and thus are not highly penetrating. As such, adequate shielding against alpha particles can be provided

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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by a single sheet of paper and external exposures do not present a significant hazard. Because they are highly ionizing, however, their RBE is substantially greater than that of gamma rays and they can significantly damage cells and tissues if internalized.

Beta particles are electrons emitted from the nucleus of a radionuclide by the decay of a neutron into a proton, an elec- tron, and an antineutrino. The energy of the ejected beta particle can vary. Some energetic beta particles may penetrate tens of millimeters into the skin and thus pose both an external and an internal hazard. “Beta burns” are characteristic of exposure to fallout, which contains a high number of beta-emitting radionu- clides.34

Differences in radiation quality may have implications for the development of radiation countermeasures. Neutrons, for example, are more likely to cause damage by direct effects on cellular macromolecules than gamma radiation (which medi- ates its effects indirectly through the generation of free radicals). Consequently, fission-spectrum neutrons appear to be signifi- cantly more mutagenic and thus potentially more carcinogenic than gamma radiation. In hybrid B6CF1 mice, a 97% neutron exposure of 150 cGy is approximately equivalent in mutagenic potential to 750 cGy of 60Co gamma rays. For this strain of mice, amifostine administered prior to neutron exposure had a dose reduction factor of 1.4 for mutagenic endpoints, whereas for gamma exposures, the dose reduction factor was 2.4.44

Physiological Variables Cells are most sensitive to ionizing radiation during mitosis

and one of the chief determinants of the sensitivity of individ- ual tissues (and thus of organs) is the rapidity of cell division occurring at the time of irradiation. Consequently, tissues with high rates of cellular turnover, such as bone marrow and the gastrointestinal (GI) epithelium, are exquisitely sensitive to radi- ation whereas tissues with low rates of turnover (e.g., muscle, kidney) are intrinsically radioresistant.

In individuals, specific genetic defects that cause impaired DNA damage recognition and repair, such as mutations in the ATM (ataxia-telangiectasia mutated) or NBS1 (Nijmegen break- age syndrome) gene loci, are associated with profound hypersen- sitivity to ionizing radiation and a predisposition to malignancy. Ataxia-telangiectasia and Nijmegen breakage syndrome are both autosomal recessive disorders, and it is possible that some degree of heightened radiosensitivity could occur in persons heterozy- gous for mutations in these genes. The incidence of heterozygos- ity for such diseases, however, is low, representing no more than 1%–2% of the population for ATM mutations and significantly lower than that for NBS1 mutations.45,46 Other genetic lesions associated with radiosensitivity have been identified, but all such diseases are rare and most of the variability observed in radiosen- sitivity between individuals is not associated with known single nucleotide polymorphisms or other genetic defects.

Studies (primarily in rodents) of the contribution of phys- iological variables to radiosensitivity demonstrate that signif- icant differences are observed between strains in this regard, confirming that complex genetic factors are important determi- nants of radiosensitivity. Age and sex also appear to account for observed differences in the lethality of radiation exposures, with older and younger animals and females exhibiting lower LD50/30

values.47–49 Whether such variables influence outcomes after acute exposures for large animals or humans has not been deter- mined.

dicentric chromosome

ring aberration

fragments

normal chromosome

Figure 30.4. Cytogenetic abnormalities noted after irradiation in peripheral blood lymphocytes of a patient exposed to high-dose radiation. Dicentric chro- mosomes and ring abnormalities are relatively radiation- specific and are characteristic of changes observed. See color plate. Used with permission from REAC/TS.

BIODOSIMETR Y AND RADIOLOGICAL TRIAGE

Cytogenetic Biodosimetry

The major determinant of clinical outcome following an acute radiation exposure is the dose received by the affected individ- ual. Estimating this dose (in a process termed “biodosimetry”) thus becomes a critical part of clinical management of such indi- viduals. Of the many biodosimetry techniques that have been evaluated, the measurement of cytogenetic changes has been and remains the gold standard for radiation dose estimation (Figure 30.4). The current gold standard for cytogenetic biodosimetry is the lymphocyte metaphase-spread dicentric assay, in which lymphocytes are stimulated to divide and then incubated with colcemid to arrest the dividing cells in metaphase. Metaphase chromosome spreads are then prepared on microscope slides and radiation dose is estimated by quantifying the incidence of dicentric chromosomes. This assay is extremely labor inten- sive and sample preparation and scoring take a minimum of 72 hours. With the advent of concerns about radiological or nuclear terrorism and the potential that such attacks could result in large numbers of casualties, the need for more rapid and more accurate forms of radiological triage has increased. To address this and other challenges in triage, the U.S. government spon- sored an International Conference on Biodosimetry and the 7th International Symposium on ESR Dosimetry at the Uniformed Services University of the Health Sciences in 2006. The follow- ing discussion has been adapted from papers presented at that conference.50

Prior to 1960, determination of dose relied on the reconstruc- tion of the accident (including health physics studies and time and motion simulation) and analysis of any physical dosime- ters that might have been present. Medical management was reactive, heavily weighted toward clinical response to the evo- lution of various syndromes characteristic of ARS or of acute local cutaneous injury. Since that time, the dicentric chromo- some assay has been extensively developed and harmonized to international standards.

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Table 30.6: Proposed Biodosimetry Technique as a Function of Expected Dose

Dose Range (Gy)

Proposed Validated Dosimetry Method Prodromal Effects Manifest Symptoms Survival Expectancy

0.1–1 Dicentric/PCC None to mild (1–48 h) None to slight decrease in blood count

Almost certain

1.0–3.5 Lymphocyte depletion kinetics/ dicentrics/PCC

Mild to moderate (1–48 h) Mild to severe bone marrow damage

0%–10% Death

3.5–7.5 Lymphocyte depletion kinetics/ PCC

Severe (1–48 h) Pancytopenia, mild to moderate GI damage

10%–100% Death within 2–6 wk

7.5–10.0 Lymphocyte depletion kinetics/ PCC

Severe (<1 h–48 h) Combined BM and GI damage 90%–100% Death within 1–3 wk

>10.0 PCC Severe (mins to <48 h) GI, neurological, cardiovascular damage

100% Death within 2–12 d

BM, bone marrow; GI, gastrointestinal; PCC, chromosome condensation. Used with permission from NATO/RTO and Prasana.

Because cytogenetic analysis is time-consuming and labor intensive, other, less precise techniques have been developed that enable the treating physician to estimate the relative magnitude of a patient’s exposure fairly quickly and with some degree of confidence. The early initiation of therapy based on such tech- niques may offer critical benefits, as studies indicate that the likelihood of survival can be significantly increased with appro- priate aggressive medical intervention and care.51 For purposes of acute triage after a radiation event, some authorities have recommended that medical personnel rely heavily on clinical signs, lymphocyte kinetics, the time to emesis, and, as resources permit, cytogenetic biodosimetry.52,53 The Biological Dosimetry Team at the U.S. Armed Forces Radiobiology Research Institute (AFRRI) has developed a multiparameter triage scheme that provides an immediate statistical evaluation of dose.54 These techniques have been incorporated into a diagnostic program adapted for the laptop computer and, more recently, for hand- held PDAs (Biodosimetry Assessment Tool, available online at http://www.afrri.usuhs.mil/outreach/biodostools.htm).

Standardized international protocols have been established for the conventional lymphocyte metaphase-spread dicentric assay, which has been used over several decades to guide the man- agement of victims with severe radiation exposure. More recently, another cytogenetic test, the premature chromosome condensa- tion (PCC) assay, has been shown to offer certain advantages over conventional metaphase-spread chromosome-aberration biodosimetry techniques.55 The latter techniques are robust, but as mentioned previously they are laborious and time-consuming. In addition, for potential high-dose irradiation above the median lethal dose, it is expected that radiation-induced cell death and delay in cell cycle progression into mitosis will interfere with dose estimation. To overcome this limitation, quantitative analy- sis of radiation-induced damage may be performed using resting peripheral lymphocytes in lieu of metaphase spreads. Use of interphase cytological assays, such as the PCC assay, can elimi- nate the inherent problems associated with the use of metaphase- spread cytogenetic assays. The PCC assay requires only a small amount of blood (∼0.5 mL) and chromosomal damage may be visualized within a couple of hours of the blood sample becom- ing available. A modification of the PCC assay, the interphase- based rapid interphase chromosome aberration assay, is a simple alternative to the metaphase-spread based dicentric assay. In the

rapid interphase chromosome aberration assay, damage involv- ing specific chromosomes is analyzed in chemically induced PCC spreads after fluorescence in situ hybridization with specific whole-chromosome DNA hybridization probes. The use of fluo- rescence in situ hybridization greatly expands the dose range over which the PCC technique can be used and facilitates the recogni- tion of chromosome exchange aberrations.56 In summary, PCC techniques are reliable at a wide range of doses and may be used to characterize low-dose exposures as well as life-threatening acute high doses of both low-linear energy transfer radiation, such as gamma rays, and high-linear energy transfer radiation, such as neutron or alpha particle radiation.57 In addition, PCC assays can discriminate between total- and partial-body exposures.

In 2000-2001, radiation experts suggested that the dicentric assay could be adapted for the triage of mass casualties.58,59 Lloyd and colleagues described an ex vivo simulation of an accident with mass casualties receiving whole- or partial-body irradiation in the 0- to 8-Gy range. Faced with a hypothetically urgent need for rapid results, clinical triage was accomplished by scoring as few as 20 metaphase spreads per subject, compared with the typ- ical 500–1,000 spreads scored in routine analyses for estimating dose. In such a situation initially 20 cells could be scored per person and a preliminary dose communicated to the treating physicians. If the patient’s clinical symptoms suggested a dose significantly higher than the preliminary screening estimate, the estimate could be improved by scoring up to 50 cells. Using the dicentric assay in this triage mode, a throughput of 500 or more patient samples per week per laboratory may be feasible.60

Achieving such throughputs would facilitate rapid, accurate dose assessment for victims of all but the largest radiological incidents.

Table 30.6 lists AFRRI recommendations on the type of definitive biodosimetry to use when a preliminary estimate of a given dose has been obtained.61

Historical Experience with Early Phase Acute Biodosimetry

Table 30.7 lists selected radiation accidents where the dicentric and PCC biodosimetry techniques have played an important role in the clinical management of radiological casualties. More detailed summaries of some notable recent applications of the techniques are provided herein.

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Table 30.7: Selected Use of Acute Phase Cytogenetic Assays in Radiation Accidents

Number of Dicentrics Year of People (Chromosomal

Accident Location Accident Exposed Abnormalities) PCC

Cuidad Juarez, Mexico62 1984 7? 7? N/A

Chernobyl, Russia63 1986 116,000 158 N/A

Goiânia, Brazil64 1987 250 129 N/A

Lilo, Georgia65 1986–1987 Multiple 4 N/A

Kiisa, Estonia66 1994 4 4 N/A

Istanbul, Turkey (multiple cases)67 1995 21 21 ?18

Tokai-mura, Japan68−70 1999 3 Unknown

1

43

3

Meet Haifa, Egypt71 2000 7 5 N/A

Bangkok, Thailand72 2000 28? 28 28

Ghent, Belgium73 2005 1 1 1

Referral Laboratory – incident summary74 2003–2005 23 18 Uncertain

Referral Laboratory – incident summary74 1968–2003 996 996 Uncertain

Adapted from reference 50. Adapted from earlier work by Prasanna and colleagues (Prasanna et al., 2004).

Sevan’kaev has summarized the results of the cytogenetic studies of the 1986 Chernobyl incident.63 Cytogeneticists used chromosomal aberration dosimetry in the acute phase of the Chernobyl accident as a method of dose assessment. A good cor- relation between doses calculated based on chromosomal aber- rations (dicentrics) and severity of ARS was observed clinically.

Soon after the Chernobyl accident, a radiation accident involving a 137Cs therapy source occurred in Goiânia, Brazil, in September 1987, in which more than 50 individuals were exposed to moderate to high doses (0.2–7 Gy) of gamma radiation. Radi- ation experts applied a cytogenetic technique (i.e., frequencies of dicentrics and rings in peripheral lymphocytes) in the acute phase to estimate absorbed dose.64 Ramalho and Nascimento have described a follow-up study in which they found a two-log decline in the dicentric lymphocyte frequency. They reported an average disappearance half-time of lymphocytes containing dicentric and centric rings of approximately 130 days, which is significantly shorter than the value of 3 years usually cited in the literature.

The radiation accident at Tokai-mura in 1999 is a famous and well-studied uranium criticality accident that is important both because it was witnessed (allowing careful reconstruction of the event) and because physicians used multiparameter triage tech- niques in the acute phase medical management of the victims. Despite the very high radiation doses received by two of the vic- tims (∼8 and 20 Gy, respectively), the frequency of chromosome aberrations in circulating lymphocytes was found to be a reli- able indicator of the absorbed dose of radiation. Chromosome painting techniques were found to be accurate in the evaluation of both dicentrics and translocations.68,70

Table 30.8 presents a comparison between various acute phase techniques for this criticality event. All table entries repre- sent data contemporaneous with acute patient care and not from a retrospective analysis. The physicians who attended the victims of this accident evaluated lymphocyte kinetics and other param-

eters in real time, and the results of chromosome biodosimetry were available quickly enough to impact clinical decisions when taken in the context of the patients’ evolving ARS. These dif- ferent techniques provided useful and generally consistent dose estimates that allowed meaningful inferences about each patient’s prognosis. A general symposium proceedings including a retro- spective improved analysis of the source term, power spectra, and medical treatment in this accident is available.75

Several groups have proposed modifications of cytogenetics protocols that would facilitate the use of such techniques after mass casualty incidents.54,76 Standardization and validation of cytogenetic biodosimetry protocols between laboratories will be critical for the enhancement of overall capacity.77

Electron Paramagnetic Resonance Physical Dosimetry

Electron paramagnetic resonance (EPR) or electron spin reso- nance (ESR) spectroscopy is a technique for studying chemical

Table 30.8: Acute Phase Estimates of Dose (Gy) After the Tokai-Mura Event (1999)

Method Patient O Patient S Patient Y

Na-24 blood (n only) 9.1 5.0 1.2

Rings + dicentrics 21 6.6 2.8

PCC (γ equivalent) >20 7.8 2.6

Na-24 WBC 1.6

Lymphocyte kinetics >10 6–10 1–4.5

Survival Death 82 d postexposure

Death 210 d postexposure

Survival

Original work by Goans from reference 78.

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Table 30.9: Selected Use of Acute Phase EPR in Radiation Accidents

Place of Accident Date Type of Accident Materials

USA78–81 1991 Accelerator; various radiation accidents

EPR (bone; digits)

San Salvador82 1991 60Co irradiator EPR (bone; femur)

Tammiku, Estonia85 1994 RED TL (quartz pots) EPR (sugar samples)

Georgia83 2001 RED EPR (bone; vertebra, ribs)

Review of general and combined acute phase accident dosimetry54,76,86−88

2005 Overview of acute phase dosimetry

RED, radiological exposure device; TL. Used with permission from Elsevier.

species that have one or more unpaired electrons. Paramag- netic centers (molecules or atoms with unpaired electrons) are produced by the action of radiation on materials. The para- magnetic centers created by ionizing radiation are propor- tional to the absorbed dose and EPR can be used as a non- destructive probe of the structure and concentration of these paramagnetic centers. In the EPR measurement, irradiated mate- rials are placed in a magnetic field and electron spin transi- tions are induced by an electromagnetic field of the appro- priate frequency (typically in the gigahertz range) and then quantitated.

Electron paramagnetic resonance differs from nuclear mag- netic resonance in that with EPR electron spins are excited rather than the spins of atomic nuclei. Most stable molecules have all their electrons paired and thus are not detected by EPR tech- niques, which are sensitive only to paramagnetic species. From the perspective of biological dosimetry, this limitation is actually an advantage in that ordinary chemical solvents and matrices do not give rise to EPR spectra. Thus, the EPR technique is one of great specificity, and bone and teeth, serving in this capacity as natural physical dosimeters, have been found to provide the EPR signals of the greatest stability.

EPR dosimetry has been used primarily in the retrospective analysis of radiation accidents and has been quite valuable in this regard. It has been particularly helpful when an amputa- tion has occurred and when bone fragments have been available from a site of severe local irradiation. These samples have often been obtained through surgical amputation days to weeks post- accident. Table 30.9 presents selected cases in which EPR has been useful in radiation accidents.

For at least the last 10 years, EPR has increasingly been con- sidered a health physics and medical tool for the acute phase analysis of radiation incidents. In the United States, various reports are available describing accelerator accidents and cases of severe, acute local injury in which EPR dosimetry has been performed.78–81 A 1991 San Salvador accident involving a 60Co source was characterized by significant heterogeneity of expo- sure, with the highest doses being delivered to the feet and lower legs of the victims. Desrosiers presented a detailed EPR analysis of a femur available from that accident.82 More recent analysis of the multicasualty radiation accident in Lilo, Georgia has used EPR techniques to reconstruct the dose received by one victim by using one vertebra and two rib samples removed from the victim for medical reasons.83

In the 1994 radiation accident in Tammiku, Estonia three brothers stole a large amount of 137Cs from a poorly guarded

radioactive waste depository and took it to their home. Various members of the family were exposed to this source, chronically and in a nonuniform manner. In particular, the most severely injured patient received 1,830 Gy to the femur and thigh, and an approximately 4 Gy acute whole-body dose. He soon died of multiorgan failure. Other members of the family received 0–4 Gy whole-body dose over 28 days and up to 20–30 Gy of acute local dose to the hands. This case is interesting because various acute phase modalities were used in dose reconstruction: 1) chromo- some aberration dicentric analysis, 2) Glycophorin A somatic mutation assays, 3) thermoluminescence dosimetry, 4) optically stimulated luminescence, 5) EPR, 6) chemiluminescence, and 7) Monte Carlo modeling of spatial effects. The use of EPR in this event was a valuable adjunct to clinical analysis of the ARS and of acute local injury.84,85

ACUTE RADIATION SYNDROME

General Considerations

ARS or “radiation sickness,” occurs when individuals are exposed in a short period of time to high-energy penetrating radiation with doses of 1 Gy or more (or equivalent dose) to the whole body. Some experts suggest that ARS begins at 6–7 Gy with severe manifestations at levels of exposure above 7 Gy. Significant par- tial body exposures can also result in the development of ARS. ARS affects multiple organ systems, with symptoms from dif- ferent organ systems predominating at varying doses. The most frequently recognized components of ARS are the hematopoietic, GI, and neurovascular syndromes, which result from cellular dys- function or cell death within each of these tissue compartments. Cutaneous injury from trauma, radiation, and/or thermal burns is also frequently encountered in radiation accidents. This so- called cutaneous radiation syndrome, in which cutaneous injury is solely attributable to radiation exposure, represents a clinical entity distinct and separate from systemic ARS.89 In other cases, radiation injury in conjunction with trauma or thermal injury will directly impact multiple organs, resulting in the extremely complicated physiological state of “radiation combined injury.” Radiation combined injury is associated with high mortality and the multiorgan failure syndrome. The complexities presented by individual patients notwithstanding, categorizing the syn- dromes is still useful, both for discussion purposes and because such categorizations enable the clinical team to identify the most life-threatening injuries and thus make better triage and man- agement decisions.

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Table 30.10: Phases of Radiation Injury

Dose (Gy) Prodromal Phase Manifest Phase Prognosis without Supportive Care

0.5–1.0 Mild Modest decline in blood counts Survival

1.0–2.0 Mild–moderate Some bone marrow damage Survival >90%

2.0–3.5 Moderate Moderate–severe bone marrow damage Probable survival

3.5–5.5 Severe Severe bone marrow damage; modest GI damage Death within 3.5–6 wk (50% of victims)

5.5–7.5 Severe Pancytopenia and moderate GI damage Death probable within 2–3 wk

7.5–10.0 Severe Severe GI and bone marrow damage Death probable within 2 wk

10.0 Severe Severe GI damage, radiation-induced lung injury, altered mental status; at higher doses (>20.0 Gy), cardiovascular collapse, fever, shock

Death within 2 wk

Adapted from Reference 89.

In the absence of cutaneous injury or nonradiation-related injuries, ARS follows a relatively predictable (or deterministic) course for each of its constituent syndromes, with the lowest threshold dose for the hematopoietic syndrome and the highest for the neurovascular form (Table 30.10). In general, the severity of ARS is directly proportional to dose, whereas the timing of the onset of symptoms is inversely proportional.90,91 For exam- ple, ARS has a hematological threshold dose of approximately 0.7 Gy with severe reductions in blood counts occurring above 3 Gy.92 As previously noted, the LD50 for persons receiving no supportive care is approximately 3.5 Gy, due primarily to infec- tion in the setting of neutropenia or hemorrhage in the setting of thrombocytopenia, but increases to 6–7 Gy with optimal sup- portive care (e.g., antibiotics, hematopoietic growth factors, and transfusions). Human mortality resulting from hematological insult has a peak incidence at approximately 30 days but con- tinues through day 60. Because humans recover from hemato- logical damage more slowly than other mammals, an LD50/60 is used, in contrast to the LD50/30 for animals.93 A marked reduc- tion of both the LD50 and the time from radiation exposure to death would likely occur following a nuclear detonation. This would be due to the complex patterns of ARS, radiation combined injury, and cutaneous radiation syndrome that would occur.

Clinical Progression

In terms of its temporal progression, ARS is divided into four sequential phases: prodromal, latent, manifest (illness), and recovery or death. The stages are described in detail.

Prodromal Phase As detailed in Table 30.11, a variety of symptoms and

signs may result within minutes to hours depending on the dose received. These symptoms and signs can be divided into two main groups: GI and neuromuscular. The GI symptoms include diarrhea, intestinal cramps, dehydration, and anorexia, whereas the neuromuscular symptoms include fever, sweating, headache, hypotension, apathy, and easy fatigability.93 The pro- dromal symptoms that are indicative of doses that would be fatal to 50% of the population are nausea, vomiting, anorexia, and easy fatigability. The presence of initial fever, headache, imme- diate vomiting and diarrhea, hypotension, and/or disorientation after exposure portends a fatal outcome. As a rule, persons who

vomit within 2 hours of irradiation have likely received a dose sufficient to cause at least moderate ARS. Using the 2-hour eme- sis rule for triage decisions (i.e., to determine which patients have been exposed to significant doses when there are multiple casualties) however might be problematic because it is difficult to distinguish radiation-induced vomiting from emesis due to psychological factors relating to the stressful situation.

Latent Phase The latent stages of ARS (Table 30.12) are characterized by

a relatively asymptomatic period. With 2–3 Gy, the prodromal symptoms abate after a few days and the latent period ensues for 2–3 weeks with continued declines in lymphocytes, neutrophils, and platelets. When the dose is high enough to induce the GI and neurovascular forms of ARS, the phase is frequently shortened or eliminated, respectively.

Manifest (Illness) Phase During this stage (Table 30.13) the tissue compartments that

are damaged become dysfunctional, thereby dictating the form of ARS. At very high doses (e.g., 100 Gy) all organ systems are severely compromised and death quickly ensues from neurovas- cular dysfunction.

Recovery or Death Recovery or death follows the manifest (illness) phase. At

higher doses, the time to recovery can be prolonged, with sub- stantial residual deficits due to late fibrosis and other complica- tions. Patients receiving high doses of radiation may experience other delayed effects of acute radiation exposure, such as radia- tion pneumonitis, radiation nephropathy, cataracts, and cogni- tive decline.94,95

Acute Hematopoietic Syndrome

The hematopoietic syndrome is usually encountered with doses that exceed 2 Gy, although the dose thresholds may be lower under compromising conditions, for example, significant cuta- neous damage.96 This syndrome has the four well-characterized sequential phases described previously. The prodromal symp- toms are nonspecific and include nausea, vomiting, and anorexia. Rapid declines in lymphocytes herald the onset of full-blown hematopoietic syndrome. A latent period follows over 1–2 weeks with continued declines in peripheral blood cell counts, possibly

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Table 30.11: Prodromal Phase: Severity/Dose and Medical Response

Signs/Symptoms Mild Moderate Severe Very Severe Lethal ∗ After Exposure (1–2 Gy) (2–4 Gy) (4–6 Gy) (6–8 Gy) (>8 Gy)

Vomiting

Onset ≥2 h 1–2 h <1 h <30 min <10 min

Incidence (%) 10–50 70–90 100 100 100

Diarrhea None None Mild Heavy Heavy

Onset – – 3–8 h 1–3 h <1 h

Incidence (%) – – <10 10 ∼100

Headache Slight Mild Moderate Severe Severe

Onset – – 4–24 h 3–4 h 1–2 h

Incidence (%) – – 50 80 80–90

Temperature Normal Increased Fever High fever High fever

Onset – 1–3 h 1–2 h <1 h <1 h

Incidence (%) – 10–80 80–100 100 100

Consciousness Normal Normal Normal Possibly altered Unconscious s–min

Onset – – –

Incidence (%) – – – 100 (>50 Gy)

Medical Response Outpatient Observation or treatment at a specialized hospital if needed

Treatment at a specialized hospital

Treatment at a specialized hospital

If dose <10–12 Gy consider treatment; ≥12 Gy palliative care

∗ Individuals with exposures as high as 12 Gy may survive for more than 6 months with appropriate medical management. Modified from the International Atomic Energy Agency, Diagnosis and Treatment of Radiation Injuries, Safety Report Series No. 2, Vienna; 1998.

resulting during the manifest phase in infection, fatigue, and hemorrhage.

Hematopoietic cells are among the most radiosensitive cells in the body due to their rapid turnover. Mitotically active pre- cursor cells are substantially reduced after 2–3 Gy, resulting in a decreased supply of red blood cells, white blood cells, and platelets. At these doses, the supply of mature cells from the

diminished precursor pools may be insufficient to maintain an adequate number for proper physiological function, thereby resulting in the cytopenias characteristic of the hematopoietic syndrome. Certain subpopulations of the precursor cells are more radioresistant, presumably because the cells are in the non- cycling (G0) or radioresistant stage (late S) of the cell cycle.97 This population may play a vital role in hematological reconstitution

Table 30.12: Latent Phase

Signs/Symptoms Mild Moderate Severe Very Severe Lethal ∗ After Exposure (1–2 Gy) (2–4 Gy) (4–6 Gy) (6–8 Gy) (>8 Gy)

Latency period (d) 21–35 18–28 8–18 ≤7 None

Lymphocytes (109 cells/L), days 3–6

0.8–1.5 0.5–0.8 0.3–0.5 0.1–0.3 0.0–0.1

Granulocytes >2.0 1.5–2.0 1.0–1.5 ≤0.5 ≤0.1

Diarrhea None None Uncommon Days 6–9 Days 4–5

Epilation (d) None Moderate, ≥ 15 Moderate, 11–21 Complete, <10 Complete, <10

Medical response Outpatient Hospitalization recommended

Hospitalization required

Hospitalization required

Hospitalization required, palliative treatment if ≥12 Gy

∗ Individuals with exposures as high as 12 Gy may survive for more than 6 months with appropriate medical management. Modified from the International Atomic Energy Agency, Diagnosis and Treatment of Radiation Injuries, Safety Report Series No. 2, Vienna; 1998.

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Table 30.13: Manifest (Illness) Phase

Signs/Symptoms Mild Moderate Severe Very Severe Lethal ∗ After Exposure (1–2 Gy) (2–4 Gy) (4–6 Gy) (6–8 Gy) (>8 Gy)

Onset (d) 21–35 18–28 8–18 ≤7 0

Lethality (%) 0 0–50 20–70 50–100 ∼100

Onset (wk) – 6–8 4–8 1–2 ≥1 d–2 wk

Clinical Manifestations

Fatigue Yes Yes Yes Yes Yes

Epilation – Yes Yes Yes Yes

Infection – Yes Yes Yes Yes

Bleeding – Yes Yes Yes Yes

Shock – – – – Yes

Coma – – – – Yes

Lymphocytes (109 cells/L) 0.8–1.5 0.5–0.8 0.3–0.5 0.1–0.3 0.0–0.1

Platelets (109 cells/L) 60–100 30–60 25–35 15–25 <20

Medical Response Outpatient Hospitalization recommended

Hospitalization required

Hospitalization required

Hospitalization required, palliative treatment if ≥12 Gy

∗ Individuals with exposures as high as 12 Gy may survive for more than 6 months with appropriate medical management. Modified from the International Atomic Energy Agency, Diagnosis and Treatment of Radiation Injuries, Safety Report Series No. 2, Vienna; 1998.

with exposures as high as 7–8 Gy, although at the cost of a compromised capacity for self-renewal. Fortunately, most indi- viduals involved in radiation accidents receive inhomogeneous exposures, because of the radiation mixture (e.g., photons, and beta or alpha particles), the energy of the radiation (i.e., pen- etrating or not), the individual’s distance from the source, the physical environment, and/or the degree of internal or external contamination that occurs. As a consequence, persons receiving potentially lethal doses of radiation may still survive due to spar- ing of small areas of bone marrow that can serve as a reservoir for the rapid reestablishment of hematopoiesis.95,98

The rates of decline for the various circulating cells depend on the sensitivity of the cell type (i.e., stem, precursor, and fully differentiated cells) and their turnover time. Lymphocytes, which undergo apoptosis, decline the most rapidly, whereas platelet and other leukocyte counts are depressed less quickly. Figure 30.5 illustrates lymphocyte depletion kinetics (discussed later). Having the longest circulating half-life and being resis- tant to apoptosis, erythrocytes demonstrate the slowest declines. Thus, the acute hematopoietic syndrome predisposes an indi- vidual to infection, hemorrhage, and anemia, which follow the decline of the leukocytes, thrombocytes, and erythrocytes from as early as 10 days to several weeks after a high-dose exposure.94

Due to the long circulating half-life of erythrocytes, the body’s compensation mechanisms, and the general availability of trans- fusions given that there is time to organize them, anemia, if it occurs, is seldom life threatening unless other trauma or bleeding results secondary to thrombocytopenia.

Lymphocytes demonstrate a somewhat unusual response to radiation. Terminally differentiated cells (e.g., rhabdomy- ocytes) are usually more radioresistant than intermitotic cells (e.g., intestinal crypt cells, erythroblasts). Lymphocytes, which are long-lived and the chief cells responsible for adaptive immu- nity, are highly radiosensitive and undergo rapid apoptosis when

exposed to comparatively low doses of radiation. Lymphopenia therefore occurs more rapidly than the other cytopenias, and assuming no other insult, a predictable dose-dependent decline is expected after radiation. For example, a potentially lethal dose is characterized by a 50% drop in lymphocyte count within the first 24 hours followed by a more severe decline over the next day.96

Neutrophils are part of the innate immune system and are the first responders to infection. Thus, they are the most crit- ical blood cell type in combating acute infection. Circulating neutrophils have a half-life of approximately 7 hours before marginating and entering the tissue pools where they survive for an additional 1–2 days (in the case of infection, these cells are recruited from the circulation into the tissue and consumed resulting in a marked reduction in their half-life). Maturation of neutrophil precursors in the bone marrow until their release into the circulation as mature neutrophils normally takes approx- imately 2 weeks. Following irradiation, declines in circulating neutrophils result from depletion of the marrow reserves of mature cells and death of rapidly dividing, early progenitor cells in the bone marrow. Thus, the loss of progenitor cells and the unusual kinetics of neutrophil production and release account for the delayed onset of the hematopoietic syndrome.99 To com- plicate matters, a transient increase in the granulocyte count fre- quently occurs within the first 24–48 hours due to remobilization from the venous, splenic, and bone marrow pools. This transient increase in the granulocyte count is followed by a decline and eventual recovery if the radiation dose the victim receives is sur- vivable. Some observers have reported that with doses of less than 5 Gy, a second abortive rise or stabilization in the granulocytes counts may occur approximately 10 days postexposure, followed by the true nadir. This abortive rise, if observed, reflects the pro- duction and release of granulocytes from residual hematopoietic tissue and suggests a better prognosis.100

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Figure 30.5. Lymphocyte depletion kinetics in the 1945 LANL-1 criticality accident. Reprinted from reference 144. See color plate.

The loss of progenitor cells with radiation exposure also results in a decrease in platelets, which have a mean survival time of 8–11 days. The resultant thrombocytopenia contributes to hemorrhage that occurs with the hematopoietic syndrome. Most authorities recommend platelet transfusion to reduce the risk of spontaneous hemorrhage when platelet counts fall below 10,000/µL in asymptomatic patients and in the range 10,000– 50,000/µL if there is clinical bleeding or if invasive proce- dures are anticipated. The final component of the hematopoietic syndrome, anemia, is characterized by a hemoglobin mass of less than 10 g/dL. The long mean lifespan of red cells (which approaches 120 days) makes anemia less of an immediate con- cern in the hematopoietic syndrome than the other cytopenias.

Acute Gastrointestinal Syndrome

The GI syndrome also has four sequential stages but occurs at higher radiation doses than the hematopoietic syndrome (typically becoming manifest at total body irradiation doses of ≥7 Gy). The GI mucosa is a self-renewing tissue and the mor- bidity and mortality observed in the GI syndrome reflect the denudation of the epithelial lining of the GI tract in the setting of concurrent myelosuppression. The prodromal stage is charac- terized, again, by prompt nausea, vomiting, and diarrhea, which because of the higher initiating radiation doses are typically more severe than the symptoms observed with the hematopoietic syn- drome. In some cases, this may be followed by a latent period lasting several days, although the duration of latency declines as the exposure dose increases. The manifest stage then follows with severe diarrhea, nausea, vomiting, and fevers. Other systemic effects may include dehydration, ileus, malabsorption, electrolyte derangements, GI bleeding, renal impairment, and eventual car- diovascular collapse. As with the hematopoietic compartment, the dividing precursor cells are more radiosensitive than the differentiated cells. The radiosensitive epithelial stem cells are

confined to the crypts and provide a continuous supply of new cells. These new cells differentiate as they move up the villi or luminal surface to become functionally mature cells, which are then extruded. Hence, sufficient radiation sterilizes the divid- ing crypt cells with eventual disruption of the mucosal barrier resulting in septicemia and usually death.93,98 Kolesnick, Fuks, and colleagues have argued that endothelial damage is the pri- mary lesion regulating crypt cell survival and intestinal injury, but this hypothesis remains controversial.101–103

Acute Neurovascular Syndrome

The neurovascular syndrome may be observed at acute doses of greater than 20–30 Gy and is thought to reflect cerebral edema and cardiovascular collapse, although hypotension may also be seen at lower doses. As with the hematopoietic and GI syndromes, the prodromal phase is characterized by nausea, vomiting, and diarrhea, but this typically occurs within minutes of exposure in persons suffering the acute neurovascular syndrome. Disori- entation, confusion, and prostration are characteristic of the prodromal phase and loss of balance and seizures may occur. Papilledema, ataxia, and reduced or absent deep tendon and corneal reflexes may be noted during the physical examination. This phase is followed, possibly without a latent period, by a severe manifest phase of fever, respiratory distress, disorienta- tion, ataxia, persistent diarrhea, seizures, cardiovascular collapse, and coma. The course is inexorable and death invariably follows within a few days. The clinical course of rapid deterioration mim- ics that of acute sepsis and septic shock, both of which must also be considered in the differential diagnosis.91,98

Acute Cutaneous Radiation Injury (≤90 days)

The skin is composed of the epidermis and dermis. The epider- mis provides a durable waterproof protective barrier of stratified

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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squamous epithelium between the body and external environ- ment. The stratum germinativum (or basal layer) containing the basal stem cells is the innermost layer of the epidermis. Cells produced in the basal layer differentiate and migrate toward the surface, where they maintain some proliferating potential in the stratum spinosum (squamous layer). The cells then pass through additional layers where they finally make their way to the stratum corneum, where they eventually slough off. The turn- over time ranges from 4 to 7 weeks. The dermis, connected to the epidermis by a basement membrane, contains a dense network of connective tissue, hair follicles, capillaries, lymphatics, sweat glands, nerve endings, sebaceous glands, and apocrine glands. The highly radiosensitive epithelial stem cells, follicular, seba- ceous, and sweat germinal cells provide a continuous supply of new cells to their respective structure. These new cells differen- tiate as they become functionally mature cells and are eventually lost. With irradiation a large proportion of these cells may die and without replenishment result in disruption of skin integrity, epilation, dry skin, and if the dose is high enough, loss in thermal regulation. The late effects of radiation are mainly attributable to the death of the endothelial cells within the papillary vasculature and are discussed in detail elsewhere.104,105

Radiation, whether from the blast or fallout from an impro- vised nuclear device, conventional nuclear bomb, or radiological dispersal device, has the potential to cause life-threatening injury as a direct result of radiation and nonradiation-related cutaneous injury. Significant cutaneous radiation injury independently pre- dicts lethality, thus increasing the risk of death when combined with other trauma.89,98,106 Cutaneous radiation injury will usu- ally be combined with other aspects of ARS but it may occur in isolation if the exposure is restricted to low energy x-rays or beta radiation. Mechanical, chemical, and thermal injuries frequently accelerate and exacerbate the cutaneous radiation injury (in cases in which multiple mechanisms have contributed to the injury a more appropriate term for the clinical syndrome encountered might be “combined skin injury”). Moreover, the damage to the skin is almost invariably inhomogeneous due to factors such as the position of the individual in relationship to the blast or source and/or the presence of physical barriers providing partial body protection.

The effects of radiation on the skin are dose, depth, and vol- ume dependent. Most individuals receiving a radiation dose to the skin of 5 Gy or higher will experience a transient skin reaction of erythema, edema, itching, and/or tingling within 24 hours of the causative exposure. This prodromal period is followed by a latent period of 2–3 weeks. This period is followed by an orderly progression of erythema, hyperpigmentation, and dry and wet desquamation if the focal doses to skin are approximately 15–24 Gy. In the case of extremely high doses (≥50 Gy), the period of latency may not occur and the injury may progress from ery- thema to necrosis within days (Table 30.14).104 Figures 30.5A–E demonstrate the progressive stages of cutaneous injury in a vic- tim receiving a focal high-dose exposure to the right hand. Clin- icians should remember to include radiation injury as part of the differential diagnosis of desquamation or ulceration of unclear etiology, particularly when the patient lacks a history of a burn injury.

Radiation Combined Injury

In many of the scenarios of concern, burns or other wounds in combination with radiation are highly likely. It is estimated

Table 30.14: Skin Injury and Time of Onset

Stage/Symptoms∗ Dose Range (Gy) Time of Onset (d)∗

Epilation 3 14–18

Erythema >3–10 14–21

Dry desquamation 8–12 25–30

Moist desquamation 15–20 20–28

Blister formation 15–25 15–25

Ulceration (without skin) >20 14–21

Necrosis >25 >21

∗ The time to progression of each stage (e.g., epilation, erythema, dry desquamation) is shortened with increasing dose (not shown). Modified from the International Atomic Energy Agency, Diagnosis and Treatment of Radiation Injuries, Safety Report Series No. 2, Vienna; 1998.

that 60%–70% of persons exposed to significant doses of radia- tion from the atomic bombings of Hiroshima and Nagasaki also sustained traumatic injury. Similarly, in the Chernobyl accident, approximately 10% of the 237 acutely exposed first responders received both significant radiation doses and burns.107 The com- bination of radiation injury with other injuries, whether blast, burn, trauma, or infection, results in high lethality. The LD50/30

for a given radiation exposure and the time to death for exposed animals both decrease significantly in the setting of combined injury.108 This effect has been observed for the combination of radiation injury with burns, wounds, and experimentally induced infections across multiple species. Data derived from studies involving the combination of sublethal radiation expo- sure and thermal injury are summarized in Table 30.15 and are representative of findings with other permutations of radiation combined injury.109

Delayed Effects of Acute Radiation Exposure

In persons surviving the initial phases of ARS, or receiving sub- stantial partial body exposures, tissue and organs other than

Table 30.15: Effect of Combining Sublethal Total Body Irradiation and Burns on Mortality

Model Injury Mortality (%)

20% burn 12

Dog 100 cGy total body irradiation (TBI) 0

Combined burn + TBI 73

10%–15% burn 0

Pig 400 cGy TBI 20

Combined burn + TBI 90

31%–35% burn 50

Rat 250 cGy TBI 0

Combined burn + TBI 95

1.5% burn 9

Guinea pig 250 cGy TBI 11

Combined burn + TBI 38

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those mentioned previously can manifest late radiation effects, referred to collectively as the delayed effects of acute radia- tion exposure (DEARE). For example, persons exposed to high doses of radiation (typically in excess of 6–8 Gy) often develop impairment of lung or kidney function, starting approximately 3 months after the exposure event. Acute, subacute, and chronic radiation syndromes may present as a clinical continuum or there can be a prolonged latency between exposure and the manifes- tation of radiation-produced organ dysfunction. Although the hematopoietic and GI syndromes are largely attributable to the direct cytotoxic effects of radiation on rapidly dividing tissues, the DEARE are thought to reflect chronic inflammation induced by vascular damage or other injury to the connective tissue. The interested reader may refer to several reviews on this topic for additional information.110–112

Radiation-induced Malignancy

Individuals exposed to doses of radiation that do not produce immediate acute effects are still likely to be concerned about their risk of developing radiation-induced cancer. In general, the risk of secondary cancer increases with increasing dose, although outcomes for specific individuals cannot be predicted with any certainty. This is in contrast to organ injury in which the severity of dysfunction increases with increasing dose once the thresh- old dose for injury is surpassed. In the future it may be pos- sible to estimate an individual’s risk of radiation-induced can- cer more precisely by assessing the radiation exposure in light of other pertinent factors, such as the volume of tissue irradi- ated, the individual’s history of exposure to other carcinogens (e.g., cigarette smoking), and the victim’s age and family history. At present, however, there is no way to reduce an individual’s risk of radiation-induced cancer after the radiation exposure has occurred.

TREATMENT OF ACUTE RADIATION SYNDROME

Medical Management of Acute External Radiation Injury

Treatment for ARS in the absence of combined injury is usu- ally only required in those who have received radiation doses of 2 Gy or more.113 Such pure radiation injury is compara- tively rare, however, and patients who present with combined injuries due to mechanical, thermal, and/or chemical causes should be triaged as described elsewhere in the chapter and man- aged using relevant burn or trauma protocols. Because radiation is not immediately life threatening, nonradiation-related injuries should be addressed first. The management of acute radiation injury depends on multiple factors including the location of exposure (external or internal), the extent of exposure (partial or whole body), the dose and type of radiation, concurrent injuries or illnesses, age and weight of the patient, pregnancy status, and (if internal contamination is suspected) the particular radionu- clides involved.

Infection is a major cause of death in patients with ARS, so supportive care including wound care, antimicrobial treat- ment and prophylaxis for infection, and mitigation of cytope- nias and immune suppression with cytokines, and possibly stem cell transplantation, all play vital roles in proper manage- ment.89,94–96,98,100,113 Several recent cases of high-dose exposure illustrate that with aggressive supportive care restoration of bone marrow function may be possible even after exposures as high as

10–12 Gy, although such recovery has not translated into long- term survival because of progressive GI and pulmonary dys- function.11 In the case in which a person receives a supralethal dose of radiation, it is appropriate to withhold aggressive treat- ment, especially in a setting of mass casualties, where resource constraints may be significant.114

General skin management guidelines have emerged with the goal to minimize desquamation and infection.104,105,115 Areas of acute erythema and dry desquamation (Radiation Therapy Oncology Group [RTOG] Grade I) should be washed with luke- warm water or with mild soap and water, whereas temperature extremes and mechanical irritation should be avoided. Moistur- izing cream, such as nonscented, lanolin-free hydrophilic cream, may be helpful in early or minor reactions, but should be discon- tinued if wet desquamation occurs. Moist desquamation (RTOG Grade II–III) is managed by keeping the wounds clean and using antiseptic dressings to minimize infection, desiccation, and fur- ther trauma to the wound. Skin necrosis and ulceration (RTOG Grade IV) may require skin grafts with nonirradiated skin. Alter- natively, smaller defects may be treated with hyperbaric oxygena- tion to stimulate reepithelialization.104

Radiation injury management can be divided into three cat- egories: acute (≤ 72 hours), intermediate (3–30 days), and late (> 30 days). Here, radiation management during the acute and intermediate periods is discussed.

Acute Management Both external and internal decontamination should be per-

formed along with medical and surgical stabilization as soon as possible. Prodromal symptoms such as nausea/vomiting, diar- rhea, and headache may be controlled with conventional agents such as 5-HT3 receptor antagonists and fluids, loperamide, and acetaminophen (paracetamol), respectively. All blood products should be leukoreduced and irradiated to minimize graft-versus- host-disease (GVHD), which could pose a clinical dilemma as some of the signs and symptoms of GVHD are similar to those of severe ARS (e.g., diarrhea, fever, hyperbilirubinemia, and pan- cytopenia). Herpes simplex virus serum titers should be deter- mined, and if positive, acyclovir should be initiated for pro- phylaxis and maintained until hematopoietic recovery occurs. In addition to addressing the victim’s physical symptoms and injuries, treating physicians should be sensitive to the potentially profound psychological impact of radiation injury. Patients and their families are likely to have concerns and anxieties that need to be addressed, particularly in the case of high-dose exposures when the prognosis may be poor.

In those who are expected to develop severe neutropenia, hematopoietic colony-stimulating factor (CSF) treatment should be initiated within 24 hours assuming that the radiation and nonradiation-related injuries are potentially survivable (Table 30.16).89 The only U.S. Food and Drug Administration (FDA) approved cytokines for management of treatment-associated neutropenia at the time of this writing are the recombinant forms of granulocyte CSF (G-CSF, filgrastim), the pegylated form of G-CSF (pegfilgrastim), and granulocyte macrophage–CSF (GM- CSF, sargramostim). G-CSF (filgrastim or pegfilgrastim) has a favorable toxicity profile compared with GM-CSF, with equal efficacy. These hematopoietic factors have enhanced neutrophil recovery following chemotherapy, resulting in a reduction of neutropenic fevers and hospitalizations, decreased duration of neutropenia in radiation accident victims, and also increased sur- vival in irradiated animal models.89,116 Several other cytokines

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Table 30.16: Treatment Guidelines for Radiation Exposure

Gy

Cytokine Antibacterial/Viral/ Consider Stem Cell Treatment Fungal Treatment # Transplant (SCT)

>100 Casualties

Healthy person, no injuries 3–7∗ 2–7# 7–10 (12?) for allogeneic SCT; 4–10 (12?) for autologous or syngeneic graft

Combined injuries 2–6∗ 2–6# –

≤100 casualties

Healthy person, no injuries 3–10∗ 2–10# 7–10 (12?) for allogeneic SCT; 4–10 (12?) for autologous or syngeneic graft

Combined injuries 2–6 2–6# –

ˆ Prophylactic antibiotic, antiviral, and antifungal therapy: fluoroquinolone; acyclovir if seropositive for HSV or with an underlying medical condition, and fluconazole, respectively.

∗ In the elderly (>60 years) and nonadolescent children, consider initiating therapy at a lower dose, that is, 2 Gy. Also, G-CSF should be started in those who develop neutropenia (<0.5 × 109 cell/L) if they are not already receiving it.

# Therapy should be continued until no longer neutropenic. Follow the current Infectious Diseases Society of America Guidelines if the patient develops neutropenic fever while receiving prophylactic therapy.

Used with permission from ACP.

such as interleukin-11, thrombopoietin, FLT-3 ligand, and ker- atinocyte growth factor have shown preclinical efficacy.96,113

Intermediate Management Prophylaxis for bacterial and fungal infections should be

given to those with severe neutropenia (i.e., absolute neutrophil count ≤ 0.5 × 109cells/L) and should be continued until the absolute neutrophil count exceeds 0.5 × 109cells/L or changed if resistance is encountered. Antibiotics should not target the beneficial anaerobes in the GI tract. Extended spectrum flu- oroquinolones (e.g., levofloxacin) have activity against Gram- negative and Gram-positive bacteria, lack activity against anaer- obic bacteria, and are not myelosuppressive, and thus are probably the optimal agents to use in this setting. Patients suscep- tible to severe life-threatening infections should receive prompt antibiotic treatment on an empirical basis if they show clini- cal evidence of infection such as fever. Fluconazole prophylaxis should also be initiated as it has been shown to decrease the inci- dence of fungal infections and mortality in patients undergoing allogeneic bone marrow transplants. In those who become sig- nificantly leukopenic or immunosuppressed, cytomegalovirus polymerase chain reaction can be monitored with leukocyte recovery. If cytomegalovirus nucleic acids are detected, the patient can be treated with either ganciclovir or valganciclovir.117

Selected patients without significant combined injuries who receive doses that fully ablate the marrow but may otherwise be survivable (i.e., >7 Gy but <10–12 Gy) may benefit from stem cell transplantation. Stem cell transplantation for those receiving total body doses of more than 10–12 Gy is probably of no benefit because death would result from non-bone marrow–related mul- tiorgan dysfunction.114 The accurate determination of whether a patient would likely improve with stem cell transplantation is difficult because the benefits of transplantation appear to be within a narrow dose window; patient selection is further com- pounded by the likely inhomogeneous exposure to the body. Liberal use in uncertain situations may result in death because

stem cell transplantation may lead to death from GVHD. In the rare cases of patients with an identical twin or who have previ- ously stored autologous HSCs, autologous or syngeneic stem cell transplantation may be beneficial and should be considered.

Medical Countermeasures and Treatments

In recent years, medical countermeasures against radiation have typically been classified according to the following schema

■ Radioprotectants – given before exposure (or in the midst of ongoing exposure) as prophylaxis against radiation injury

■ Radiation mitigators – given after exposure and prior to the onset of symptoms to reduce the biological consequences of radiation exposure

■ Therapeutics – given after the radiation effect is manifest ■ Decorporation – given to reduce the total body burden of an

isotope following its internalization ■ Blocking Agents – given to reduce organ uptake of an isotope

following its internalization

Elucidation of the complex nature and evolution of radiation injury has dissipated hopes for a medical panacea. Antioxidants and radioprotectants such as amifostine must be present at the cellular level at the time of irradiation to offer tangible bene- fits in reducing acute injury, and therapeutics targeting specific signaling pathways will likely demonstrate time-sensitive win- dows of opportunity during which administration may provide clinical benefit and outside of which efficacy may erode fairly sharply. Modulation of cytokine activity through the use of anti- inflammatory agents or monoclonal antibodies may offer organ- specific or more general benefits but whether these compounds will improve overall outcomes remains to be demonstrated. A consensus is emerging that combinations of therapeutics will almost certainly be required to produce substantial reductions in mortality rates. Developing and confirming the efficacy of such

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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combinations will be one of the more challenging tasks for sci- entists in coming years.118 The manifestations of acute radiation syndrome reflect a molecular and physiological cascade of events unfolding over time. This may afford opportunities for interven- tion at multiple time points, and how medical countermeasures are sequenced may prove to be an important determinant of a regimen’s overall efficacy.

Table 30.17 lists the various organ-specific syndromes asso- ciated with acute radiation exposure and the currently available countermeasures for prophylaxis, mitigation, and treatment of these syndromes. None of the drugs likely to be used in the management of patients with ARS or DEARE are U.S. FDA– approved for radiation injury. At the time of this writing, only potassium iodide (KI), Prussian Blue, Ca-DTPA and Zn-DTPA (see Decorporation Therapy for Internally Deposited Radionu- clides later) are specifically FDA-approved in the United States as countermeasures for internal radionuclide contamination from radiation injury.

INTERNALLY DEPOSITED RADIONUCLIDES

Internal contamination of individuals can occur anytime radioactive materials are free to spread in an environment, with the most common routes of intake being inhalation and absorp- tion through wounds. Despite engineering and health physics controls, activities during the various stages of the nuclear fuel cycle (i.e., mining, processing, fabrication of fuel elements, reac- tor operations and repair, decommissioning, fuel reprocessing, waste management) and in other industrial processes occa- sionally result in the accidental release of radioactive material. Unless heralded by fires and explosions, gaseous and particu- late releases might not be evident until detected by air monitors. The ingestion pathway is uncommon in industrial settings, but may become critical for the general public after an accidental release of airborne or liquid radioactive material into the environ- ment. Various documents give an overview of current thoughts on techniques pertinent to the mitigation of internal contami- nation.130,131

Following an accidental intake of radioactive material, the radiation dose, toxicity, and treatment methods are dependent on various factors such as the identity of the radionuclide and its physical and chemical characteristics (physical and biologi- cal half-life, particle size, chemical composition, solubility, tissue tropism, and so forth). For radionuclides internalized through the inhalation pathway, particle characteristics (size, chemical composition, and chemical solubility in body fluids) are impor- tant determinants of the radiation dose received. The size of aerosol particles determines the region of the respiratory tract where deposition occurs, but the ultimate fate of inhaled parti- cles is also critically dependent on their physicochemical prop- erties. Highly insoluble particles, for example, may remain in the lung for long periods, during which time a small fraction will be transported to the tracheobronchial lymph nodes by pul- monary macrophages. Insoluble particles may also be swallowed and therefore are often excreted primarily in the feces.

The spectrum of radiation injury caused by internal contam- ination with radioactive materials will necessarily reflect their biological disposition. When the disposition of such materials is nonuniform, as it will be in almost all cases of internal contami- nation, the clinical presentation of injury is unlikely to conform to classic descriptions of ARS. Clinicians should therefore antic-

ipate atypical patterns of injury in patients with known internal contamination. Patients in whom the internal contamination is unsuspected will likely present significant diagnostic challenges to treating physicians, as was the case with the Russian dissi- dent Alexander Litvinenko, whose poisoning with 210Po went undetected for several weeks despite his severe illness.

General medical and health physics assessment after an inhalation event should include initial attempts to determine the maximum credible amount internalized. Nasal swabs taken within a few minutes postaccident can aid in radionuclide iden- tification if positive and in estimating the amount of material inhaled. If there is evidence for significant intake, preparations should be considered for urine and fecal bioassay and whole- body or lung counting. There is a high false-negative rate when using nasal swabs due either to the elapsed time postevent, sam- pling technique, or clearance from the nasal region. Positive nasal smears bilaterally and/or a history of external contamina- tion above the waist and contamination around the nose, can be clues to possible intake. Mansfield has offered a rough rule of thumb that the combined activity of both nasal swipes totals approximately 5% of deeper lung deposition, using the ICRP 30 lung model as a reference.132 Experience has shown that this tech- nique generally overestimates deep lung deposition (sometimes substantially) but is useful for initial estimates and decisions about the initiation of therapy, pending the results of bioassays.

Whole body or wound counting may be useful to identify those radionuclides that emit penetrating x-rays or gamma rays. It may also be utilized for radionuclides emitting energetic beta particles that can be detected by their bremsstrahlung. The initial problem for the health physicist and for the treating physician is to estimate the maximum credible amount internalized. This estimate directs further medical care.

In all cases involving internal contamination, it is the chem- istry of the stable element in the human body that determines radionuclide biokinetics. The biological half-life (TB) of the sta- ble element (which is equivalent to that of the radioisotope) and the physical half-life (TP) of the radioisotope act in concert to produce the effective half-life (Teff) of an isotope, which is given by

1/Teff = 1/TP+1/TB.

Thus, the effective half-life is less than either the physical or bio- logical half-lives. As an illustrative example, radioactive iodine is chemically identical to nonradioactive iodine, and the biological clearance of the radioactive and normal isotopes is indistinguish- able. The toxicity of 131I, however, derives from its radioactivity. The biological effects and toxicities of 131I are therefore a function of both its half-life (8 days) and its concentration in the serum and thyroid. These effects and toxicities decline as a function of both the radioisotope’s clearance and its radioactive decay.

TREATMENT FOR INTERNAL RADIONUCLIDE CONTAMINATION

Hospital emergency personnel triage victims of a radiation inci- dent by using traditional medical and trauma criteria. In gen- eral, personal protective equipment appropriate for managing blood-borne/airborne pathogens (e.g., N95 respirators, gloves and suitable surgical gowns) are all that is necessary for treating patients with external contamination, internal contamination,

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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Table 30.17: Currently Available Medical Countermeasures for ARS and DEARE

Syndrome Timing Treatment Comment

Hematopoietic Neutropenia Prophylaxis None

Mitigation CSFs (G-CSF, GM-CSF, pegylated G-CSF) to decrease duration and intensity of neutropenia

Treatment for radiation exposure >2 Gy should begin within 1–2 d;89 CSF use has been associated with rare fatal splenic rupture119

Antibiotics at time of neutropenia Consider antibiotic prophylaxis for expected neutropenia120

Therapeutic CSFs as above

Supportive care: antibiotics for febrile neutropenia

Allogeneic stem cell transplantation

Limited utility due to severe morbidity/mortality associated with concurrent nonhematopoietic injuries sustained at marrow-lethal doses of radiation89

Thrombocytopenia Prophylaxis None

Mitigation Cytokines (oprelvekin [recombinant human interleukin-11])

Limited if any human experience with irradiated patients; label indication is for prevention/mitigation of thrombocytopenia following myelosuppressive chemotherapy in adult patients with nonmyeloid malignancies

Therapeutic Supportive care: platelet transfusion

Anemia Prophylaxis None

Mitigation Cytokines (erythropoietin)

Therapeutic Cytokines (erythropoietin)

Supportive care: red blood cell transfusion

Allogeneic stem cell transplantation

Lymphopenia Prophylaxis None

Mitigation None

Therapeutic Allogeneic stem cell transplantation

GI Nausea/vomiting Prophylaxis Oral and IV antiemetics: 5-HT3 receptor antagonists ± dexamethasone

Therapeutic 5-HT3 receptor antagonists Preferred121

Dopamine antagonists

Benzodiazepines

Corticosteroids

Mucosal injury Prophylaxis Keratinocyte growth factor (KGF) KGF is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematological malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support; safety and efficacy of KGF have not been established in patients with nonhematological malignancies

Mitigation Cytokines (G-CSF, GM-CSF) Mixed results in small human trials with fractionated radiotherapy122,123

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Syndrome Timing Treatment Comment

Therapeutic GI decontamination: fluoroquinolones, vancomycin, polymyxin B sulfate, antifungals

Very limited human data; animal data demonstrate reduction in bacteremia124

L-Glutamine Very limited human data125

Supportive care: total parenteral nutrition, elemental diets, fluids, electrolyte repletion

Diarrhea Prophylaxis None

Mitigation None

Therapeutic Antidiarrheals: loperamide, diphenoxylate/atropine, tincture of opium

Hemorrhage Prophylaxis Antacids: proton pump inhibitors, H2 receptor antagonists, sucralfate, other antacids

Reduces risk of upper GI bleeding in critically ill patients; limited data in patients with ARS126

Mitigation None

Treatment Supportive care: transfusions

Cardiovascular central nervous system

Prophylaxis None

Mitigation None

Therapeutic Palliative care

Chronic organ injury Prophylaxis None

Mitigation Pentoxifylline for early and late pulmonary toxicity

Single randomized clinical trial in patients with lung or breast cancer127

Therapeutic Pentoxifylline + α-tocopherol for radiation-induced superficial fibrosis (RIF)

Randomized clinical trial in patients with RIF after radiotherapy128

Suppression of renin-angiotensin system for radiation nephropathy: Angiotensin-converting enzyme inhibitors, angiotensin II, type I receptor antagonists

Anecdotal human evidence of efficacy129

Combined injury – blast, thermal effects

Prophylaxis None Experimental models suggest that mortality from combined injuries will be significantly higher than mortality from pure radiation injury for any given dose of radiation108

Mitigation None

Therapeutic Surgical interventions should be performed within 48 h or delayed 5–6 wk

or radiation-related injury from external sources. In some cases, however, Level C or even Level B personal protective equip- ment is recommended (Chapter 13). In the history of radia- tion accidents, no healthcare provider has received an external dose of more than 0.005 Sv while providing normal patient care. Healthcare workers may perceive a large risk in treating patients with radiation injury but this is not substantiated by actual expe- rience. It is, however, necessary to practice appropriate contam- ination controls to minimize doses to providers.

After immediately life-threatening injuries are stabilized, radionuclide-specific therapy may be considered. The major goal of radionuclide-specific therapy after internal contamina-

tion is decorporation (removal from the body) of the internally deposited radionuclide. Early and effective decorporation can substantially reduce the overall committed dose of radiation that the internally contaminated individual receives as a result of the radionuclide exposure. In general, treatment strategies for inter- nal contamination fall into one of several major categories.133

■ Reducing and/or inhibiting absorption of the isotope in the GI tract by use of Prussian Blue to bind 137Cs

■ Blocking uptake to the organ of interest by administering potassium iodide to block uptake of radioactive iodine by the thyroid

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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■ Diluting the ingested radionuclide by administering fluids for internal contamination with tritium

■ Altering the chemistry of the radioactive isotope by adminis- tering sodium bicarbonate to convert uranyl ions to uranium bicarbonate, a less nephrotoxic form of uranium, in the renal tubules

■ Displacing the isotope from receptors by administering cal- cium to compete with radiothorium

■ Using traditional chelation techniques by administering DTPA to enhance excretion of internalized plutonium

Early identification of the radionuclide is crucial in the med- ical management of the acute phase. From medical experience with industrial radiation accidents, decorporation therapy is gen- erally recommended for intakes of 5–10 times the recommended annual limit of intake (ALI) and strongly recommended for intakes exceeding 10 ALI, when the ALI is that inhalation intake necessary to give a committed effective dose equivalent of 0.05 Sv (5 rem). It would be unusual to treat a nonpregnant adult with an intake below 1 ALI. If, however, the patient requests treat- ment and there are sufficient resources available, physicians may justify therapy for intakes below 1 ALI according to the radiation safety principle that exposures should be “as low as reasonably achievable” (ALARA). In an extreme event involving thousands of contaminated individuals, it is important to remember that population dose can be reduced by a factor of 2–10 or more sim- ply by sheltering in place, depending on the quality of the shelter, whereas medical decorporation therapy can only affect dose by a factor of 2–3.134

Because internal contamination by radionuclides is often considered by physicians as a type of poisoning, poison con- trol centers are occasionally contacted initially for information on reducing the body burden of the specific radioactive ele- ment. It is therefore important that toxicologists and all physi- cians in Poison Control Centers have access to the most current treatment modalities. Table 30.18 lists decorporating, chelating, and blocking agents available for treating or blocking internal radionuclide deposition; Table 30.19 provides dosing recom- mendations for these drugs.135 These drugs and dosage rec- ommendations are currently consistent with recommendations from the U.S. National Council on Radiation Protection. Note, however, that in the United States there are relatively few drugs actually approved by the FDA for these indications. The drugs that are approved as chelating agents or decorporation agents in the United States are noted with an asterisk in Tables 30.18 and 30.19 below. Uses of these drugs for other indications and other radionuclides must be considered “off-label.” Some other countries, such as those within the European Union, have addi- tional approved drugs.

Treating physicians should be aware that most chelating and decorporating agents are radionuclide-specific and that the value of decorporation therapy may be dependent on the context of the patient’s exposure (see, for example, the U.S. FDA guide- lines for use of potassium iodide).136 Using radionuclide chela- tors/blockers in an effective and targeted way following a nuclear detonation, for example, would present significant challenges, and may, in fact, not be feasible or desirable. Internal exposures will vary considerably and it is likely that only a comparatively small number of people might incur doses that actually war- rant treatment. It is, however, also likely that this population will have received the highest external doses from fallout and that the doses received through external exposure will be the

Table 30.18: Decorporation Therapy Recommendations for Radionuclides of Concern

Radionuclide Treatment Preferred Treatment

Actinium DTPA DTPA

Americium DTPA DTPA

Arsenic BAL; Penicillamine; DMSA?

BAL

Barium Strontium therapy† Strontium therapy†

Berkelium DTPA DTPA

Bismuth BAL? BAL?

Cadmium DTPA; EDTA; DMSA DMSA

Californium DTPA DTPA

Calcium Strontium therapy† Strontium therapy†

Carbon No treatment available N/A

Cerium DTPA DTPA

Cesium Prussian Blue Prussian Blue

Chromium DTPA; DMSA DMSA

Cobalt Pencillamine; DTPA; EDTA; DMSA; N-Acetylcysteine; Penicillamine; BAL

DTPA and EDTA

Copper Penicillamine; Trientine

Penicillamine

Curium DTPA DTPA

Einsteinium DTPA DTPA

Europium DTPA DTPA

Fission products (mixed)

See text below N/A

Fluorine Aluminum hydroxide Aluminum hydroxide

Gallium Penicillamine Penicillamine

Gold Penicillamine; BAL BAL

Indium DTPA DTPA

Iodine KI; Propylthiouracil; Methamizole; Potassium perchlorate

KI

Iridium DTPA; Penicillamine Penicillamine?

Iron Deferoxamine; Deferiprone; Deferasirox

Deferoxamine

Lanthanum DTPA DTPA

Lead DMSA; BAL with EDTA DMSA

Manganese DTPA; EDTA EDTA

Magnesium EDTA EDTA

Mercury BAL; Penicillamine; DMSA?

BAL

Molybdenum ? ?

Neptunium Deferoxamine Deferoxamine

Nickel DTPA; Imuthiol Imuthiol

Niobium DTPA DTPA

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Radionuclide Treatment Preferred Treatment

Palladium Penicillamine; DTPA Penicillamine

Phosphorus Phosphorus therapy† Phosphorus therapy†

Plutonium DTPA DTPA

Polonium BAL; DMSA?; Penicillamine?

BAL

Potassium Diuretics Diuretics

Promethium DTPA DTPA

Radium Strontium therapy† Strontium therapy†

Rubidium Prussian Blue Prussian Blue

Ruthenium) DTPA DTPA

Scandium DTPA, EDTA DTPA

Silver No treatment available N/A

Sodium Diuretic Diuretic

Strontium Strontium therapy† Strontium therapy†

Sulfur No treatment available N/A

Technetium Potassium perchlorate Potassium Perchlorate

Thorium DTPA DTPA

Tritium Force fluids Water diuresis

Uranium Bicarbonate Bicarbonate

Yttrium DTPA; EDTA DTPA

Zirconium DTPA DTPA

† For strontium and phosphorus therapy, see Table 30.19. BAL = British anti-lewisite (dimercaprol; 2,3-dimercaptopropanol) DMSA = Dimercaptosuccinic acid (succimer) DTPA = Diethylenetriaminepentaacetate EDTA = Ethylenediaminetetraacetic acid

Original work by Goans.

predominant cause of morbidity and mortality for these vic- tims. Internal contamination from inhalation or ingestion of radionuclides in fallout will therefore be at best a secondary health concern compared with the thermal, blast, prompt radia- tion, and combined injuries associated with the detonation. An additional consideration is that the composition of fallout will be complex, reflecting a disparate mix of radionuclides and likely including compounds for which no or only minimally effective decorporating or blocking agents exist.

THE PSYCHOLOGICAL AND BEHAV IORAL CONSEQUENCES OF RADIATION EVENTS

Incidents resulting in the release of radiation, particularly if the event represents a deliberate attack, will produce uncertainty, anxiety, and fear in many otherwise psychologically normal and healthy individuals. These feelings may manifest directly or be expressed as anger, disbelief, sadness, irritability, arousal, sleep disturbance, dissociation, or increased use of alcohol, stimulants such as caffeine and tobacco, or drugs. In general, such feelings, and the behavioral symptoms associated with them, represent normal responses to profoundly abnormal events.137 For most persons, acute posttraumatic psychiatric and behavioral symp-

toms will subside with time. Individuals exposed to risks that actually threaten their lives or who sustain injuries are at the highest risk of psychiatric morbidity, which may meet the criteria for psychiatric diagnoses such as Acute Stress Disorder or Post- traumatic Stress Disorder.138 For many persons, knowledge that one has been exposed to a toxin such as radiation can be a potent traumatic stressor.138 Terrorist attacks are likely to produce sub- stantial levels of persistent psychiatric illness and morbidity in the persons targeted. For example, among 267 U.S. Pentagon staff surveyed two years after the attacks of September 11, 2001, 14% had probable posttraumatic stress disorder and 7% had proba- ble depression. Direct exposure to the September 11th terrorist attack on the Pentagon, injury during the attack, and exposure to dead bodies were associated with higher frequencies of per- sistent psychiatric illness and psychological distress.139 How the additional threat posed by radiation – for example, the risk of carcinogenesis years later – would affect psychiatric well-being after a terrorist event is unclear.

In the aftermath of an event, the public will seek advice from both healthcare providers and the scientific community to deter- mine the extent of both internal and external contamination. Those who have been exposed or anticipate possible exposure are likely to experience feelings of vulnerability, anxiety, and lack of control. Internal contamination with radionuclides may be particularly anxiety provoking because the patient essentially has little control over isotope decorporation therapy and must rely on evaluation from the medical community. In addition, if there is a lack of consensus among experts, this can increase the fear and anger of exposed individuals.

The stress of radiation exposure may also cause some victims to seek medical treatment, even when none is indicated or risk is minimal. For example, there have been many cases at industrial sites where workers have been exposed to accidental inhalation of minimal quantities of actinides. Some of these workers have requested treatment with DTPA and other medications for years after the event, even when assured that chelation therapy would provide little medical efficacy. Psychological distress after a radi- ological incident may also manifest as nonspecific somatic com- plaints (a presentation sometimes referred to as “MIPS,” multiple idiopathic physical symptoms or “MUPS,” multiple unexplained physical symptoms).140

Acute stress disorder and posttraumatic stress disorder are the disorders most commonly associated with public response to a radiation event. In addition, major depression, increased substance use, family conflict, and generalized anxiety disorder may also occur. In the acute aftermath of a radiation event, many unexposed patients will fear that they have been exposed and will misattribute signs and symptoms of autonomic arousal to radiation poisoning (after the 137Cs contamination in Goiânia, Brazil, 8.3% of the first 60,000 people screened presented with signs and symptoms of autonomic arousal consistent with acute radiation sickness).140 In the longer term, patients may present to primary care providers with multiple somatic complaints for which no etiology can be determined. Such effects can be very widespread. In 2006, for example, the United Nations Chernobyl Forum stated that the “mental health impact of Chernobyl is the largest public health problem caused by the accident to date” and concluded that the accident had had a serious impact on mental health and well-being in the general populations of the countries (Belarus, Ukraine, and Russia) most affected by the event.1

A well-organized and effective medical response will instill hope and confidence, reduce fear and anxiety, and support the

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Table 30.19: Dose Schedules by Drug or Treatment Modality

Drug or Treatment Modality Dosage

BAL IM: 300 mg/vial for deep IM use, 2.5 mg/kg (or less) q 4 h × 2 d, then bid for 1 d, then qd for days 5–10

DTPA (Ca or Zn) IV: 1 g in 250 mL NS or 5% glucose, given in 1–2 h, or IV push over 3–4 min

IM: 1 g can be given with procaine to reduce pain (not U.S. FDA approved)

Inhalation: 1g in 1:1 dilution with water or NS over 15–20 min (not U.S. FDA approved)

Pediatrics (<12 y): 14 mg/kg as above, not to exceed 1.0 g

D-Penicillamine PO: 250 mg, qd between meals & at bedtime. May increase to 4 or 5 g qd in divided doses

Deferoxamine IM or IV (IM is preferred): 1 g IM or IV (2 ampules) slowly (15 mg/kg/h); repeat as indicated as 500 mg IM or IV q 4 h × 2 doses; then 500 mg IV q 12 h for 3 d

DMSA PO (for lead poisoning in pediatric patients): Start dosage at 10 mg/kg or 350 mg/m2 oral q 8 h × 5 d. Reduce frequency of administration to 10 mg/kg or 350 mg/m2 q 12 h (two-thirds of initial daily dosage) for an additional 2 wk of therapy (course of treatment = 19 d).

EDTA (Ca) IV: Ca-EDTA 1000 mg/m2/d added to 500 mL D5NS infused over 8–12 h.

Imuthiol IV: For mild-moderate poisoning, the recommended dose is 2 g qid in divided doses. Titrate upward in dose if indicated.

PHOSPHORUS THERAPY

Potassium phosphate, dibasic PO: 250 mg phosphorus per tablet.

Adults: 1–2 tabs po qid, with full glass of water each time, with meals and at bedtime.

Children over 4 y: 1 tablet qid.

Potassium Iodide (KI) All PO

Adults >40 y: with thyroid exposure >500 cGy: 130 mg/d.

Adults 18–40 y: with thyroid exposure >50 cGy: 130 mg/d.

Pregnant or lactating women: 130 mg/d.

Children and adolescents 3–18: with thyroid exposure >5 cGy: 65 mg/d.

Infants 1 mo–3 y: 32.5 mg/d.

Neonates from birth to 1 mo: 16 mg/d

Propylthiouracil (PTU) PO: 50 mg tabs, 2 tid × 8 d

Prussian Blue PO: Begin with 1 g tid po with 100–200 mL water; may titrate up to 4 g qid for thallium or high 137Cs intake.

Pediatrics, 2–12 y: 1 g po tid

Sodium Bicarbonate IV: 2 ampules sodium bicarbonate (44.3 mEq each, 7.5%) in 1,000 mL NS, 125 mL/L, or 1 ampule of sodium bicarbonate (44.3 mEq, 7.5%) in 500 mL NS, 500 mL/h.

PO: 2 tablets q 4 h until urine pH = 7–8, or 4 g (8 tablets) 3 tid

STRONTIUM THERAPY

Aluminum hydroxide PO: 60–100 mL, once

Aluminum phosphate gel PO: 100 mL immediately after exposure once

Ammonium chloride PO: 1–2 g qid for 6 d

Calcium PO: Generous doses; at least 1.5–2 g daily

Calcium gluconate IV: 5 ampules (500 mg calcium each) in 500 mL D5W over 4 h; continue × 6 d

Sodium Alginate PO: 10 g powder in a 30 mL vial, add water and drink

Water diuresis PO: >3–4 L/d

Original work by Goans.

continuity of basic community functions. Mental health pro- fessionals including psychologists and psychiatrists should be an integral part of the teams that perform initial screening and triage. When feasible, the establishment of an “Emergency Ser- vices Extended Care Center” may provide a functional mecha-

nism for monitoring patients who remain fearful and are not reassured by negative findings on clinical laboratory studies.140

Reinforcing individuals’ self-sufficiency and providing action- able information that can be used to protect oneself and one’s family can decrease distress. Distributing appropriate medical

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countermeasures can also provide substantial reassurance, with concomitant psychological benefits.

CASE STUDIES IN RADIATION MEDICINE

Goiânia (Large 137Cs Source in the Public Domain)

On the afternoon of September 29, 1987, a physicist in the town of Goiânia, Brazil notified the National Nuclear Energy Com- mission of Brazil about the potential of a serious radiation acci- dent. A 50.9-TBq (1,375-Ci) 137Cs radiation therapy device had been removed by three men on or about September 13, 1987 from an abandoned radiotherapy clinic and sold to a junkyard as scrap.141 It is believed that the source capsule was ruptured on September 18. The relatively soluble CsCl mass was divided into smaller pieces and distributed among various friends and neighbors. The accident became known 16 days later. A physicist contacted by medical authorities was able to identify the nature of the source and subsequent widespread contamination. The physicist’s involvement was prompted when the wife of the junk- yard owner brought a piece of the source to the attention of her physician, saying that it was responsible for illness in many of her friends.

In total, approximately 110,000 residents of Goiânia were monitored in the Olympic Stadium and 249 were found to be contaminated, either internally or externally or both. Four main foci of contamination were noted: three junkyards and the resi- dence where the source was ruptured. Handling of the radioactive Cs generally caused internal contamination by ingestion. Four individuals died in the accident, three from external exposure and one, a 6-year-old child, from ingestion of powdered Cs. In addition, the town was extensively contaminated. During decon- tamination efforts, a total of 12,500 drums and 1,470 boxes were filled with contaminated debris. More recent developments from this accident have been described in a subsequent International Atomic Energy Agency publication.142

The Radiation Accident in Estonia (Large 137Cs Source in a Private Home)

On October 21, 1994, an Estonian citizen, RiH, along with his two brothers, visited a radioactive waste facility to scavenge for scrap metal, overriding the electrical alarm system and cutting various padlocks. RiH climbed into one of the vaults to obtain salvageable metal and passed a large 137Cs source to his brothers. At this time, none of the brothers realized that this metallic object was highly radioactive. During the theft, RiH injured his leg slightly when an aluminum drum fell against it. Shortly after entry into the repository, RiH began to feel ill and went home. Other occupants of the house were the man’s stepson (RT), the boy’s mother and the boy’s great-grandmother. The Cs source was initially placed in the pocket of RiH’s coat, which was hanging in the hall. Eventually, it was placed in a kitchen drawer along with various tools. Details of the radiation injury to members of the household and the resulting radiation-induced pathology are described in an International Atomic Energy Agency publication.143

Soon thereafter, RiH was hospitalized with severe injury to his leg. During the initial medical history, RiH claimed that he received the injury while working in the nearby forest and he was therefore treated for crush injury. On November 2, 1994, RiH died without medical authorities having any suspicion of radi-

ation exposure as the etiology of RiH’s terminal illness. Mean- while, by November 9, 1994, the stepson RT had developed signs and symptoms that indicated that he had come in contact with the source multiple times while working on his bicycle.

Shortly thereafter the 4-month old pet dog died. The dog had slept much of the time in the kitchen near the Cs source. RT was also eventually admitted to the hospital with severe hand burns, which physicians correctly diagnosed as radiation-induced cuta- neous injury. As a result of this diagnosis the police were notified, and the police in turn notified the Estonia Rescue Board, which immediately dispatched staff. A Russian medical delegation also arrived soon thereafter to provide medical and health physics consultation.

After an extensive radiation dose reconstruction, the inves- tigators estimated that RiH received a dose of approximately 1,830 Gy to his thigh and approximately 4 Gy to the rest of his body. Clinically, RiH experienced many of the effects of the acute hematopoietic syndrome along with severe, extensive local injury to his thigh (the dose rate of the stolen source was estimated to be 2,000–3,000 Gy/hour). Twelve days following his exposure he died from neutropenic sepsis and acute renal failure. An autopsy showed acute radiation necrosis of right thigh and hip, along with hemorrhage and intestinal thinning of the intestinal wall. The cause of death was ARS with both hematopoietic and GI components, along with severe local radiation necrosis.

The investigators estimated that the stepson, RT, received 20–30 Gy to his left hand, 8–10 Gy to his right hand, and approx- imately 2.5 Gy to the whole body during various episodes of bicy- cle maintenance. Other family members received hand doses in the range 8–20 Gy and whole-body doses in the range 1–2.5 Gy. The dose estimations were based on each individual’s recollec- tion of the degree of occupancy of various locations in the house. In addition, spatial computer analysis, chromosome aberration analysis, and other specialized assays were used.

Criticality Accidents in the United States

Los Alamos Plutonium Sphere Cases Two criticality events occurred with the same 6.2-kg delta-

phase plutonium sphere at Los Alamos National Laboratory.144

The first incident occurred on August 21, 1945, when a worker was preparing a critical assembly by stacking tungsten carbide bricks around the plutonium core as a reflector. He moved the final block over the assembly but, noting that this block would make the assembly supercritical, he withdrew it. The brick fell onto the center of the assembly, resulting in a super-prompt critical state of approximately 6 × 1015 fissions.145 The worker sustained an average whole-body dose of approximately 5.1 Gy and a dose to the right hand of approximately 100–400 Gy. The patient died of sepsis 28 days after the accident.

The second criticality accident occurred in 1946 during an approach to criticality demonstration at which several observers were present. The operator used a screwdriver as a lever to lower a hemispherical beryllium shell reflector into place. While holding the top shell with his left thumb in an opening at the spherical pole, the screwdriver slipped and caused a critical configuration. The fission yield in this accident was estimated at 3 × 1015 fis- sions. The operator received an estimated acute whole-body dose of approximately 21 Gy, with a dose to the left hand 150 Gy and somewhat less to the right hand. Seven observers were exposed in the range 0.27–3.6 Gy. The operator died 9 days later.

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A CB

D E

Figure 30.6. Progression of skin lesions in a patient receiving a focal high-dose exposure to the right hand. (A) Shortly after exposure, (B) approximately 12 hours postexposure, (C) day 25 postexposure, (D) day 34 postexposure, and (E) day 46 postexposure. Images provided by the Radiation Emergency Assistance Center/Training Site. See color plate. Used with permission from REAC/TS.

Los Alamos Liquid Criticality Event On December 30, 1958, during purification and concen-

tration of plutonium, unexpected plutonium-rich solids were washed from two vessels into a single large vessel that contained layered, dilute aqueous and organic solutions. The tank con- tained approximately 295 L of a caustic stabilized organic emul- sion. The added nitric acid wash is believed to have separated the liquid phases. Accident analysis shows that the aqueous layer was initially slightly below delayed critical (approximately 203 mm thick, critical thickness 210 mm). When the stirrer was started, the central portion of the liquid system was thickened, changing system reactivity to super-prompt critical. The excursion yield was approximately 1.5 × 1017 fissions. Bubble generation was the negative feedback mechanism for terminating the first neutron spike. The system was driven permanently subcritical by mixing of the two layers. This accident resulted in the death of the oper- ator 35 hours postaccident. The dose to the upper extremity was estimated at 120 Gy ± 50%. Two other persons received acute doses of 1.34 Gy and 0.53 Gy.

Wood River Junction Criticality Event This liquid process accident occurred on July 24, 1964, at

the United Nuclear Fuels Recovery Plant, Wood River Junction, RI. A chemical processing plant was designed to recover highly enriched Ur from scrap material left over from the production of fuel rods. Uranyl nitrate solution U(93) was poured into a carbonate reagent vessel. The critical excursion occurred when nearly all of the Ur had been transferred, resulting in approx- imately 1.1 × 1017 fissions. It is probable that the system oscil-

lated, resulting in a series of excursions with total energy release equivalent to 1.3 × 1017 fissions. The acute dose to the operator was estimated to be 100 Gy. Two supervisory personnel received approximately 1 Gy and 0.6 Gy. The operator died 49 hours after the accident.

Clinical Course of the Criticality Cases

Case 1 – Los Alamos plutonium sphere (hematopoietic syndrome; cutaneous radiation injury syndrome; whole-body dose approxi- mately 5.1 Gy, dose to right hand 100–400 Gy)

The patient was a 26-year-old man whose medical history was significant only for Wolff-Parkinson-White syndrome diag- nosed 3 years prior to the incident. On admission to the hospital, his vital signs were within normal limits and his only initial complaint was numbness and tingling of both hands. The initial physical examination was also within normal limits.

Within 30 minutes postaccident, the patient’s right hand had become diffusely swollen. Emesis began approximately 1.5 hours postevent, and nausea continued intermittently for the next 24 hours. The patient experienced subjective improvement but had a low-grade fever, gastric distress, and weakness during days 3–6. By day 5, the patient experienced a distinct rise in temperature with tachycardia and began to appear increasingly toxic. On day 10, he developed severe stomatitis, a paralytic ileus, and diarrhea. Clinical signs of pericarditis were noted on day 17, and the patient’s mental status deteriorated. The clinical course was notable for progressive pancytopenia. Figure 30.6 demonstrates

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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an exponential decrease of lymphocytes during the first 4 days postaccident.

Within 36 hours of the accident, blisters were noted on the volar aspect of the right third finger, and within another day extensive blistering was noted on both palmar and volar surfaces of the hand. A decision was made on day 3 to drain the blisters surgically but by the third week, the right hand had progressed to dry gangrene. Desquamation of the epidermis involved almost all of the skin of the dorsum of the forearm and hand. In addition, epilation was almost complete at the time of death.

On day 24, the patient’s temperature had risen to 41.1◦C. He had lost a great deal of weight, developed thoracoabdominal erythema, and had signs of sepsis. The patient became comatose and died on the same day. During the patient’s clinical admis- sion, treatment consisted of fluid support, penicillin antibiotic therapy, thiamine, and two blood transfusions.

On autopsy, severe skin necrosis was observed as well overt dry gangrene. The cardiorespiratory system was significant for pericarditis, cardiac hypertrophy, pulmonary edema, and alve- olar hemorrhage. The spleen was noted to have no germinal centers and the mucosa of the large bowel and the buccal mucosa were ulcerated. The bone marrow was noted to be hypoplastic and lymph nodes also showed significant lymphocyte depletion. The testes demonstrated significant atrophy with aspermia. A solitary ulcer was noted in the large colon as well as a right renal infarct.146

Case 2 – Los Alamos plutonium sphere (GI syndrome; cutaneous radiation injury syndrome; acute dose approximately 21 Gy, dose to the left hand 150 Gy)

The patient was a 32-year-old man, admitted to the hospital within 1 hour of the accident. His medical history was generally unremarkable. His occupational history was significant only for several prior, generally chronic occupational exposures, none exceeding 0.005 Gy in a week. The patient complained of nausea in the hour prior to admission and vomited once in the first hour after the accident.

The general condition of the patient was good in the first 5 days postaccident. On the fifth day there was a precipitous drop in his leukocyte count, and his condition quickly declined. The patient rapidly lost weight, became mentally confused on the seventh day, became comatose, and died on the ninth day.

Medical therapy during the 9-day course was largely sup- portive. Penicillin (50,000 U) was given intramuscularly every 3 hours beginning on day 5 because of granulocytopenia. Blood transfusions were also given daily after the fifth day. On day 6, fever and tachycardia developed, and on day 7, the patient developed a severe paralytic ileus. The patient died on day 9 in cardiovascular shock. At the time of death, both hands showed extensive radiation damage.

On autopsy, examination of the skin was remarkable for early vesicle formation in the abdominal skin and marked epidermal damage. The cardiorespiratory system was remarkable for car- diac hemorrhage, myocardial edema, and the terminal bronchi showed features of aspiration pneumonia. The spleen exhibited no germinal centers and the mucosa of most of the GI tract showed sloughing, most pronounced in the jejunum and ileum. Widespread degenerative changes were noted in the adrenal cor- tex as well as hyaline degeneration in the renal tubular epithelium. Examination of the red bone marrow (myeloid tissue) showed it to be of liquid consistency.146

Case 3 – Los Alamos Liquid Criticality Event (Central nervous system syndrome; dose to the upper extremity 120 Gy ± 50%)

The patient was a 50-year old man with no significant medical history. The clinical course has been divided into four separate phases

■ Phase 1 (20–30 min postevent): immediate physical collapse and mental incapacitation, progressing eventually into semi- consciousness

■ Phase 2 (90 min): signs and symptoms of cardiovascular shock accompanied by severe abdominal pain

■ Phase 3 (28 h): subjective minimal clinical improvement ■ Phase 4 (2 d): rapid development of irritability and mania,

progressing to coma and death

The clinical course was remarkable for continuing, profound hypotension, tachycardia, and intense dermal and conjunctival hyperemia. The patient died 35 hours after exposure.

On autopsy, examination of the bone marrow was most significant for absence of mitotic activity. The lungs showed pyknotic, degenerating cells in the pleura, degenerating lympho- cytes and neutrophils in the subpleural connective tissue and many areas of focal atelectasis interspersed with foci of emphy- sema. All lymph nodes were markedly atrophic and lymphoid follicles in the spleen were greatly depleted.

Examination of the heart showed acute myocarditis, myocar- dial edema, cardiac hypertrophy, and a fibrinous pericarditis. Examination of the brain demonstrated cerebral edema, dif- fuse vasculitis, and cerebral hemorrhage. The GI system showed necrosis of the anterior gastric wall parietal cells, acute upper jejunal distention, mitotic suppression throughout the entire GI tract and acute jejunal and ileal enteritis.147

Case 4 –Wood River Junction (Central nervous system syndrome; approximately 100 Gy)

The patient was a 38-year man with no significant medi- cal history. Following the initial criticality excursion, the patient appeared stunned, ran from the building, and immediately vom- ited. He also experienced instantaneous diarrhea and complained of severe abdominal cramping, headache, and thirst and he was perspiring profusely. His initial vital signs showed borderline blood pressure elevation and tachycardia. Approximately 4 hours after the accident, the patient experienced transient difficulty in speaking, hypotension, and tachycardia. A portable chest x-ray 16 hours after admission revealed hilar congestion. The physical examination showed the left hand and forearm to be edematous and also demonstrated left-sided conjunctivitis and periorbital edema (Figure 30.7). On day 2, the patient became very disori- ented, hypotensive, and anuric. The patient died 49 hours after the accident in cardiovascular shock.

At autopsy, interstitial edema of the left hand, arm, and abdominal wall was noted. Examination of the heart, lungs, and abdominal cavity revealed acute pulmonary edema, bilateral hydrothorax, hydropericardium, abdominal ascites, acute peri- carditis, interstitial myocarditis and inflammation of the ascend- ing aorta. Examination of the GI tract showed severe subserosal edema of the stomach and of the transverse and descending colon. The bone marrow was noted to be aplastic, and the lymph nodes, spleen, and thymus were depleted of lymphocytes. The brain showed minimal effects, with rare foci of microglial change.

.

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Figure 30.7. Wood River Valley patient 24 hours postac- cident. Note edema in the left arm. Figure reprinted with permission of the New England Journal of Medicine.

The testes showed interstitial edema and overt necrosis of the spermatogonia.148

RECOMMENDATIONS FOR FUR THER RESEARCH

New treatments for radiation injury are emerging that may accel- erate healing of acute radiation injuries and/or minimize the delayed effects of acute radiation exposure such as fibrosis, radi- ation nephropathy, and other complications. Current research is exploring the possibility of translating therapies that have been efficacious in the treatment of chemotherapy-induced myelo- suppression, GVHD, thermal burns, ischemic injury (e.g., dia- betes), and other disorders to be used for the management of radiation-induced injury.

Many of the therapies currently under consideration as potential radiation countermeasures were developed to address problems of supportive oncology. Many chemotherapeutic agents share with radiation the property of killing rapidly divid- ing cells and thus producing toxicity profiles (e.g., with pro- nounced bone marrow and GI toxicity) that mimic the effects of radiation. Drugs and therapeutics that have demonstrated efficacy in preventing, mitigating, or treating such toxic effects are obvious candidates for development as radiation counter- measures. The efficacy of CSFs such as filgrastim, pegfilgrastim, and sargramostim in shortening the duration of neutropenia after chemotherapy is well established and these products are widely used clinically for this purpose. Palifermin (also known as keratinocyte growth factor) is licensed for the mitigation of mucosal toxicity in patients receiving bone marrow transplants and has been evaluated in animal models as a radiation counter- measure. Farrell and colleagues demonstrated that keratinocyte growth factor given prior to radiation and/or chemotherapy pro- tected mice from GI injury and mortality.149 More recent studies with postradiation administration of keratinocyte growth factor, alone and in combination with other radiation countermea- sures, have demonstrated mucosal protection that may result in improved survival in preclinical models.150,151 Newer agents, such as the second-generation thrombopoietin receptor agonists,

are being studied for the mitigation of chemotherapy-induced thrombocytopenia and other side effects of chemotherapy. None of these agents are currently licensed in the U.S. for the treatment of radiation injury. Such agents are now being studied in animal models of acute radiation exposure and it is possible that the benefits observed when they are used to reduce the toxicity of chemotherapy will translate into the radiation setting.

Others forms of injury not directly targeting rapidly divid- ing cell populations also appear to share common mechanistic pathways with radiation injury. Trauma, for example, appears to up-regulate many of the same proinflammatory cytokines (e.g., transforming growth factor–β and tumor necrosis factor–α) and matrix metalloproteinases as acute radiation exposure, whereas other cytokines (e.g., platelet-derived growth factor and fibroblast growth factor) might be at insufficient levels for max- imal healing.152–154 Treatments that affect cytokine levels have demonstrated significant efficacy at mitigating the acute effects of many kinds of injury in clinical studies and preclinical models, and it is reasonable to hypothesize that they may demonstrate efficacy in the treatment of radiation-induced injury and/or radi- ation combined injury. For example, becaplermin, a recombi- nant human platelet-derived growth factor, is FDA-approved for lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or deeper with an adequate blood supply, and it may also have efficacy in radiation-related injury.155 The role that individual cytokines play in the healing process is com- plex, however, and applications or generalized class inhibition of some of the cytokines may have either beneficial or deleterious properties depending on the stage of the healing process.156–158

Commercially available tissue-engineering products have also demonstrated efficacy in wound repair by providing a protective barrier and possibly an environment rich in cytokines for the treated wound.

The direct administration of cytokines also appears to offer great promise. Combination therapy with cytokines clearly shortens the duration of hematopoietic pancytopenia in preclin- ical models. Herodin et al., demonstrated that in animal models the combination of stem cell factor + Flt3-ligand + throm- bopoietin + interleukin 3 (regimen name: SFT3) reduced the period of thrombocytopenia and blood transfusions required after 7 Gy of total-body irradiation. Furthermore, the addition of pegfilgrastim to the combination shortened the period of neutropenia compared with the control and SFT3 groups. Bone marrow activity recovered faster in the SFT3 groups compared with the control. Of note, no long-term mutagenic toxicity appears associated with SFT3.159 Herodin et al., also demon- strated that postradiation administration of keratinocyte growth factor and SFT3 resulted in 75% survival at 30 days compared to the controls of less than 10% (p < 0.01). Thus, treatments that address multiorgan failure appear promising.151

Therapies that treat or mitigate both the acute and late effects of radiation exposure are being investigated. For exam- ple, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists have been shown to decrease chemi- cal, mechanical, and radiation acute and/or late effects in a variety of organs.160–164 Suppressing or regulating the acute or chronic inflammatory response also appears to expedite the healing process. Although being more susceptible to infection, neutrophil-depleted mice, for example, have demonstrated more rapid wound closure, presumably as a result of the suppres- sion of neutrophil-mediated inflammation.165 There is emerg- ing evidence to suggest that treatments that suppress the ongoing

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inflammatory response may accelerate repair while minimizing late sequelae such as fibrosis and scarring.166

The poisoning of Russian dissident Alexander Litvinenko in London in 2006 with 210Po has underscored the lethality poten- tially associated with the internalization of radionuclides and thus the importance of developing new and improved meth- ods of decorporating radionuclides. In recent years, the Radia- tion Countermeasures Program at the U.S. National Institutes of Allergy and Infectious Diseases, National Institutes of Health has funded research to support the development of orally avail- able DTPA, nano-engineered sorbents, chitosan-based materials, and other novel chelating agents. Several of these projects have demonstrated improved decorporation and toxicity profiles in preclinical models and work is continuing at the time of writing. The goal is to expand the limited armamentarium of decorpo- rating agents in coming years to include agents to treat per- sons internally contaminated with radionuclides (such as 90Sr, 60Co, and 210Po) for which no licensed therapies are currently available.

Another area of concern and controversy is the exposure of large numbers of people to low doses of ionizing radiation from an atomic bomb explosion or from diagnostic procedures resulting in stochastic late effects, specifically cancer. One area of current interest is the population effect of the widespread use of CT scans. In a prominent 2007 article, Brenner and Hall suggest that 1.5–2% of all cancers in the United States may be attributable to radiation from CT studies.167 The study is mainly based on the linear no-threshold model for cancer induction and extrapolates medical data from atomic bomb survivors. The linear no-threshold model, however, has been the subject of con- tinuing controversy because no increased evidence of cancer has been observed at doses of less than 10 cGy in adults and infants. Some authorities have rejected the linear no-threshold model as the basis for radiation exposure risk assessment at very low doses. For example, the French Academy of Medicine “denounces uti- lization of the linear no-threshold (LNT) relation to estimate the effect of low doses to a few mSv.”168 A second issue involves utilizing the medical data on atomic bomb survivors for esti- mating the effects of diagnostic radiation. Although absolute energy exposure may be similar, the qualities of the ionizing radiation that produce such exposures are different. Diagnostic medical devices use x-rays and typically result in highly nonuni- form exposures, whereas the prompt radiation associated with fission and delayed radiation from fallout results in more nearly uniform exposures to both electromagnetic (gamma rays and x-rays) and particulate (alpha particles, beta particles, and neu- trons) forms of radiation. It remains to be demonstrated that the carcinogenic potential of these different kinds of exposure are identical. Uncertainty also remains as to the risk imposed by in utero exposures below 10 cGy because of the contradictory epidemiological data.169 Regardless, the development of highly safe therapies for use in large exposed populations to minimize stochastic effects is warranted, especially at doses at which there is clear evidence for increased cancer induction, that is, more than 10–20 cGy.

Finally, for countermeasures such as those described herein to be useful, emergency management officials must have reli- able mechanisms for delivering them to exposed individuals in a timely fashion. Delivery of products from centralized stockpiles may be sufficient for countermeasures that can be administered 24–48 hours after exposure but will likely be inadequate for highly time-sensitive countermeasures such as potassium iodide. The

U.S. National Academy of Sciences recently reported on strate- gies for stockpiling and distributing potassium iodide, and other authors have proposed alternative strategies of forward deploy- ment that could facilitate the rapid distribution of other time- sensitive countermeasures.170,171

CONCLUSIONS

As noted in the introduction, mass exposure to radiation does not occur frequently but such events, when they do occur, present tremendous challenges to affected communities. With the con- cerns of recent years about nuclear or radiological terrorism, it would also appear that the risk of deliberate mass exposures to radiation has increased. Nations, regions, and communities must maintain their primary focus on preventing the occurrence of radiological and nuclear accidents but should engage in pru- dent consequence management planning as well. Planning must include provision for the medical and public health response to radiation emergencies, including the management of large num- bers of potentially contaminated patients, the performance of accurate biodosimetry and dose assessment, the rapid delivery and distribution of pertinent medical countermeasures, the clini- cal care of radiological casualties, and the extension of emergency psychological and social services to traumatized communities.

In future years, the application of novel scientific tools and techniques to the challenges of radiobiology and normal tis- sue injury will likely result in significant advances in the ability to diagnose, mitigate, and treat both the ARS and the delayed effects of acute radiation exposure. The application of genomic, proteomic, and metabolomic probes to irradiated tissue may result in new ways to perform rapid dose assessments and the development of a truly predictive biodosimetry. In the realm of therapeutics, a better understanding of the systems biology of radiation injury will likely lead to the rational design of targe- ted radiation countermeasures, an enhanced understanding of the role of growth factors, and pleiotropic cytokines in miti- gating radiation injury. Improved methods, perhaps involving novel approaches to cell therapy and regenerative medicine, for promoting immune reconstitution and tissue repair after high- dose irradiation are on the horizon. After a period of comparative neglect, the future for the fields of radiobiology and normal tissue injury appears to be bright.

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172. Adapted from Glasstone S, Dolan P. The Effects of Nuclear Weapons. Department of the Army Pamphlet No. 50–3 (1977; Department of the Army, Washington, DC.

173. Adapted from Glasstone S, Dolan P. The Effects of Nuclear Weapons. Department of the Army Pamphlet No. 50–3 (1977; Department of the Army, Washington, DC.

Koenig, K. L., & Schultz, C. H. (Eds.). (2009). Koenig and schultz's disaster medicine : Comprehensive principles and practices. Cambridge University Press. Created from apus on 2023-10-16 21:32:31.

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