The end of the Cold War more than a decade ago brought with it the promise of a decreased likelihood of thermonuclear war and the use of strategic nuclear weapons. Unfortunately, recent events within the United States and around the world have forced us to critically re-evaluate our preparedness not only for the chemical and biological threats discussed in this series, but also for smaller scale radiation-related terrorism scenarios. These could range from deliberate dispersal of radioactive material to detonation of crude nuclear weapons by organizations bent on using the most deadly means available to promote their cause.
The increased probability of such an event is related to many factors, including the greater ubiquity of technical knowledge obtainable through sources as easily accessible as the Internet; an increase in the availability of radioactive isotopes, particularly after the collapse of the former Soviet Union; and the relative laxity of security measures in regard to this nuclear source material.1-2 These factors, considered in the context of recent terrorist incidents, make it clear that contingencies for dealing with such events from a medical standpoint should be an essential part of any emergency response plan regarding the threat of terrorism.
Depending on the severity of the event, the logistical response to radiation-related terrorism would likely necessitate the coordination of local, state, and federal resources such as the Federal Emergency Management Agency, the Nuclear Regulatory Commission, and the Environmental Protection Agency, among others. At the local level, increased awareness and preparedness by both pre-hospital and hospital personnel likely to be on the front lines of disaster management will need to take place. While health care professionals on these front lines will use common medical treatments regardless of age considerations, there are clearly unique aspects concerning children's increased vulnerability and their modes of treatment, as well as their physical and psychosocial responses that need to be considered by all individuals involved in treating childhood victims. This article reviews the general medical approach to the patient exposed to ionizing radiation, with a special emphasis on the unique concerns of the pediatrie patient.
METHODS OF DISPERSAL
One of the first considerations in any medical response to a radiation exposure event is the method of radiation dispersal. In terms of intentional release, the first category would include the use of conventional detonation devices (eg, explosives) to dispense radioactive material into the environment. The most common manifestation of this type of mechanism would be a radiologie dispersal device, commonly referred to as a dirty bomb. In addition, this category could also include the deliberate release of radioactive material through sabotage of a radiologie facility such as a radiotherapy clinic or radiopharmaceutical factory, at one end of the spectrum, to an intentional attack on a commercial nuclear power plant, at the other end of the spectrum.3 Understanding the nature of the incident can help to assess the likelihood of severe radiation exposure in addition to the possibility of other traumatic, nonradiologic injury.
The second category of radiation dispersal involves the use of conventional nuclear weapons that use an uncontrolled fission or fusion reaction to release massive amounts of radiation. Although fusion weapons have far greater capacity for destruction, only a handful of technologically advanced countries have the materials, financing, and technology to produce them. On the other hand, the detonation of even a crudely constructed small fission weapon could cause significant damage from both the initial release of ionizing radiation as well as the subsequent nuclear fallout, resulting in devastating amounts of morbidity and mortality for a prolonged period.
Current knowledge regarding the medical management of the acute and long-term effects of radiation injury in humans owes a great deal to the experiences garnered from the aftermath of the nuclear detonations in Hiroshima and Nagasaki in 1945, the experimental detonations in the Marshall Islands by the US government (1946-1958), and more recently, from the nuclear accident at the Chernobyl power plant in 1986 and the less publicized cesium-137 leakage accident in Goiania, Brazil, in 1987. In the latter incident, Brazilian villagers found a relatively small amount of cesium-137 in a canister from an abandoned radiotherapy machine. Within days after the canister was broken apart in an attempt to salvage the mysterious glowing material, four individuals, including one child, had died, 30 suffered serious radiation injury, and hundreds more were treated for exposure. Detailed summaries and medical overviews of all of these incidents are available in the literature, and references to them are made throughout this review.4-9
TYPES OF RADIATION
In general, the medical effects of ionizing radiation depend on the type or types of radiation to which an individual has been exposed, the amount of radiation absorbed, and the duration of the exposure. There are two types of ionizing radiation: paniculate and electromagnetic. Alpha and beta radiation are examples of particulate radiation. While alpha particles are relatively large and slow moving, and do not penetrate clothing or skin, if inhaled or ingested they can be significant sources of internal radiation and damage. On the other hand, beta particles, which are found primarily in nuclear fallout, are much smaller and travel faster, and therefore can penetrate the unprotected dermis resulting in so-called beta burns, which are indistinguishable from thermal burns. As with alpha particles, effects on internal organs only occur if inhaled or ingested.10
Patterns of Early Lymphocyte Response in Relation to Dose
Of more significant potential to cause tissue damage is gamma radiation, which, along with x-rays, is a form of electromagnetic radiation. Gamma radiation can be emitted both during a nuclear detonation and in fallout, as well as during exposure to the isotopes of certain elements such as cobalt and cesium. Of greatest potential to cause tissue damage, however, are neutrons, which are emitted only during a nuclear detonation. Their ready penetration of biological tissue can result in damage 20 times greater than that due to gamma rays.10,11
UNITS OF MEASUREMENT
The second factor that determines the medical effects of radiation is the dose. In general, the greater the dose, both acute and accumulated over time, the greater the acute and long-term consequences suffered by the individual. The quantification of the radiation dose has been measured historically by the radiation absorbed dose (rad); however, this terminology has been replaced by the international measure, the gray (Gy), which is equal to 100 rad. Since the biological response to radiation is also dependent on the type of radiation absorbed by the tissue - for example, 1 Gy of neutron radiation has greater effects than 1 Gy of gamma radiation - dose equivalents also are measured in units that take this varying energy transfer into account. These units are the roentgen equivalent man (rem) which equals 1 J/kg, or the sievert (Sv), which is the international unit equivalent to 100 rem.
ACUTE RADIATION SYNDROME
Although historically the most common radiologie injuries encountered have been localized exposures to the hands and extremities of individuals manipulating radioactive materials in the nuclear industrial and medical radiation field,12 the following discussion focuses mainly on the acute radiation syndrome (ARS), which refers to the medical effects of either uniform or nonuniform whole body exposure. It is generally recognized that attention to the clinical manifestations of ARS gives the best guide to medical therapy as well as to the ultimate prognosis of victims who have received significant radiation exposure.13 Victims of whole body exposure of less than 0.7 Gy are unlikely to manifest any of the signs or symptoms of ARS.14
The acute radiation syndrome occurs in a series of clinically recognizable phases beginning with a prodromal period, followed by a latent phase during which symptoms subside, then reappearance of illness, followed eventually by recovery or death.11 The prodromal phase can occur within hours of exposure and consists of nausea, fatigue, and vomiting. With higher doses, symptom onset is more rapid and may include fever and prostration as well. This complex of symptoms has been referred to as acute radiation sickness. After a period of 1 to 2 days, these complaints disappear, and a symptom-free latent period ensues, the duration dependent on the dose of radiation received. After this variable latent period, overt illness then reoccurs, the specific symptoms of which are determined by the organ system most affected, which is in turn dependent on the effective dose absorbed.11-14
With dosages between approximately 0.7 and 4 Gy, the hematopoietic system is most affected, manifested as pancytopenia due to bone marrow hypoplasia and consequent immunosuppression." The predominant complications of this syndrome include infections, bleeding, and anemia, which begin to occur an average of 2 to 3 weeks after exposure.14 Since the lethal dose for 50% of individuals within 60 days of whole body radiation is 4.5 Gy assuming optimal care,15 a significant portion of patients with the hematopoietic syndrome are expected to survive if given appropriate therapy.
Threshold Radioactive Exposures and Recommended Prophylactic Single Doses of KI
At dosages in excess of 8 Gy, gastrointestinal manifestations are most prominent, secondary to damage to the mucosal epithelium. The subsequent gastrointestinal syndrome results in massive diarrhea with fluid and electrolyte imbalance and sepsis from enteric organisms. Death ensues within days if not aggressively treated. The onset of these gastrointestinal symptoms, which are distinct from those in the prodromal phase, usually occurs within a week.16
The neurovascular syndrome is likely to occur at doses in excess of 20 to 40 Gy. It is manifested initially by vomiting and diarrhea within minutes of exposure, followed by hypertension, decreased consciousness, possible convulsions, and death within 1 to 2 days. In order to be exposed to such a high radiation dose, the individual generally needs to be so close to a nuclear detonation that death from thermal burns and blast effects would likely occur.11
ASSESSMENT OF EXPOSURE
An accurate assessment of the radiation dose involved is key to medical classification and management. Physical dosimetry using environmental monitoring devices may be difficult to perform due to location or physical damage to the devices in the chaos of the exposure event. In addition, physical dosimetry does not take into account individual sensitivity to exposure.13 For these reasons, at both Chernobyl and Goiania, assessments relied more heavily on biological dosimetry.17,18
Commonly used forms of biological dosimetry involve such measures as determining the rate of fall of peripheral lymphocyte counts over time as a direct correlate of the degree of whole body radiation (Figure). This method is relatively accurate for doses up to 3 Gy. At higher radiation doses, measures of peripheral granulocytopenia, which occurs between 1 and 4 weeks after exposure as the release of granulocytes from the marrow is aborted, are also useful. Additionally, cytogenetic studies examining the frequency of dicentric chromosomes in blood or bone marrow historically have been of benefit, particularly during the Chernobyl incident.16 Finally, since higher doses of radiation cause a faster onset of prodromal symptoms, measuring the duration to onset of these symptoms is valuable in assessing the dose absorbed.10,11,16
Decontamination and Sampling
Depending on the method of radiation dispersal, traumatic injuries such as thermal burns, lacerations, and fractures from blast effects may be the most acute life-threatening medical concerns. Such injuries may need attention before any specific radiation injuries are addressed. It is important not to delay basic and advanced life-support measures if the patient cannot be moved to assess contamination status. Unlike victims of chemical or biological exposure, it will be unlikely that the injured patient is a significant source of medical hazard to health care providers during a radiation exposure incident."
If possible, once the patient has been stabilized, decontamination consisting of clothing removal and washing with soap and water should take place along a prescribed decontamination route, preferably before transport to a medical facility for more definitive treatment. Because this may not occur for practical reasons, hospital contingency plans for radioactive decontamination may need to be enacted to prevent contamination of the treatment areas.19
Careful debridement of any residual radioactive material should be performed if possible. If internal contamination is thought to have occurred due to particle ingestion, selective use of cathartics in the conscious patient and gastric lavage should be considered. Conversely, if catharsis is not deemed necessary and prodromal symptoms due to ARS become severe, anti-emetics can also be administered as needed.16
After the patient is stabilized and decontaminated, urinary, fecal, skin, and wound samples should be obtained in addition to nasal swabs to identify potential inhalation of paniculate radiation.20 Measures of biological dosimetry should then be performed expeditiously and include an initial complete blood cell count, which should be repeated every 6 to 8 hours for the first 24 to 48 hours, and daily thereafter.21 Initial attention is paid to the fall in lymphocyte count, followed later by decreases in the neutrophil and reticulocyte counts.7·21 If possible, cytogenetic analysis of cultured lymphocytes obtained before the fall in counts should be undertaken for further completion of biological dosimetry.11
The decision to initiate specific pharmacotherapy in addition to supportive care is an issue that should be undertaken with authoritative advice at the local or federal level if possible.20 The most widely used post-exposure treatment to date involved the distribution of 1 8 million doses of potassium iodide (KI) to children and adults in Poland after the Chernobyl accident in 1986.22 Potassium iodide is used to inhibit thyroid uptake of radioactive iodine (131I), the most significant radionuclide released from nuclear reactors. Both the fetus after 12 weeks gestation and the young child are uniquely sensitive to 131I intake because of their proportionately smaller thyroid gland, resulting in greater susceptibility to thyroid cancer at a given radioactive dose compared to adults.23 This increased latent risk for thyroid cancer in children was found in childhood survivors of the atomic bombs in Japan,24 the Marshall Islands residents exposed to nuclear fallout during the 1 950s,25,26 and most recently in Belarus, Ukraine and the Russian Federation following the Chernobyl nuclear accident.22-23,27
Administration of KI within 1 hour after a 131I thyroid dose greater than 0.1 to 0.3 Gy effectively blocks 90% of uptake; with administration at 4 to 5 hours there is a 50% block; and after 1 2 hours there is little effect.28 Despite the slight risk of hypothyroidism, particularly in neonates, KI prophylaxis is justified in newboms, children, adolescents, and pregnant women exposed to 131I because of the significantly increased risk for thyroid cancer. Current recommended dosages for KI are listed in the Table.29
Potassium iodide exerts its protective effects for approximately 24 hours. The decision to repeat the dose depends on a number of factors, including the likelihood of continued exposure. Such broad recommendations likely would be made at the federal or international level based on the location and nature of the event. Iodide can be administered in a variety of forms including scored KI tablets, which can be crushed and placed in suspension, Lugol's solution (10% KI), or super-saturated potassium iodide drops.11,22
There is practical experience with other specific therapies also, most notably the administration of ferric ferrocyanide (Prussian Blue) to the patients exposed to cesium- 1 37 in Goiania. In its soluble form, Prussian Blue serves as an ion exchanger effective in removing cesium, thallium, and rubidium.20 During the accidental leakage of cesium137 at Goiania, 249 individuals were exposed to this radioisotope. Prussian Blue was administered to 46 of the individuals, including 5 children. Although specific doses for children have not been evaluated, no significant side effects were noted when these children received standard adult dosages.30 The generally recommended dose is l g taken orally three times a day for 1 week or longer.10
Diethylenetriaminepentaacetic acid (DTPA) is a powerful chelating agent effective in removing heavy metal isotopes such as plutonium. It is used intravenously as Ca-DTPA to induce urinary excretion of the more radioactively stable complexes it forms with several heavy metal isotopes. A general rule is that if the contaminant has an atomic number greater than 92 (uranium), DTPA can be used in an attempt to chelate the agent.20 The adult dose is l g of Ca-DTPA in 1 OO mL of normal saline given over 60 minutes.10 Pediatrie dosing information is unavailable.
Diethylenetriaminepentaacetic acid should not be used after uranium exposure because it can increase the potential for renal damage. Instead, alkalinization of the urine, which produces a more stable and less nephrotoxic intermediary, should be pursued with intravenous or oral bicarbonate and increased fluid intake and diuretics.20
For tritium exposure, increased fluid intake can decrease the effective biological half-life by up to 50% if given early.20 As with all of these therapies, the sooner they can be initiated after identification of the contaminant, the more beneficial the potential outcome.
Regardless of the specific radioisotope involved, supportive therapy is central to maximizing the likelihood of survival in significant whole body exposure. The majority of patients with survivable exposures beyond the generally asymptomatic level of 0.7 Gy eventually manifest hematopoietic symptoms.13 Supportive merapy therefore is focused on blood component transfusions to prevent bleeding, antibiotics and antiviral drugs to prevent infection, and measures designed to recover bone marrow activity, specifically the use of hematopoietic growth factors and bone marrow transplantation.
Platelets are the first and most important blood component needed. Singledonor, irradiated platelets should be administered repeatedly to maintain a platelet count above 20 X 109/L.7 Red blood cell transfusions are generally needed later for the delayed onset of anemia. Transfusion should be used to maintain the hematocrit above 30% to provide a margin of error should severe bleeding occur.16
Although prophylactic antibiotics generally are not indicated in non-neutropenic radiation patients, their use to treat febrile, neutropenic patients is similar to that given to immunocompromised cancer therapy patients according to individual institution and hospital guidelines. Prophylactic agents such as trimethoprim-sulfamethoxazole and acyclovir for herpes simplex in patients with neutropenia and frequently associated T-cell dysfunction are recommended. The use of protected environments such as laminar airflow rooms may delay infection, but have not been shown to definitively improve survival.16,31
Hematopoietic Growth Factors
Hematopoietic growth factors, eg, granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF)1 were used at Chernobyl and Goiania in attempts to lessen the severity and duration of neutropenia, and thereby the risk of infection. Their use should be considered in patients with a significant likelihood of severe neutropenia as determined by their estimated radiation dose. For maximum benefit, treatment should begin within 24 to 72 hours after initial exposure.3,11
Bone Marrow Transplantation
In the instance of likely irreversible bone marrow failure despite maximal therapy, bone marrow transplantation has been used, most notably in the aftermath of Chernobyl. Although the ultimate benefit is not entirely conclusive because of morbidity and mortality associated with consequences such as graft-versus-host disease, the decision to use bone marrow transplantation is made in only selected patients by experts evaluating the likelihood of death caused by other toxic effects unrelated to neutropenia.16 The availability of suitable donors is a factor as well. If transplantation is considered, human leukocyte antigen typing should be conducted before a significant decrease in lymphocyte count occurs.18
Treatment of the patient with the gastrointestinal syndrome involves vigorous intravenous fluid and electrolyte replacement therapy. Since the absorptive capacity of the gut is severely damaged, hyperalimentation may be needed. Despite these interventions, death often results secondary to bleeding, damaged bowel mucosal integrity, and enteric septic shock.16
ACUTE SUSCEPTIBILITY IN CHILDREN
The injury manifestations and treatment guidelines above are generally similar regardless of patient age. On the other hand, children are much more susceptible to serious injury from both external and internal radiation. They have a lower breathing zone than adults and therefore will have greater proportional exposure to the settling paniculate effects of fallout. Very young children are also more likely to engage in pica of potentially contaminated materials in their environment. Although not related to pica, the ingestion of radioiodine through its efficient transmission from a contaminated environment into goat, cow, and human breast milk is thought to be a significant mechanism for radioiodine uptake in children.32 Given the same amount of milk consumption, a child's thyroid gland concentrates much more iodine than that of an adult.7
Other risk factors for children include their higher respiratory rate, which makes them directly more susceptible to inhalation of radioactive particles. From an external radiation standpoint, the skin of a child is thinner and more delicate. Along with their proportionately greater body surface area, children therefore have a higher likelihood of more severe radiation and thermal burns after a given radiation exposure. Because of their relative lack of intravascular volume reserve compared to adults, children are much more susceptible to dehydration, especially during the initial prodromal phase of ARS. In addition, very young children and babies are unable to shield their eyes during a nuclear detonation, resulting in a greater propensity to ocular effects.
LONG-TERM SUSCEPTIBILITY IN CHILDREN
Of even greater importance in children are the long-term health effects of ionizing radiation that may not become apparent until months or years after exposure. Clearly, the longer life expectancy of children can account for greater potential over a lifetime for long-term radiation effects to become manifest.33 On the other hand, it is clear from the survivors of Hiroshima, the Marshall Islands, and Chernobyl that many of these effects occur predominantly in individuals who were children at the time of exposure and not in adults after the same latent period. The most dramatic of these is the increased incidence of thyroid cancer documented in childhood survivors of each of the above events. This increased incidence has a variable latency but was as short as 3 to 4 years after Chernobyl.34 The fact that there is little risk of thyroid cancer in patients exposed after age 20 makes the urgency of KI administration greater in children.3 A second long-term effect more prevalent in the pediatrie age group is the increased risk of radiationinduced leukemia, which is approximately twice the risk as that of adult survivors after Hiroshima.33 This increased incidence begins after 2 years, peaks at 6 years, and extends to a total of 25 years.34 These effects are not surprising since the hematopoietic cells of children have a higher mitotic index than those of adults and are therefore more prone to mutagenesis.
Other malignancies shown to occur with greater prevalence after childhood exposure to radiation is the later development of breast cancer in girls not only who were adolescents at the time of the Hiroshima detonation, but also who were exposed prepubertally. The latent period for radiation-induced breast cancer in these individuals was a minimum of 10 years.35 Exposure of radiation to the fetus in utero also has significant effects, ranging from an even higher risk of leukemia than that for children to an increased incidence of mental retardation, microcephaly, and postnatal growth retardation.33,35
Although the physical effects are often more easily quantifiable, the psychosocial effects of real or perceived radiation exposure affect a far greater number of individuals.36 Children have unique developmental characteristics that make them much more vulnerable psychologically. Depending on the age of the child, this increased vulnerability can manifest itself in a variety of ways including developmental regression, greater dependency on parents, sleep problems (including nightmares), altered play, and social withdrawal. The inability of some children to understand surrounding events may be compounded by the chaos of the event and possible separation from their parents or caregivers.
During the Chernobyl incident, the factor associated with the highest psychological distress among adults was being a mother with children younger than 18 years.37 It was demonstrated that there is a direct correlation between a parent's response to a disaster and that of the child.38 Although many of the symptoms that children manifest are to be expected, referral to a mental health professional may be appropriate if significant symptoms persist beyond several weeks.37 It is crucial for both parents and health care providers to be aware of these vulnerabilities to help children resolve the psychosocial effects of the event regardless of their etiology.
Heightened public awareness of the threat of radiation-related terrorism, in addition to risks already associated with accidental exposure to ionizing radiation, give pediatricians a platform from which to address the unique needs of children in the aftermath of a radiation exposure event. Although many acute needs are common to adults and children, there are differences in both the physiological and behavioral responses of the pediatrie patient that should be anticipated. It is therefore important that mass casualty exercises involving radiation exposure scenarios include children, that appropriate supplies and medications for children such as KI are readily available, that research protocols regarding diagnosis and management of radiation injury include children, and that pediatricians become involved at all levels of the planning and implementation of the medical response. Beginning with personal education about the medical effects and treatment of radiation exposure, pediatrie health care providers have a critical role in ensuring that our most vulnerable population does not become a secondary concern.
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Threshold Radioactive Exposures and Recommended Prophylactic Single Doses of KI