The clinical manifestations of radiation injury in children are generally similar to those in adults. However, there are a number of characteristics that render the pediatric patient uniquely sensitive to the effects of radiation exposure (go to the Chapter 1 section, Children Are Not Small Adults).
Children have a greater body surface area to weight ratio than adults and skin that is more permeable and less keratinized, which renders them more vulnerable to both thermal and radiation burns. The inability of young children to shield their eyes also makes them more susceptible to ocular injury from blast, radiation, and thermal effects. This latter problem is compounded by the increased sensitivity of a child's lens to radiation damage. Children have a higher baseline respiratory rate than adults and also exist in a lower breathing zone, which makes them more vulnerable to both generalized inhalation exposure and particulate exposure from radioactive fallout. Children also have a lower intravascular volume reserve, rendering them more susceptible to dehydration from the gastrointestinal (GI) losses encountered in acute radiation syndrome (ARS).
Infants and young children are also more likely to engage in pica of radioactively contaminated materials in their environment. In addition, radioiodine, a common byproduct of nuclear reactor activity, is efficiently transmitted through both human breast milk and cow's milk, which are staples of the childhood diet.
The well-documented long-term effects of radiation exposure to the fetus and child are potentially of even greater concern for the more broadly exposed pediatric population. These effects can occur anywhere from months to years after initial exposure. The collective experience from the events in Hiroshima and Nagasaki, the Marshall Islands, and most recently Chernobyl, clearly show that children are more susceptible to developing many more long-term consequences of radiation exposure than adults over the same latent period. The most well-studied of these outcomes is the increased incidence of thyroid cancer in children after the Chernobyl accident in Belarus, Ukraine, and the Russian Federation. These thyroid cancers began within 4 years of exposure and continue to the present. Thyroid cancer incidence was dramatically increased almost exclusively in those younger than 20 years of age at the time of exposure, underscoring the unique susceptibility of the pediatric thyroid gland to radiation-induced malignant transformation.
The incidence of leukemia from Hiroshima and Nagasaki was twice as high in children as in adult survivors. This increased incidence began within 2 years, peaked at 6 years, and then regressed to baseline after 25 years. There was a particularly high incidence of chronic myelocytic leukemia and acute myelocytic leukemia, which are cancers not typically seen in non-irradiated pediatric populations.
In addition to thyroid and hematologic malignancies, the incidence of breast cancer in female Japanese survivors of the atomic bomb was increased among those who were 10 to 19 years of age at the time of exposure compared with those older than age 20. The minimum period of latency appeared to be 10 years after exposure. There was also a surprisingly higher incidence of subsequent breast cancer in girls who were younger than age 10 at the time of exposure, indicating increased sensitivity even in prepubertal girls with little breast tissue.
A number of effects have also been documented from fetal exposure to radiation throughout gestation, such as children born to female survivors in Nagasaki and Hiroshima. These effects include a higher incidence of mental retardation, microcephaly, and postnatal growth retardation, particularly with exposures in the first trimester. Fetal exposure after the first trimester was associated with a significantly greater risk of development of leukemia and thyroid cancer.
Children involved in a radiation-related incident will be particularly vulnerable to psychological trauma, as in any disaster or terrorist event. Depending on the child's stage of development, this increased vulnerability can manifest as generalized fear and anxiety, developmentally regressive behavior, sleep and appetite problems, altered play, school problems, or greater dependence on caregivers. This latter problem may be exacerbated by physical separation from parents in the chaos of the event. Repetitive television and news broadcasts relating to the event may even traumatize children in areas remote from the actual disaster, convincing them that they are also at risk.
Children also experience stress by witnessing the reactions of their parents. In one survey of adults exposed to the Chernobyl accident, the group displaying the highest level of psychological distress were mothers with children younger than 18 years of age. This finding has relevance to children, because a direct correlation exists between a parent's response to a disaster and the response of the child.
Any treatment plan regarding children exposed to radiation should take these unique vulnerabilities and parental reactions into consideration. Although many of the psychological reactions of children involved in a radiation-related incident are to be widely expected as an initial response, severe reactions or those persisting beyond several weeks may prompt the need for involvement by pediatric mental health professionals. Go to: Chapter 8, Mental Health.
The first priority during the care of anyone exposed to radiation is to treat life-threatening injuries before addressing radiation exposure and contamination. In general, evolving injuries such as burns, lacerations, and fractures need to be stabilized before decontamination and subsequent transport to facilities where radiation-specific injuries are managed. In most instances, radiation levels will not be known, and survey instruments may not be available. Contamination risks to medical responders will be minimal in most cases, unlike situations involving biological and chemical exposures. However, simple precautions such as wearing gloves and wrapping victims in sheets or blankets to reduce the spread of contamination should be done before transport.
Treatment of acute radiation syndrome (ARS) includes both general supportive care and specific actions and medications. No one is known to have survived whole body doses of radiation exceeding about 8 Gy. Therefore, those receiving doses of greater than 8 Gy can be considered expectant, although they may survive for a few months with extensive medical care. ARS is usually caused by direct radiation exposure, not internal contamination.
Supportive therapy is a key factor in minimizing morbidity and mortality with significant whole body exposure, regardless of the type of radiation. A baseline history should be obtained before or shortly after supportive therapy is initiated. The history should include information regarding the source of radiation, the duration of exposure, the interval between exposure and presentation, and the physical property of the radioactive compounds (e.g., solid, liquid, particulate). The review of systems and physical examination should be as complete as possible, particularly focused on those organ systems that show early signs of damage, such as the skin and the hematopoietic, GI, and neurovascular systems.
The first step is to make sure the victim has been medically stabilized and decontaminated, and that appropriate samples have been obtained for biological dosimetry. Next, the first symptoms likely to occur during the prodromal phase, such as nausea, vomiting, and diarrhea, should be addressed. Treatment of these early manifestations of ARS may range from minimal intervention to the use of parenteral fluids and antiemetic agents. Antiemetic agents include ondansetron or granisetron at dosages commonly used to prevent nausea and vomiting during chemotherapy. For children 4-18 years of age, ondansetron is usually given at 0.15 mg/kg TID (three times a day), and granisetron at 10 µg/kg/day. However, antiemetics may be contraindicated initially, particularly if catharsis is deemed necessary for internal decontamination.
During the first day, the focus should be not only on treating acute symptoms, but also on systematically recording them as a way of estimating the dose involved. When combined with other biodosimetric indices, the time to onset of clinical symptoms is particularly useful in determining prognosis and the extent of supportive care that may be needed much later in the clinical course.
Maintenance of adequate nutrition is important to counter the catabolic effects of radiation and to allow healing and recovery. Oral feeding is preferred if possible to maintain functioning of the intestinal mucosa and reduce risk of infection from parenteral feeding. Parenteral feeding may be necessary if the patient is not able to tolerate oral feedings or if fluid loss is profound due to diarrhea.
The main focus of supportive therapy in patients with survivable exposures between 1 and 8 Gy centers around the hematopoietic system. Hematopoietic syndrome may not become clinically apparent until after a latent period of 2-4 weeks. A key feature of this syndrome is neutropenia.
Established or suspected infection after exposure to radiation is usually characterized by neutropenia and fever. In general, such patients can be managed the same as other febrile neutropenic patients. However, important differences between the two conditions exist. Most individuals exposed to irradiation are otherwise healthy. They also generally are exposed to total body irradiation without the shielding that is used in therapeutic exposure to irradiation. Patients with neutropenia after radiation are also susceptible to irradiation damage to other tissues (e.g., lungs, CNS, etc.), which may require therapeutic interventions not needed in other types of neutropenic patients. Furthermore, irradiated individuals may respond to antimicrobial therapy in unpredictable ways, as has been shown in experimental studies in which metronidazole and pefloxacin therapies were detrimental to irradiated laboratory animals.
Hematopoietic growth factors, such as granulocyte colony stimulating factor (G-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF), are not Food and Drug Administration (FDA)-approved for the management of radiation-induced marrow aplasia. However, these growth factors have been used in the aftermath of a number of radiation accidents (e.g., Chernobyl and Goiania) in an effort to lessen the severity and duration of neutropenia and thereby reduce the risk of infection. The experience with these few clinical cases, along with even more convincing data from controlled studies in animals, suggest that early cytokine therapy can significantly enhance survival. Benefit is maximal if treatment begins within the first 24-72 hours after radiation exposure. In the absence of significant complicating injuries, cytokine therapy is recommended for radiation doses >3Gy in adults, and >2Gy in children. Practical limitations, such as limited availability and supply of cytokines, need to be considered when determining the level of exposure that indicates this treatment.
None of these cytokines is approved for the specific indication of radiation-induced illness. The long-acting form of G-CSF (pegfilgrastim) is FDA approved as a one-dose therapy for the management of chemotherapy-induced neutropenia in adults and adolescents weighing more than 45 kg. It is not approved for younger children and infants. The other two FDA-approved cytokines are G-CSF (filgrastim) and GM-CSF (sargramostim). These are administered daily until the absolute neutrophil count reaches >1,000. Dosages for adults and children are 5 µg/kg/day for G-CSF and 250 µg/m2/day for GM-CSF.
Each institution or agency should follow established guidelines to develop a standardized plan for the management of febrile, neutropenic patients. Antimicrobials should be used mainly in radiation victims who develop fever and neutropenia. An empirical regimen of antibiotics should be selected, based on the degree of neutropenia and on the pattern of bacterial susceptibility and nosocomial infections in the particular area and institution (Table 6.8). Broad-spectrum empirical therapy (see below for choices) with high doses of one or more antibiotics should be initiated at the onset of fever. The antimicrobial spectrum should include efficacy against gram-negative aerobic organisms, which account for more than 75% of the isolates causing sepsis. Aerobic and facultative gram-positive bacteria (mostly alpha-hemolytic streptococci) cause sepsis in about 25% of victims, so coverage for these organisms may also be necessary, especially in institutions where infection from these organisms is prevalent. Antimicrobials that decrease the number of strict anaerobes in the gut (e.g., metronidazole) generally should not be given, because they may promote systemic infection and death from aerobic or facultative anaerobic bacteria.
If infection is confirmed by cultures, the empirical regimen may require adjustment to provide appropriate coverage for the specific isolate(s). After the patient becomes afebrile, the initial regimen should be continued for a minimum of an additional 7 days. Therapy may need to be continued for at least 21-28 days or until the risk of infection has declined because of recovery of the immune system. A mass casualty situation may mandate the use of oral antimicrobials.
The initial antibiotic regimen should be modified when microbiological culture shows specific bacteria that are resistant to the initial antimicrobials. Modification, if needed, should also be considered after a thorough evaluation of the history, physical examination findings, laboratory data, chest radiographs, and epidemiologic information. If resistant gram-positive infection is evident, vancomycin should be added. If diarrhea is present, fecal cultures should be examined for enteropathogens (e.g., Salmonella, Shigella, Campylobacter, and Yersinia).
Antifungal coverage with amphotericin B is indicated for certain situations, including:
Oral and pharyngeal mucositis and esophagitis suggest Herpes simplex infection or candidiasis. Either empirical antiviral therapy, antifungal therapy, or both, should be considered in this situation.
Prophylactic antimicrobials should also be considered in any individuals exposed to doses >2 Gy, when the absolute neutrophil count is <0.5 x 109 cells/L. Whenever possible, exposure dose should be estimated by biological dosimetry and detailed history of exposure.
Platelets are the blood products most commonly needed for treatment of radiation-induced marrow aplasia, because they have a shorter lifespan than red blood cells and will likely regenerate later (i.e., marrow transplant is not necessary). Prophylactic transfusions have traditionally been recommended when platelet counts are <20 x 109 cells/L, although a level of 10 x 109 cells/L in the absence of overt bleeding may be adequate unless surgery is planned. A platelet count >75 x 109 cells/L is desirable before surgery.
Red blood cell transfusions are used to maintain a hemoglobin of 80-100 g/L, which provides a sufficient reserve in case of severe bleeding. Limited experience with granulocyte transfusions has not revealed any significant clinical benefit, so it cannot be recommended at this time. All blood products should be leukoreduced and irradiated to 25 Gy to prevent the risk of cytomegalovirus infection and transfusion-associated graft versus host disease, respectively.
The use of bone marrow transplantation in victims of radiation exposure dates back to the 1950s and on up to the 1999 radiation accident in Tokaimura, Japan. Despite the theoretical benefit of stem cell transplantation, the cumulative experience in these clinical situations (e.g., Chernobyl and Goiania) have not demonstrated any clear lifesaving benefit. However, it is difficult to interpret the results from these events because of the lack of precision with which the radiation exposure was known in most patients and the heterogeneity of comorbid conditions.
From a theoretical standpoint, comprehensive supportive therapy alone can save many patients with exposures <8 Gy, while death from complications of gastrointestinal syndrome is virtually inevitable in those with exposures >10 Gy. Therefore, the decision to pursue stem cell transplantation will need to be carefully considered for a narrow subset of patients with exposures between 8 and 10 Gy and no other significant comorbidity. The limitations of stem cell transplantation include potential complications (e.g., graft-versus-host disease), potential for morbidity associated with other organ toxicity, and a limited pool of suitable donors. In the rare instance in which a syngeneic donor (i.e., a twin sibling) or previously harvested stem cells are available, stem cell transplantation may be considered for those with exposures of 4-10 Gy. This recommendation applies to both adults and children.
External decontamination should be performed before treatment of internal contamination, which depends on the chemical nature of the radioisotope, its physical quantity, and the nature of radioactivity. A risk/benefit decision must be made. For small amounts of radioactive material or those with a short half-life, treatment may be unnecessary. Medical providers need to consult health physicists or medical physicists for information about the nature and amount of internal contamination. The National Council on Radiation Protection and Measurements Report No. 65 Management of Persons Accidentally Contaminated with Radionuclides is a valuable reference.
Treatment of internal contamination reduces the absorbed radiation dose and the risk of future biological effects. Administration of diluting and blocking agents enhances elimination rates of radionuclides. Treatment with mobilizing or chelating agents should be initiated as soon as practical when the probable exposure is judged to be significant. Gastric lavage and emetics can be used to empty the stomach promptly and completely after the ingestion of poisonous materials. Purgatives, laxatives, and enemas can reduce the time that radioactive materials are present in the colon.
Thyroid uptake of radioactive iodine can be reduced if potassium iodide (KI) is taken before or shortly after exposure. The main exposure routes for radioiodine are through inhalation and through ingestion of contaminated food, milk, or water. In 1986 during the Chernobyl nuclear reactor disaster, large populations in the proximity of Chernobyl—most notably in Belarus, northern Ukraine, and the Russian Federation—were not initially aware of the danger and were not evacuated, sheltered, or treated with KI. Since 1990, the incidence of thyroid cancer in children has increased significantly. To date, the largest public health action involving the use of KI involved the distribution of 18 million doses to children and adults in Poland after the Chernobyl accident. KI was distributed to 90% of the children younger than 16 years and to about 25% of the adults in Poland from the 4th day to the 7th day after the beginning of the release of radioactivity from the Chernobyl power plant. Although no significant increase in thyroid cancer has been noted in KI-treated populations in Poland, there are several factors that may have contributed to this difference. The dose of radioactive iodine to the Polish population may have been less than that to the population closer to Chernobyl. Also, the children in the Chernobyl area may have been more iodine-deficient than the children in Poland and therefore more susceptible to uptake of the radioactive iodine from Chernobyl.
The main reason for targeting pregnant women and children specifically for KI prophylaxis is that the smaller thyroid gland of the fetus and child concentrates proportionately more radioactive iodine than that of an adult, resulting in the well-documented increased risk of thyroid cancer in this age group. Despite the fact that the fetal thyroid is not functional until approximately 12 weeks gestation, KI administration is still recommended during the first trimester for maternal protection.
Although the potential side effects of stable iodine administration are well-described, during the Chernobyl experience, virtually no major side effects were seen in the 10 million children to whom it was administered. Moderate effects observed in Poland included transient hypothyroidism in 12 neonates and otherwise occasional gastrointestinal symptoms and rash in others. In the adult population of 7 million who received KI, only two severe reactions were noted, both in individuals with an already known allergy to iodine. The incidence and severity of these side effects would be expected to be greater with repeated dosing, but there are minimal data available regarding the true risk associated with repeated KI administration.
The indication for using KI to block uptake of radioactive iodine by the thyroid depends on the predicted thyroid dose and the age of the patient (Table 6.9). KI dosages are also age-dependent. If KI is administered, timing of the dose is of major importance. If given before or within 1 hour of the exposure, >90% blockage of uptake can be expected. After 4-5 hours, there is 50% blockage. After 12 hours, the effect is minimal. Because of the short time period for effective administration, supplies of KI need to be already in place in areas at highest risk of exposure, such as around nuclear power plants from which high levels of radioiodine might be released.
Because of the expected increased risk of side effects with repeated dosing, particularly in pregnant women and neonates, the decision to repeat KI administration because of ongoing unavoidable exposure needs to be made at a broader public health level, carefully considering the risk-benefit ratio. Regardless of how many doses are given, the thyroid function of the newborn should be monitored through a TSH level 2-4 weeks after administration, and thyroid hormone should be given to those found to be hypothyroid. Because of the risk for transmission to the child from breast milk, nursing should be interrupted until public health authorities recommend resumption.
KI is stockpiled as tablets for logistical reasons, but it may be difficult for very young children to take the medication in this form. When dissolved in water, KI is very salty; however, a variety of liquids such as raspberry syrup, low-fat chocolate milk, orange juice, or flat soda such as cola make the taste more acceptable. Although KI pills are available over-the-counter, KI is also available in prescription form as potassium iodide oral solution, USP (saturated) (SSKI) containing 1,000 mg/mL. SSKI has such a high concentration of KI that accurate dose titration for children would be complicated by dilution calculations. For detailed instructions for home preparation, go to: http://www.fda.gov/cder/drugprepare/kiprep.htm.
Ferric hexacyanoferrate, also known as Prussian blue, is a prescription medication approved by the FDA for the treatment of internal contamination with cesium or thallium. Prussian blue is taken orally, is not absorbed by the gastrointestinal tract, and serves as an ion exchanger during the enterohepatic cycling of these isotopes. During the Goiania incident, 249 individuals were exposed to cesium-137 from an abandoned medical radiotherapy device. Forty-six of these individuals were treated with Prussian blue, including 13 children who received daily doses up to 3 g/day in 3 divided doses. Prussian blue treatment reduced the whole-body effective half-life of Cs-137 by 46% in adolescents and by 43% in children 4-12 years of age.
Dosage and administration of Prussian blue:
Treatment should start as soon as possible after contamination is suspected and continue for a minimum of 30 days.
Prussian blue is manufactured as a 500-mg gelatin capsule and is available directly from the manufacturer, Heyl, in Germany. Supplies are also maintained by the U.S. Strategic National Stockpile and are available from the Radiation Emergency Action Center/Training Site (REAC/TS), Oak Ridge, TN. Significant side effects are rare and consist mainly of mild to moderate constipation.
Diethylenetriaminepentaacetate (DTPA) is a powerful chelating agent effective in removing some heavy metal isotopes. In 2004, the FDA approved calcium-DTPA and zinc-DTPA for treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination. These chelators, however, should not be used to decorporate for uranium because of potential renal toxicity. Instead, for uranium, urine alkalinization with bicarbonate should be done in an effort to promote excretion (Table 6.10).
There are two salts of DTPA, Ca-DTPA and Zn-DTPA. In general, treatment should be started with Ca-DTPA on the first day and then changed to Zn-DTPA on the second day. This is because Ca-DTPA is more effective than Zn-DTPA on the first day, while being no more effective than Zn-DTPA later on. It does, however, have increased risks of causing metabolic abnormalities. It is supplied as 1 g in 5 mL of diluent, and is currently available from the U.S. Strategic National Stockpile and from the Radiation Emergency Action Center/Training Site (REAC/TS), Oak Ridge, TN, and directly from the manufacturer in Germany.
No significant side effects from its usage have been reported, although cases of nausea, vomiting, diarrhea, chills, fever, pruritus, and muscle cramps have been noted in the first 24 hours after administration when given repeatedly and with short intervals allowed for recovery.
The initial dose of Ca-DTPA is 1 g intravenous (IV). On day 2, start Zn-DTPA at 1 g as daily maintenance dose. Pregnant women should begin and continue with Zn-DTPA. Nursing mothers should not breastfeed if they are suspected of having internal radionuclide contamination.
The initial dose of Ca-DTPA is 14 mg/kg IV. On day 2, start Zn-DTPA at 14 mg/kg as daily maintenance dose.
Because every element has one or more radioactive isotopes, there are hundreds of different radioactive isotopes. Each radioactive isotope behaves chemically the same as the non-radioactive isotope of the same element. Treatment of internal radioisotope contamination depends on the specific chemical properties of each isotope. The main radioactive isotopes that have caused internal contamination in people are described above. Detailed information about the diagnosis and treatment of these and other radioactive isotopes is available in the National Council on Radiation Protection Report No.65 and also by calling REAC/TS or the Armed Forces Radiobiology Research Institute (AFRRI).