TABLE 1999 Acute Radiation Syndrome

Four distinct phases are seen in the unfolding of ARS: prodromal phase; latent phase; manifested illness phase; and recovery phase or death. The prodromal phase is a transient period of self-limiting symptoms that may occur within minutes, hours, or days after exposure. The acuity of onset and the duration of this phase are directly related to the dose received. The prodromal phase is an autonomic nervous system response that initiates gastrointestinal symptoms such as anorexia, nausea, vomiting, and, with high doses, diarrhea. In addition, neuromuscular symptoms often accompany the autonomic response and may include hypotension, pyrexia, diaphoresis, cephalgia, and fatigue. The latent phase is a symptom-free interval that follows the resolution of the prodromal phase. Shorter latent phases correspond to higher levels of dose received. The latent period may last 1 to 3 weeks with a dose of less than 4 Gy (400 rad), but the latent period may last only a few hours when a dose above 15 Gy (1500 rads) is received.

The manifest illness phase is often divided into three dose-dependent subsyndromes. In ascending order of severity, these syndromes are clinically related to injury of the hematopoietic, gastrointestinal, and cardiovascular/central nervous systems. The toxic effects to these organ systems are not discrete. There is considerable overlap as well as additive detrimental effects among these syndromes.

HEMATOPOIETIC SYNDROME The hematopoietic system is the first organ system to manifest injury from whole-body irradiation and symptoms are seen from doses above 1.5 to 2 Gy (150 to 200 rad). Self-limiting prodromal symptoms begin within several hours or days and typically resolve within 48 hours. An asymptomatic latent period follows and typically lasts for one to three weeks. Radiation destroys circulating lymphocytes and damages stem cells in the bone marrow and lymphatic system. The rapid decline in lymphocytes is a hallmark of the hematopoietic syndrome and is one of the best early indicators of the extent of radiation injury. Granulocytes, and to a lesser extent, platelet counts, display an initial rise followed by an accelerated decrease reaching a nadir at about 30 days. The red blood cell population also decreases in concentration with resultant mild anemia, but to a lesser extent than other blood cell lines. The kinetics of blood cells are discussed below in more detail in reference to dose estimation. The effects of this syndrome result in pancytopenia and immunosuppression with subsequent hemorrhage and infection as the principal causes of morbidity and mortality. Survival is possible with extensive medical intervention.

GASTROINTESTINAL SYNDROME At doses higher than those resulting in the hematopoietic syndrome, toxicity to the gastrointestinal tract occurs. Gastrointestinal syndrome is the second subsyndrome of the manifest illness phase of ARS and may occur after doses above 6 to 7 Gy (600 to 700 rad) are received. This syndrome is distinguished from the hematopoietic syndrome by the onset of nausea, vomiting, and, often, diarrhea within hours after exposure. These prodromal symptoms are followed by a short latent period of one week or less. Reappearance of gastrointestinal symptoms then occurs with severe nausea, vomiting, diarrhea, and abdominal pain. There is damage of the intestinal mucosal barrier with massive fluid losses resulting in profound dehydration and electrolyte disturbances. The denuded gastrointestinal mucosa allows enteric flora to disseminate into the bloodstream. Declines in blood cell populations are similar to that which occurs with the hematopoietic syndrome, but abnormalities occur sooner and with greater magnitude. With the concurrent immunocompromised state, a fulminating enterocolitis follows. There are few documented cases of gastrointestinal syndrome in humans, all of which resulted in fatalities.

CARDIOVASCULAR AND CENTRAL NERVOUS SYSTEM SYNDROME The cardiovascular and central nervous system syndrome is the third subsyndrome of the manifest illness phase of ARS that occurs after doses above 20 to 30 Gy (2000 to 3000 rad) are received. This syndrome presents with immediate prostration, nausea, vomiting, explosive, bloody diarrhea as well as hypotension. Alterations in consciousness including lethargy, disorientation, ataxia, tremors and convulsions occur within hours after exposure. Hypotension is persistent and refractory to treatment. This syndrome is universally fatal with death occurring within 24 to 72 hours, predominately due to circulatory collapse. The lymphocyte count promptly falls to near-zero levels. Granulocytosis develops early and persists until death.

In addition to these organ system injuries of the manifest illness syndromes, radiation doses above 8 to 9 Gy (800 to 900 rad), may damage the pulmonary system with resulting pneumonitis, fibrosis, and interstitial edema.8

DOSE ESTIMATION If the patient was not wearing a personal dose monitor (dosimeter) at the time of the accident, estimations of dose can be calculated from the circumstances of the accident. The dose received is a function of the individual's proximity to the source, the type and energy of the particular source, as well as the duration of exposure and extent of shielding. This information may not be available at the time of the patient's presentation to the emergency department and estimates of the radiation injury received must be obtained by assessing physical symptoms and laboratory data.

Hematological Data for Estimating Radiation Injury The earliest laboratory indicator of biological damage from radiation is a marked decrease in peripheral lymphocytes, often within eight hours postexposure. The more precipitous the decline in lymphocytes, the greater the dose received. ( Fig 199:1). The lymphocyte count 24 hours postexposure is useful in predicting the patient's clinical course. If the lymphocyte count is maintained above 1200/pL, no clinical support is required. If the count falls below 500/pL, a severe clinical course can be anticipated. If the entire lymphocyte count is depleted within six hours, a fatal outcome is likely.

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FIG. 199-1. Estimated radiation dose and degree of injury from early changes in lymphocyte counts. Approximate whole-body dose: Curve A—3.1 Gy (310 rad); Curve B—4.4 Gy (440 rad); Curve C—5.6 Gy (560 rad); Curve D—7.1 Gy (710 rad). (Reproduced from Health Physics 72:514, 1997 with permission from the Health Physics Society. Figure has been modified from its original version.)

Because circulating lymphocytes are very radiosensitive, dose estimation by lymphocyte count is less reliable with doses above 3 Gy (300 rad) and more accurate estimates can be obtained from the granulocyte pattern. In contrast to lymphocytes, circulating granulocytes are not directly killed by radiation. However, damage to blood progenitor cells in bone marrow results in a later decline in the granulocyte population. A transient increase in peripheral granulocytes is seen immediately after exposure due to a stress-related release of granulocytes from the bone marrow stores into the peripheral circulation. Granulocytopenia occurs after these stores are mobilized and then localize in radiation damaged tissues, reaching a nadir at about 30 days after exposure. Granulocytes may show a transient rise about 10 to 15 days postexposure when damaged stem cells begin proliferation but die before reaching their full reproductive capability. Absence of this transient rise in granulocyte numbers indicates exposure above 5 Gy (500 rad) and is a poor prognostic sign.9

Platelet counts may slightly increase in the first few days after exposure and then fall to a nadir at about 30 days. The red blood cell population shows a milder decrease in concentration with resultant mild anemia. The decrease in the red cell line is less pronounced than other hematopoietic cells and reflects the red cells' longer life span in the peripheral circulation ( Fig 199-2).

FIG. 199-2. Typical hematological course and clinical stages after sublethal (~300 rad) exposure to total body irradiation. (Reprinted with permission from Radiobiological Factors in Manned Space Flight, copyright 1965 by the National Academy of Sciences. Washington, DC, National Academy Press, 1965.)

Dose Estimation by Cytogenetic Analysis Cytogenetic analysis of circulating lymphocytes is another method of dose estimation. Radiation induces some characteristic chromosome aberrations, particularly rings and dicentrics, in a dose-dependent manner. The frequency of these abnormalities can be scored in cytogenetic laboratories to obtain estimates of radiation dose received. This process is technically challenging, time-consuming, and expensive but is the most sensitive biological measurement for quantifying dose from whole-body irradiation.9

Clinical Symptoms for Estimating Radiation Injury The absence or time of onset of nausea and vomiting are useful for assessing the injury severity. Diarrhea is a less useful symptom unless there is prompt, explosive, bloody diarrhea, which indicates a likely fatal outcome. Individuals who have received doses less than 1 Gy (100 rad) seldom experience nausea or vomiting. Less than 1 Gy is a reliable dose estimate for individuals who remain asymptomatic 24 hours postexposure; hospital admission for these individuals is generally unnecessary.10

LETHAL DOSE The LD50/60 from exposure to ionizing radiation is defined as the dose of penetrating ionizing radiation that will result in the deaths of 50 percent of the exposed population within 60 days. Three values are commonly cited for human survival. The most commonly cited value is LD50/60 of approximately 4.5 Gy (450 rad). This value assumes intensive medical therapy is provided, including antibiotics, blood products, and reverse isolation. With only minimal treatment, such as basic first aid, the LD50/60 falls to approximately 3.4 Gy (340 rad). Victims of the Chernobyl nuclear accident have demonstrated that humans can survive radiation doses greater than anticipated. Intensive medical support to Chernobyl victims provided a high survival rate in individuals receiving less than 6 Gy (600 rad). With newer advances in medical treatment, such as stem cell transplantation and cytokine administration, it may be possible to raise the LD50/60 to 11 Gy (1100 rad). 11

TREATMENT OF WHOLE-BODY IRRADIATION The patient who has only been exposed to an external source of penetrating radiation is not radioactive or contaminated and therefore requires no special precautions for handling or treating. A rare exception is exposure to high-level neutron irradiation, which can induce radioactivity. In the unlikely event of a criticality accident, neutron exposure becomes a concern. Patient specimens of blood and urine should be collected and assayed for induced radioactivity in the body, predominately Na-24. In addition, all metal objects on the patient's body or clothing should be monitored for potential radioactivity, including jewelry, coins, dental fillings, wristwatches, and buttons.

Initial treatment of the irradiated patient is directed toward alleviating the symptoms of the prodromal phase and may include the use of antiemetics and anxiolytics. Pain management may be required if there is associated trauma. Medical treatment has been unsuccessful in the few documented cases of high radiation doses that cause major damage to the GI or CV/CNS systems. Survival is possible for individuals with lower radiation doses resulting in the hematopoietic form of ARS.

The ultimate treatment goal is to provide support during the period of deficient defenses against infection and hemorrhage until marrow recovery occurs. Supportive treatment may include IV fluids, blood products, and total parenteral nutrition, as well as reverse isolation, prophylactic antibiotics, and antifungal medications. The patient, as well as family members who may be potential blood donors, should undergo HLA typing in preparation of white cell and platelet transfusions if marrow suppression becomes severe. The most severe marrow depression occurs at two to three weeks after exposure. Spontaneous recovery of granulocytes and platelets is quite rapid after the fifth week.

Bone marrow transplantation may be considered for patients who have received doses above 8 or 9 Gy (800 to 900 rad). 12 Bone marrow transplantation is advocated only for patients who are likely to die from radiation-induced myelosuppression if they have a well-matched donor and do not have irreversible damage to other major organ systems. Transplantation was provided for 13 victims of the Chernobyl accident who had received a dose greater than 5.6 Gy (560 rad). Within the following 3 months, 11 of these 13 patients died. The causes of these deaths were multifactorial and included graft-versus-host disease, burns, traumatic injury, radiation pneumonitis, ARDS, and renal and hepatic failure.

Other treatment modalities for myelosuppression that do not carry a risk of graft-versus-host disease are being studied. The administration of hematopoietic growth factors is currently under intense clinical investigation. Hematopoietic growth factors are cytokines such as erythropoietin, interleukins, and colony-stimulating factors. These proteins have been shown to stimulate the proliferation and differentiation of the surviving stem cells and thus accelerate reconstitution of the bone marrow. These growth factors are most efficacious in animal models when administered immediately after irradiation and demonstrates the importance of early dose estimation. Patients in whom the estimated dose is high enough to cause severe marrow damage may benefit from prompt administration of these growth factors.

Obtaining data and specimens for dose estimation is therefore a crucial aspect of planning therapy and predicting the patient's clinical course. Ihe time of onset of all clinical symptoms should be carefully observed and documented. Serial blood specimens should be obtained for hematological and cytogenetic dose assessment.

If significant radiation dose was received, the patient should have long-term periodic follow-up for potential delayed effects of radiation damage such as cataracts, infertility, thyroid dysfunction, leukemia, or other neoplasms.

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