Medical Management of the Acute Radiation Syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group

The events of September 11, 2001, confirmed the vulnerability of the United States and other nations to acts of terrorism. While our ability to react to and treat victims of biological terrorism has significantly improved, a terrorist event involving radioactive material remains a threat for which improved preparation is requisite. Several international conferences on treatment of acute radiation injury have been held in the past 2 decades (1-8). The conclusions of these conferences, together with mounting preclinical data showing the benefit of early cytokine use in combination with aggressive clinical support in irradiated animals (9-13), provide valuable information to clinicians faced with treating the acute radiation syndrome. Scenarios for terrorist acts involving radioactive material have been developed, some of which indicate that mass casualties can occur. However, little information is currently available in the medical literature concerning guidelines for the medical management of large-scale, complex radiation injuries, such as those that might occur in an urban area (14-17). Therefore, this consensus document was created to help physicians who may be involved in evaluation, triage, or medical management of victims with acute radiation injury. Methods The Strategic National Stockpile (SNS) convened the SNS Radiation Working Group (Appendix) to address issues of medical management and stockpiling of pharmaceutical agents in case of a significant radiologic event. Participants were selected on the basis of their established expertise in the field. The deliberations of the SNS Radiation Working Group during a series of 4 consensus meetings beginning in August 2002 and 4 additional conference calls were used as a basis to create this document. The group reviewed the available information for cases recorded in the radiation accident registries maintained by the Radiation Emergency Assistance Center/Training Site (REAC/TS), Oak Ridge, Tennessee, and the University of Ulm, Germany (6). This information was supplemented by outcomes of clinical management and therapy for cases reported in the scientific literature. Since no prospective, controlled clinical trials have been conducted in patients with acute radiation injury, the SNS Radiation Working Group reviewed management strategies used in accidental exposures of humans and evaluated results of prospective, controlled studies of acutely irradiated animals. In some cases, recommendations for therapy are based on results of animal studies. For radiologic terrorism events, definitive studies are required in animals to demonstrate impact on mortality and other clinical end points, according to requirements for licensure under the U.S. Food and Drug Administration's Animal Rule. In cases where the members of the SNS Radiation Working Group failed to achieve consensus, the alternatives are presented with relevant reference to the published literature. The Centers for Disease Control and Prevention provided funding to some of the participants for attendance at meetings. This support played no role in the composition, deliberations, or report of the SNS Radiation Working Group. Because new approaches to individual biodosimetry and therapy that will apply to treatment of acutely irradiated persons are likely to emerge, the SNS Radiation Working Group will review scientifically based guidance annually. Defining the Threat and Public Health Response The lethality of a nuclear device was demonstrated when a 15-kiloton improvised nuclear device was detonated over Hiroshima, Japan, in 1945, resulting in approximately 150000 casualties and 75000 fatalities (18). Virtually all survivors of Hiroshima had estimated exposure of less than 3 Gy (19). Recent review of data suggests that the mean lethal dose of radiation required to kill 50% of humans at 60 days (LD50/60) of whole-body radiation is between 3.25 Gy and 4 Gy in persons managed without supportive care and 6 to 7 Gy when antibiotics and transfusion support are provided (20). Although most radiation injuries in the past 50 years have been due to accidents, society must be prepared for the intentional detonation of nuclear or radiologic devices. Modern nuclear threats can be divided into 5 general categories: 1) an attack on nuclear power plants, 2) a malevolent act using simple radiologic devices, 3) terrorist use of a radiologic dispersal device or dirty bomb, 4) detonation of an improvised nuclear device, and 5) detonation of a sophisticated nuclear weapon (21). Whereas incidents involving simple devices and radiologic dispersal devices would probably cause a limited number of casualties, those involving improvised nuclear devices and small nuclear weapons would result in mass casualties. The Joint Commission on Accreditation of Healthcare Organizations and government leaders have mandated that the health care system develop plans to prepare for response to a radiologic terrorist event. The Hospital Emergency Incident Command System (22) provides a command and coordination approach that is useful for radiation response planning. Emergency plans should clarify authority, command, and control; define organizational responsibilities; develop procedures that integrate efforts of all response agencies; identify logistic support, supplies, and equipment; and assess incident conditions and consequences (23). Given the devastation that would accompany a nuclear detonation, plans should incorporate contingency planning for significant loss of infrastructure and health care personnel in the radiation field and its environs. Contingency planning should include relocation of victims to nearby operational hospitals and medical centers and activation of regional and state disaster plans that are coordinated with federal agencies. Approaches to radiologic monitoring, triage, and therapy for exposed populations will vary, depending on the number of casualties and resources available on the scene and in emergency treatment centers and hospitals. Although disaster planning is beyond the scope of this document, it is hoped that this clinical guideline defines a need for formalization and coordinated testing of such plans by hospitals and government agencies (see www.ncrp.com). Barriers to the provision of optimal medical care include limitation of resources, loss of infrastructure, a high volume of victims, and presence of combined injury. Allocation of potentially limited resources should be determined by the number of victims and their long-term prognosis. Estimation of individual radiation dose is recommended for determining survivability of patients in a range of doses that indicate predisposition to the acute radiation syndrome. Treatment recommendations are based on this dose range, which becomes increasingly narrower as the number of casualties increases and with the occurrence of combined injuries. Essentials of Radiation Exposure and Injury Radiation injury can occur from external irradiation; external contamination with radioactive materials; and internal contamination by inhalation, ingestion, or transdermal absorption with incorporation of radiologic materials into the body's cells and tissues. These 3 types of exposure can occur in combination and can be associated with thermal burns and traumatic injuries. Injury from a nuclear detonation varies, depending on the location of the victim relative to the hypocenter and the consequent exposure to different types of energy. Three forms of energy are released from a nuclear detonation: heat, accounting for approximately 35% of total energy; shock or bomb blast, accounting for approximately 50% of total energy; and radiation, accounting for the remaining 15% of total energy. Heat and light cause thermal injury, including flash burns, flame burns, flash blindness (due to temporary depletion of photopigment from retinal receptors), and retinal burns. The blast wave results in fractures, lacerations, rupture of viscera, and pulmonary hemorrhage and edema. Radiation causes the acute radiation syndrome; cutaneous injury and scarring; chorioretinal damage from exposure to infrared energy; and, depending on radiation dose and dose rate, increased long-term risk for cancer, cataract formation (particularly with neutron irradiation), infertility, and fetal abnormalities (that is, growth retardation, fetal malformations, increased teratogenesis, and fetal death). We refer the reader to several excellent in-depth reviews of radiation effects (21, 23-25). The Acute Radiation Syndrome Studies in animals and humans exposed to radiation have allowed researchers to describe the acute radiation syndrome, also known as radiation sickness. The acute radiation syndrome occurs after whole-body or significant partial-body irradiation of greater than 1 Gy delivered at a relatively high-dose rate. The most replicative cells are the most sensitive to the acute effects of radiation, particularly spermatocytes, lymphohematopoietic elements, and intestinal crypt cells. The inherent sensitivity of these cells results in a constellation of clinical syndromes that predominates within a predictable range of doses of whole-body or significant partial-body exposure. Clinical components of the acute radiation syndrome include the hematopoietic, gastrointestinal, and cerebrovascular syndromes. The time course and severity of clinical signs and symptoms for the component syndromes at different dose ranges are reviewed in Figure 1. Each syndrome can be divided into 4 phases: prodromal, latent, manifest illness, and recovery or death. Figure 1. Approximate time course of clinical manifestations. GI CNS Depending on the absorbed dose, symptoms appear within hours to weeks, following a predictable clinical course. The prodromal phase of the acute radiation syndrome usually occurs in the first 48 hours but may develop up to 6 days after exposure. The latent phase is a short period characterized by improvement of sy