Thomas J. MacVittie

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 Administrations 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 bodys 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

Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock.

A canine sepsis model that simulates the human cardiovascular response to septic shock was produced in 10 conscious unsedated dogs by implanting an Escherichia coli-infected clot into the peritoneum, resulting in bacteremia. By employing serial, simultaneous measurements of radionuclide scan-determined left ventricular (LV) ejection fraction (EF) and thermodilution cardiac index (CI), the end-diastolic volume index (EDVI) was calculated (EDVI = stroke volume index divided by EF). By using three different methods of quantifying serial ventricular performance (EF, shifts in the Starling ventricular function curve using EDVI vs. stroke work index, and the ventricular function curve response to volume infusion), this study provides evidence (P less than 0.01) that septic shock produces a profound, but reversible, decrease in systolic ventricular performance. This decreased performance was not seen in controls and was associated with ventricular dilatation (P less than 0.01); the latter response was dependent on an adequate volume infusion. Further studies of EDVI and pulmonary capillary wedge pressure during diastole revealed a significant, though reversible, shift (P less than 0.001) in the diastolic volume/pressure (or compliance) relationship during septic shock.

Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003

Abstract Stone, H. B., Moulder, J. E., Coleman, C. N., Ang, K. K., Anscher, M. S., Barcellos-Hoff, M. H., Dynan, W. S., Fike, J. R., Grdina, D. J., Greenberger, J. S., Hauer-Jensen, M., Hill, R. P., Kolesnick, R. N., MacVittie, T. J., Marks, C., McBride, W. H., Metting, N., Pellmar, T., Purucker, M., Robbins, M. E., Schiestl, R. H., Seed, T. M., Tomaszewski, J., Travis, E. L., Wallner, P. E., Wolpert, M. and Zaharevitz, D. Models for Evaluating Agents Intended for the Prophylaxis, Mitigation and Treatment of Radiation Injuries. Report of an NCI Workshop, December 3–4, 2003. Radiat. Res. 162, 711–728 (2004). To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, appropriate models are needed that integrate the complex events that occur in the radiation-exposed organism. While the spectrum of agents in clinical use or preclinical development is limited, new research findings promise improvements in survival after whole-body irradiation and reductions in the risk of adverse effects of radiotherapy. Approaches include agents that act on the initial radiochemical events, agents that prevent or reduce progression of radiation damage, and agents that facilitate recovery from radiation injuries. While the mechanisms of action for most of the agents with known efficacy are yet to be fully determined, many seem to be operating at the tissue, organ or whole animal level as well as the cellular level. Thus research on prophylaxis/protection, mitigation and treatment of radiation injuries will require studies in whole animal models. Discovery, development and delivery of effective radiation modulators will also require collaboration among researchers in diverse fields such as radiation biology, inflammation, physiology, toxicology, immunology, tissue injury, drug development and radiation oncology. Additional investment in training more scientists in radiation biology and in the research portfolio addressing radiological and nuclear terrorism would benefit the general population in case of a radiological terrorism event or a large-scale accidental event as well as benefit patients treated with radiation.

Role of endotoxemia in cardiovascular dysfunction and mortality. Escherichia coli and Staphylococcus aureus challenges in a canine model of human septic shock.

Using different types of bacteria and a canine model simulating human septic shock, we investigated the role of endotoxin in cardiovascular dysfunction and mortality. Either Escherichia coli (a microorganism with endotoxin) or Staphylococcus aureus (a microorganism without endotoxin) were placed in an intraperitoneal clot in doses of viable or formalin-killed bacteria. Cardiovascular function of conscious animals was studied using simultaneous radionuclide heart scans and thermodilution cardiac outputs. Serial plasma endotoxin levels were measured. S. aureus produced a pattern of reversible cardiovascular dysfunction over 7-10 d that was concordant (P less than 0.01) with that of E. coli. Although this cardiovascular pattern was not altered by formalin killing (S. aureus and E. coli), formalin-killed organisms produced a lower mortality and less myocardial depression (P less than 0.01). S. aureus, compared to E. coli, produced higher postmortem concentrations of microorganisms and higher mortality (P less than 0.025). E. coli produced significant endotoxemia (P less than 0.01), though viable organisms (versus nonviable) resulted in higher endotoxin blood concentrations (P less than 0.05). Significant endotoxemia did not occur with S. aureus. Thus, in the absence of endotoxemia, S. aureus induced the same cardiovascular abnormalities of septic shock as E. coli. These findings indicate that structurally and functionally distinct microorganisms, with or without endotoxin, can activate a common pathway resulting in similar cardiovascular injury and mortality.

Combined administration of recombinant human megakaryocyte growth and development factor and granulocyte colony-stimulating factor enhances multilineage hematopoietic reconstitution in nonhuman primates after radiation-induced marrow aplasia.

This study compared the therapeutic potential of recombinant, native versus pegylated megakaryocyte growth and development factor (rMGDF and PEG-rMGDF, respectively), as well as that of the combined administration of PEG-rMGDF and r-methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF) on hematopoietic reconstitution after 700 cGy, 60Co gamma, total body irradiation in nonhuman primates. After total body irradiation, animals received either rMGDF, PEG-rMGDF, r-metHuG-CSF, PEG-rMGDF and r-metHuG-CSF or HSA. Cytokines in all MGDF protocols were administered for 21-23 d. Either rMGDF, PEG-rMGDF, or PEG-rMGDF and r-metHuG-CSF administration significantly diminished the thrombocytopenic duration (platelet count (PLT) < 20,000 per microliter)to o.25, 0, 0.5 d, respectively, and the severity of the PLT nadir (28,000, 43,000, and 30,000 per microliter, respectively) as compared with the controls (12.2 d duration, nadir 4,000 per microliter), and elicited an earlier PLT recovery. Neutrophil regeneration was augmented in all cytokine protocols and combined PEG-rMGDF and r-metHuG-CSF further decreased the duration of neutropenia compared with r-metHuG-CSF alone. These data demonstrated that the administration of PEG-rMGDF significantly induced bone marrow regeneration versus rMGDF, and when combined with r-metHuG-CSF significantly enhanced multilineage hematopoietic recovery with no evidence of lineage competition.

The Soluble Form of IL-1 Receptor Accessory Protein Enhances the Ability of Soluble Type II IL-1 Receptor to Inhibit IL-1 Action

Regulation of the activity of the proinflammatory cytokine IL-1 is complex, involving transcriptional and translational control, precursor processing, a receptor antagonist (IL-1ra), and a decoy receptor. Here we report that the soluble form of the IL-1 receptor accessory protein (AcP) increases the affinity of binding of human IL-1alpha and IL-1beta to the soluble human type II IL-1 receptor by approximately 100-fold, while leaving unaltered the low binding affinity of IL-1ra. Soluble AcP is present in normal human serum at an average concentration greater than 300 ng/ml. These findings suggest that the soluble form of IL-1R AcP contributes to the antagonism of IL-1 action by the type II decoy receptor, adding another layer of complexity to the regulation of IL-1 action.

Molecular and cellular biology of moderate-dose (1-10 Gy) radiation and potential mechanisms of radiation protection: report of a workshop at Bethesda, Maryland, December 17-18, 2001.

Abstract Coleman, C. N., Blakely, W. F., Fike, J. R., MacVittie, T. J., Metting, N. F., Mitchell, J. B., Moulder, J. E., Preston, R. J., Seed, T. M., Stone, H. B., Tofilon, P. J. and Wong, R. S. L. Molecular and Cellular Biology of Moderate-Dose (1–10 Gy) Radiation and Potential Mechanisms of Radiation Protection: Report of a Workshop at Bethesda, Maryland, December 17–18, 2001. Radiat. Res. 159, 812–834 (2003). Exposures to doses of radiation of 1–10 Gy, defined in this workshop as moderate-dose radiation, may occur during the course of radiation therapy or as the result of radiation accidents or nuclear/radiological terrorism alone or in conjunction with bioterrorism. The resulting radiation injuries would be due to a series of molecular, cellular, tissue and whole-animal processes. To address the status of research on these issues, a broad-based workshop was convened. The specific recommendations were: (1) Research: Identify the key molecular, cellular and tissue pathways that lead from the initial molecular lesions to immediate and delayed injury. The latter is a chronic progressive process for which postexposure treatment may be possible. (2) Technology: Develop high-throughput technology for studying gene, protein and other biochemical expression after radiation exposure, and cytogenetic markers of radiation exposure employing rapid and accurate techniques for analyzing multiple samples. (3) Treatment strategies: Identify additional biological targets and develop effective treatments for radiation injury. (4) Ensuring sufficient expertise: Recruit and train investigators from such fields as radiation biology, cancer biology, molecular biology, cellular biology and wound healing, and encourage collaboration on interdisciplinary research on the mechanisms and treatment of radiation injury. Communicate knowledge of the effects of radiation exposure to the general public and to investigators, policy makers and agencies involved in response to nuclear accidents/events and protection/treatment of the general public.

Therapeutic Use of Recombinant Human G-CSF (rhG-CSF) in a Canine Model of Sublethal and Lethal Whole-body Irradiation

The short biologic half-life of the peripheral neutrophil (PMN) requires an active granulopoietic response to replenish functional PMNs and to maintain a competent host defence in irradiated animals. Recombinant human G-CSF (rhG-CSF) was studied for its ability to modulate haemopoiesis in normal dogs as well as to decrease therapeutically the severity and duration of neutropenia in sublethally and lethally irradiated dogs. For the normal dog, subcutaneous administration of rhG-CSF induced neutrophilia within hours after the first injection; total PMNs continued to increase (with plateau phases) to mean peak values of 1000 per cent of baseline at the end of the treatment period (12-14 days). Bone-marrow-derived granulocyte-macrophage colony-forming cells (GM-CFC) increased significantly during treatment. For a sublethal 200 cGy dose, treatment with rhG-CSF for 14 consecutive days decreased the severity and shortened the duration of neutropenia and thrombocytopenia. The radiation-induced lethality of 60 per cent after a dose of 350 cGy was associated with marrow-derived GM-CFC survival of 1 per cent. Treatment with rhG-CSF markedly reduced the lethality associated with exposure to 350 cGy of radiation to zero. White blood cell (WBC) and platelet recovery kinetics were correlated with degree of marrow damage. The rhG-CSF reduced the severity and duration of neutropenia. Control animals required antibiotic therapy (WBC less than 1000 mm3) for a total of 16 days versus 3 days for rhG-CSF-treated dogs. The duration of thrombocytopenia was reduced, although the severity of depletion was unchanged with treatment. These data indicate that in the lethally irradiated dog, effective cytokine therapy with rhG-CSF will increase survival through the induction of earlier recovery of neutrophils and platelets.

Defining the full therapeutic potential of recombinant growth factors in the post radiation-accident environment: the effect of supportive care plus administration of G-CSF.

Radiation accidents are uncontrolled and ill-defined, the exposure is nonuniform and may be partial body, forecasting a variable dose distribution and sparing of hematopoietic stem cells. We propose that the “best” treatment protocol available now for severely irradiated personnel with acute hematopoietic syndrome is the combination of supportive care and administration of recombinant cytokines as soon as possible after irradiation. Herein, we demonstrate the significant effect of G-CSF administration on lethally irradiated canines. G-CSF administered early and continuously after irradiation increased neutrophil recovery and survival over a lethal and supralethal dose range. The respective LD50/30 for the control, supportive care-alone cohorts of 338 cGy, was increased to 488 cGy with administration of G-CSF. Clearly, the use of supportive care and G-CSF enhanced recovery of myelopoiesis and survival after lethal doses of irradiation.

Glucan: mechanisms involved in its "radioprotective" effect.

It has generally been accepted that most biologically derived agents that are radioprotective in the hemopoietic‐syndrome dose range (eg. endotoxin, Bacillus Calmette Guerin, Corynebacterium parvum, etc) exert their beneficial properties by enhancing hemopoietic recovery and hence, by regenerating the hosts ability to resist life‐threatening opportunistic infections. However, using glucan as a hemopoietic stimulant/radi‐oprotectant, we have demonstrated that host resistance to opportunistic infection is enhanced in these mice even prior to the detection of significant hemopoietic regeneration. This early enhanced resistance to microbial invasion in glucan‐treated irradiated mice could be correlated with enhanced and/or prolonged macrophage (but not granulocyte) function. These results suggest that early after irradiation glucan may mediate its radioprotection by enhancing resistance to microbial invasion via mechanisms not necessarily predicated on hemopoietic recovery. In addition, preliminary evidence suggests that glucan can also function as an effective free‐radical scavenger. Because macrophages have been shown to selectively phagocytize and sequester glucan, the possibility that these specific cells may be protected by virtue of glucans scavenging ability is also suggested.