Assessment and clinical management of internal contamination.

Internal contamination by radionuclides may occur through inhalation, ingestion and absorption through the skin or subcutaneous tissue. The clinical management of internalized radionuclides requires the integration of clinical signs and symptoms with dose estimates in biological tissues obtained from the face, nose, sputum, urine, faeces and/or skin. The assessment of ingested radionuclides includes bioassays of urine and faeces, and if available, whole body counting for radionuclides that emit penetrating x-rays or gamma-rays. An estimate of intake dose may be made at the time of initial patient evaluation by measuring radioactivity, converting counts/minute to depositions/minute with a specific gamma-ray constant, and comparing the amount to its annual limit on intake, clinical decision guide or derived reference level. Since nobody dies from internal contamination per se, medically unstable patients should be stabilized before addressing internal contamination. Whenever possible, internal contaminants should be physically removed as soon as possible after exposure. For inhaled internal contaminants, radionuclide-specific therapy may include the administration of an ion exchange resin (i.e. Prussian blue, PB) or chelating agent (i.e. diethylenetriamine pentaacetate, DTPA, that binds toradioactiveplutonium, americium, and curium), or the physical removal of insoluble particles with a high activity radionuclide (192Ir,90Sr,210Po) by bronchioalveolar lavage. Decorporation with PB, DTPA and other agents is used to enhance excretion. The treatment of wounds contaminated with an actinide includes gentle irrigation, surgical excision of contaminated tissue and DTPA. The averted dose (i.e. the total effective dose averted by therapy) may be calculated for each exposure route.

Medical management of acute radiation syndrome.

Acute radiation syndrome (ARS) is a clinical syndrome involving four organ systems, resulting in the hematopoietic syndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Since few healthcare providers have seen an ARS case, evidence-based recommendations are needed to guide medical management in a mass casualty scenario. The authors reviewed recommendations from evidence-based and narrative reviews by expert consultants to the World Health Organisation (WHO), a subsequent review of published HS cases, and infectious disease guidelines for management of febrile neutropenia. The WHO Consultancy applied a rigorous grading system to evaluate treatment strategies described in published ARS cases as of 2009, strategies to manage HS in unirradiated persons, results of ARS studies in animal models of ARS, and recommendations of prior expert panels. Major findings for HS were (a) no randomised controlled studies have been performed, (b) data are restricted by the lack of comparator groups, and (c) reports of countermeasures for management of injury to non-hematopoietic organs are often incomplete. Strength of recommendations ranged from strong to weak. Countermeasures of potential benefit include cytokines and for a subgroup of HS patients, hematopoietic stem cell transplantation. These recommendations did not change in a subsequent analysis of HS cases. Recommendations also included fluoroquinolones, bowel decontamination, serotonin receptor antagonists, loperamide and enteral nutrition for GIS; supportive care for NVS; and topical steroids, antihistamines and antibiotics, and surgical excision/grafting for CS. Also reviewed are critical care management guidelines, the role of mesenchymal stem cells for CS, the potential of a platelet-stimulating cytokine for HS, and the author's approach to clinical management of microbial infections associated with ARS based on published guidelines of infectious disease experts. Today's management of HS is supported by evidence-based guidelines. Management of non-HS subsyndromes is supported by a narrative review of the literature and recommendations of infectious disease societies.

Public health response and medical management of internal contamination in past radiological or nuclear incidents: A narrative review.

Following a radiological or nuclear emergency, workers, responders and the public may be internally contaminated with radionuclides. Screening, monitoring and assessing any internal contamination and providing necessary medical treatment, especially when a large number of individuals are involved, is challenging. Experience gained and lessons learned from the management of previous incidents would help to identify gaps in knowledge and capabilities on preparedness for and response to radiation emergencies. In this paper, eight large-scale and five workplace radiological and nuclear incidents are reviewed cross 14 technical areas, under the broader topics of emergency preparedness, emergency response and recovery processes. The review findings suggest that 1) new strategies, algorithms and technologies are explored for rapid screening of large populations; 2) exposure assessment and dose estimation in emergency response and dose reconstruction in recovery process are supported by complementary sources of information, including 'citizen science'; 3) surge capacity for monitoring and dose assessment is coordinated through national and international laboratory networks; 4) evidence-based guidelines for medical management and follow-up of internal contamination are urgently needed; 5) mechanisms for international and regional access to medical countermeasures are investigated and implemented; 6) long-term health and medical follow up programs are designed and justified; and 7) capabilities and capacity developed for emergency response are sustained through adequate resource allocation, routine non-emergency use of technical skills in regular exercises, training, and continuous improvement.

Chemical, Biological, Radiological, Nuclear, and Explosive (CBRNE) Science and the CBRNE Science Medical Operations Science Support Expert (CMOSSE).

A national need is to prepare for and respond to accidental or intentional disasters categorized as chemical, biological, radiological, nuclear, or explosive (CBRNE). These incidents require specific subject-matter expertise, yet have commonalities. We identify 7 core elements comprising CBRNE science that require integration for effective preparedness planning and public health and medical response and recovery. These core elements are (1) basic and clinical sciences, (2) modeling and systems management, (3) planning, (4) response and incident management, (5) recovery and resilience, (6) lessons learned, and (7) continuous improvement. A key feature is the ability of relevant subject matter experts to integrate information into response operations. We propose the CBRNE medical operations science support expert as a professional who (1) understands that CBRNE incidents require an integrated systems approach, (2) understands the key functions and contributions of CBRNE science practitioners, (3) helps direct strategic and tactical CBRNE planning and responses through first-hand experience, and (4) provides advice to senior decision-makers managing response activities. Recognition of both CBRNE science as a distinct competency and the establishment of the CBRNE medical operations science support expert informs the public of the enormous progress made, broadcasts opportunities for new talent, and enhances the sophistication and analytic expertise of senior managers planning for and responding to CBRNE incidents.

CONCEPTS OF OPERATIONS FOR A US DOSIMETRY AND BIODOSIMETRY NETWORK.

The USA must be prepared to provide a prompt, coordinated and integrated response for radiation dose and injury assessment for suspected radiation exposure, whether it involves isolated cases or mass casualties. Dose estimation for radiation accidents typically necessitates a multiple parameter diagnostics approach that includes clinical, biological and physical dosimetry to provide an early-phase radiation dose. A US Individual Dosimetry and Biodosimetry Network (US-IDBN) will increase surge capacity for civilian and military populations in a large-scale incident. The network's goal is to leverage available resources and provide an integrated biodosimetry capability, using multiple parameter diagnostics. Initial operations will be to expand an existing functional integration of two cytogenetic biodosimetry laboratories by developing Standard Operating Procedures, cross-training laboratorians, developing common calibration curves, supporting inter-comparison exercises and obtaining certification to process clinical samples. Integration with certified commercial laboratories will increase surge capacity to meet the needs of a mass-casualty incident.

The Pseudo-Pelger huët Cell as a Retrospective Dosimeter: Analysis of a Radium Dial Painter Cohort.

Recently, the pseudo-Pelger Huët anomaly in peripheral blood neutrophils has been described as a new radiation-induced, stable biomarker. In this study, pseudo-Pelger Huët anomaly was examined in peripheral blood slides from a cohort of 166 former radium dial painters and ancillary personnel in the radium dial industry, 35 of whom had a marrow dose of zero above background. Members of the radium dial painter cohort ingested Ra and Ra at an early age (average age 20.6 ± 5.4 y; range 13-40 y) during the years 1914-1955. Exposure duration ranged from 1-1,820 wk with marrow dose 1.5-6,750 mGy. Pseudo-Pelger Huët anomaly expressed as a percentage of total neutrophils in this cohort rises in a sigmoidal fashion over five decades of red marrow dose. Six subjects in this cohort eventually developed malignancies: five osteosarcomas and one mastoid cell neoplasm. The pseudo-Pelger Huët anomaly percentage in these cases of neoplasm increases with marrow dose and is best fit with a sigmoid function, suggestive of a threshold effect. No sarcomas are seen for a marrow dose under 2 Gy. These results indicate that pseudo-Pelger Huët anomaly in peripheral blood is a reasonable surrogate for the estimation of alpha dose to bone marrow in historic radiation cases. Hypotheses are discussed to explain late (months to years), early (hours to days), and intermediate (weeks to months) effects of ionizing radiation, respectively, on the expression of genes encoding inner nuclear membrane proteins and their receptors, on the structure and function of nuclear membrane proteins and lipids, and on cytokinesis through chromatin bridge formation.

Development of electronic training and telescoring tools to increase the surge capacity of dicentric chromosome scorers for radiological/nuclear mass casualty incidents.

Dicentric chromosome assay (DCA) is most frequently used for estimating the absorbed radiation dose in the peripheral blood lymphocytes of humans after occupational or incidental radiation exposure. DCA is considered to be the "gold standard" for estimating the absorbed radiation dose because the dicentric chromosome formation is fairly specific to ionizing radiation exposure and its baseline frequency is extremely low in non-exposed humans. However, performance of DCA for biodosimetry is labor intensive and time-consuming making its application impractical for radiological/nuclear mass casualty incidents. Realizing the critical need for rapid dose estimation particularly after radiological/nuclear disaster events, several laboratories have initiated efforts to automate some of the procedural steps involved in DCA. Although metaphase image capture and dicentric chromosome analysis have been automated using commercially available platforms, lack or an insufficient number of these platforms may pose a serious bottleneck when hundreds and thousands of samples need to be analyzed for rapid dose estimation. To circumvent this problem, a web-based approach for telescoring was initiated by our laboratory, which enabled the cytogeneticists around the globe to analyze and score digital images. To further increase the surge capacity of dicentric scorers, we recently initiated a dicentric training and scoring exercise involving a total of 50 volunteers at all academic levels without any prerequisite for experience in radiation cytogenetics. Out of the 50 volunteers enrolled thus far, only one outlier was found who overestimated the absorbed radiation dose. Our approach of training the civilians in dicentric chromosome analysis holds great promise for increasing the surge capacity of dicentric chromosome scorers for a rapid biodosimetry in the case of mass casualty scenarios.

DEVELOPMENT OF A MINIATURIZED VERSION OF DICENTRIC CHROMOSOME ASSAY TOOL FOR RADIOLOGICAL TRIAGE.

Use of ionizing radiation (IR) in various industrial, medical and other applications can potentially increase the risk of medical, occupational or accidental human exposure. Additionally, in the event of a radiological or nuclear (R/N) incident, several tens of hundreds and thousands of people are likely to be exposed to IR. IR causes serious health effects including mortality from acute radiation syndrome and therefore it is imperative to determine the absorbed radiation dose, which will enable physicians in making an appropriate clinical 'life-saving' decision. The 'Dicentric Chromosome Assay (DCA)' is the gold standard for estimating the absorbed radiation dose but its performance is time consuming and laborious. Further, timely evaluation of dicentric chromosomes (DCs) for dose estimation in a large number of samples provides a bottleneck because of a limited number of trained personnel and a prolonged time for manual analysis. To circumvent some of these technical issues, we developed and optimized a miniaturized high throughput version of DCA (mini-DCA) in a 96-microtube matrix with bar-coded 1.4 ml tubes to enable the processing of a large number of samples. To increase the speed of DC analysis for radiation dose estimation, a semi-automated scoring was optimized using the Metafer DCScore algorithm. The accuracy of mini-DCA in dose estimation was verified and validated though comparison with conventional DCA performed in 15 ml conical tubes. The mini-DCA considerably reduced the sample processing time by a factor of 4 when compared to the conventional DCA. Further, the radiation doses estimated by mini-DCA using the triage mode of scoring (50 cells or 30 DCs) were similar to that of conventional DCA using 300-500 cells. The mini-DCA coupled with semi-automated DC scoring not only reduced the sample processing and analysis times by a factor of 4 but also enabled the processing of a large number of samples at once. Our mini-DCA method, once automated for high throughput robotic platforms, will be an effective radiological triage tool for mass casualty incidents.

Rapid Response, Dose Assessment, and Clinical Management of a Plutonium-contaminated Puncture Wound.

Internalization of radionuclides occurs not only by inhalation, ingestion, parenteral injection (i.e., administration of radioactive material for a medical purpose), and direct transdermal absorption, but also by contaminated wounds. In June 2010, a glove-box operator at the U.S. Department of Energy's Savannah River Site sustained a puncture wound while venting canisters containing legacy materials contaminated with Pu. To indicate the canisters had been vented, a flag was inserted into the vent hole. The shaft of the flag penetrated the protective gloves worn by the operator. Initial monitoring performed with a zinc-sulfide alpha detector indicated 300 dpm at the wound site. After being cleared by radiological controls personnel, the patient was taken to the site medical facility where decontamination was attempted and diethylenetriaminepentaacetic acid (DTPA) was administered intravenously within 1.5 h of the incident. The patient was then taken to the Savannah River Site In Vivo Counting Facility where the wound was counted with a Canberra GL 2820 high-purity germanium detector, capable of quantifying contamination by detecting low-energy x rays and gamma rays. In addition to the classic 13, 17, and 20 keV photons associated with Pu, the low-yield (0.04%) 43.5 keV peak was also detected. This indicated a level of wound contamination orders of magnitude above the initial estimate of 300 dpm detected with handheld instrumentation. Trace quantities of Am were also identified via the 59.5 keV peak. A 24 h urine sample collection was begun on day 1 and continued at varying intervals for over a year. The patient underwent a punch biopsy at 3 h postincident (14,000 dpm removed) and excisional biopsies on days 1 and 9 (removal of an additional 3,200 dpm and 3,800 dpm, respectively). The initial post-DTPA urine sample analysis report indicated excretion in excess of 24,000 dpm Pu. Wound mapping was performed in an effort to determine migration from the wound site and indicated minimum local migration. In vivo counts were performed on the liver, axillary lymph nodes, supratrochlear lymph nodes, and skeleton to assess uptake and did not indicate measurable activity. Seventy-one total doses of DTPA were administered at varying frequencies for 317 d post intake. After allowing 100 d for removal of DTPA from the body, five 24 h urine samples were collected and analyzed for dose assessment by using the wound model described in National Council on Radiation Protection and Measurements Report No. 156. The total effective dose averted via physical removal of the contaminant and DTPA administration exceeded 1 Sv, demonstrating that rapid recognition of incident magnitude and prompt medical intervention are critical for dose aversion.

Investigation of Spatial Organization of Chromosome Territories in Chromosome Exchange Aberrations After Ionizing Radiation Exposure.

Higher-order organization of the human genome is well established with chromosomes occupying distinct domains or territories in the interphase nucleus. Spatial organization of chromosome territories in the interphase nucleus occurs in a cell-type-specific manner. Since both stable and unstable aberrations induced by ionizing radiation involve the exchange of material between two or more chromosomes, this study investigated the role of spatial organization of chromosome domains in ionizing-radiation-induced chromosome translocation events. Using multicolor fluorescence in situ hybridization, the study characterized the positioning of each human chromosome relative to its neighborhood territories in the interphase nucleus of lymphocytes and B-lymphoblastoid cells before ionizing radiation and compared this interphase positioning with the spectrum of exchanges observed after ionizing radiation in the metaphase chromosomes. In addition to multicolor fluorescence in situ hybridization, the genome-wide chromosome conformation capture technique (Hi-C) was also performed in mock and x-ray-irradiated human B-lymphoblastoid and fibroblast cells to characterize the interactions among chromosomes and to assess the genome reorganization changes, if any, after ionizing radiation exposure. On average, 35-50% of the total translocations induced by x rays and neutrons correlated with proximity of chromosome territories detected by multicolor fluorescence in situ hybridization in both lymphocytes and lymphoblastoid cells. The translocation rate observed in proximally positioned chromosome territories was consistently higher than distally located territories and was found to be statistically significant (p = 0.01) in human lymphoblastoid cells after x rays. The interchromosome interaction frequencies detected by Hi-C correlate fairly well with ionizing-radiation-induced translocations detected by multicolor fluorescence in situ hybridization, suggesting the importance of chromosome proximity effects in ionizing-radiation-induced chromosomal translocation events.

Medical management of acute radiation syndrome and associated infections in a high-casualty incident.

A high-casualty incident may result in a significant human toll due to the inability of a community to meet the health care demands of the population. A successful medical response requires health care facilities to not only communicate and integrate medical services, meet surge capacity, protect health care workers and implement triage and treatment protocols, but also to provide the venue for clinical management of acute radiation injuries and their associated infections. Today, clinical management is primarily guided by the recommendations of a Consultancy that were made at the World Health Organization (WHO). This international consensus was reached on evidence-based, clinical management of each of the four sub-syndromes that compose acute radiation syndrome (ARS), including the hematopoietic subsyndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Major findings in studies meeting inclusion criteria for management strategies for HS were that (i) no randomized controlled studies of medical countermeasures have been (or will likely ever be) performed for ARS cases, (ii) the data for management of HS are restricted by the lack of comparator groups, and (iii) reports of countermeasures for management of injury to non-hematopoietic organs are often incompletely described. Here, (i) recommendations made in Geneva are summarized; (ii) the analysis of countermeasures for HS is updated by review of two additional cases and extended to published reports not meeting inclusion criteria; and (iii) guidelines are provided for management of microbial infections based upon patient risk for prolonged immunosuppression.

Nuclear and radiological emergencies: Building capacity in medical physics to support response.

Medical physicists represent a valuable asset at the disposal of a structured and planned response to nuclear or radiological emergencies (NREs), especially in the hospital environment. The recognition of this fact led the International Atomic Energy Agency (IAEA) and the International Organization for Medical Physics (IOMP) to start a fruitful collaboration aiming to improve education and training of medical physicists so that they may support response efforts in case of NREs. Existing shortcomings in specific technical areas were identified through international consultations supported by the IAEA and led to the development of a project aiming at preparing a specific and standardized training package for medical physicists in support to NREs. The Project was funded through extra-budgetary contribution from Japan within the IAEA Nuclear Safety Action Plan. This paper presents the work accomplished through that project and describes the current steps and future direction for enabling medical physicists to better support response to NREs.

The Pseudo-Pelger HuËt Cell-A New Permanent Radiation Biomarker.

Using archival peripheral blood slides obtained from patients in the 1958 Y-12 criticality accident, the authors have recently described the pseudo-Pelger Huët anomaly (PHA) in neutrophils as a new radiation-induced biomarker. The current work provides additional evidence that PHA is also a permanent biomarker, potentially useful in retrospective dosimetry. In the Y-12 cohort, the high dose group (n = 5, 2.98-4.61 Gy-Eq) exhibited 13.0 ± 0.85 % Pelger Huët cells (mean ± SEM) in the neutrophil population compared to 6.8 ± 1.6 % in the low dose group (n = 3, 0.29-0.86 Gy-Eq; p = 0.008). An age and gender-matched control group (n = 8) exhibited 3.6 ± 0.9 % PH cells. Results of a one-way ANOVA show that the high dose group is statistically different from both the low dose group and the control group (p = 0.002). In the Y-12 cohort, PHA appears <12 h post-accident and is permanent for more than 16 y. Similar long-term persistence of the PHA mutation has been obtained from examination of peripheral blood slides from the 1971 Co accident at the Variable Dose Rate Irradiation Facility (VDRIF) in Oak Ridge, TN. In order to investigate the pseudo-PH cell as a biomarker in animal studies under well controlled dosimetry, peripheral blood slides were obtained from animals in a nonhuman primate (NHP) (Macaca mulatta) total-body irradiation (TBI) model (Co γ rays at 0.6 Gy min; dose range 1-8.5 Gy, LD50/60 6.44 Gy). In the NHP studies, the first measurement of PHA is taken at 5 h post-irradiation, then daily for days 1-5 and every 5-10 d thereafter. In the TBI model, the PH cell appears quickly (<5 h) post-irradiation, and the dose-dependent PH percentage is constant from 1 d over the 60-d monitoring period of the experiments. Using the average of data from 1-60 d, a linear dose response (PHA % slope = 0.49 ± 0.07 % Gy, r = 0.92) is obtained over the dose range 0-8.5 Gy. The authors conclude that ionizing radiation induces dose-dependent internuclear bridges in circulating neutrophils, and this morphological change can be used both as an acute phase biomarker and as a tool for retrospective dosimetry.

Inferences, Risk Modeling, and Prediction of Health Effects of Ionizing Radiation.

The combined expertise of radiation epidemiologists and laboratory experimentalists is required to accurately define health risks from exposure to a low/very low radiation dose. Although stochastic risk can be estimated when a known threshold dose is exceeded, risk must be inferred from data transference at sub-threshold doses. The clinician's dilemma is evident when complying with accepted medical practice that is complicated by potential long-term, adverse outcomes. By contrast, radiation protection regulators must make prudent judgments without complete knowledge of the scope and consequences of their actions. Only by combining the strengths of epidemiological and experimental laboratory approaches can accurate predictive modeling be achieved after exposure to a low/very low dose.

Appearance of pseudo-Pelger Huet anomaly after accidental exposure to ionizing radiation in vivo.

To evaluate the morphology of formed elements of human blood after exposure to ionizing radiation in vivo, archival smears of peripheral blood from eight individuals involved in the 1958 Y-12 criticality accident at Oak Ridge, Tennessee, were examined manually by light microscopy. For each case, increased interlobar bridging was observed in nuclei of the myeloid cells, many of which were bilobed and morphologically similar to Pelger Huet (PH) cells. The high-dose group (n = 5, 2.98-4.61 Gy-Eq) exhibited 13.0 ± 0.85% PH cells (mean ± SEM) in the neutrophil population compared to 6.8 ± 1.6% in the low-dose group (n = 3, 0.29-0.86 Gy-Eq; p = 0.008). An age- and gender-matched control group (n = 8) exhibited 3.6 ± 0.9% PH cells. Results of a one-way ANOVA show that the high-dose group is statistically different from both the low-dose group and the control group (p = 0.002). However, the low-dose group is not statistically different from the control group (p = 0.122). The mean number of nuclear lobes in blood neutrophils was also enumerated as a function of time after exposure and was found to be diminished, consistent with incomplete nuclear segmentation that is characteristic of the Pelger Huet anomaly (PHA). In contrast to these changes in myeloid cells, the morphology of erythrocytes and platelets appeared to be normal. The authors conclude that ionizing radiation induces abnormal morphology of circulating neutrophils, which is similar to the pseudo-PHA that is acquired in disorders such as myelodysplastic syndrome, acute myeloid leukemia, and leukemoid reactions. Potential molecular mechanisms by which radiation induces this morphological change are discussed. From this cohort, the biomarker appears to be present early post-accident (<9 h) and stable at least up to 16 y post-accident. Assessment of circulating pseudo-Pelger Huet cells is being investigated as a potential biodosimetric tool.

Local, regional and national responses for medical management of a radiological/nuclear incident.

Radiological and nuclear devices may be used by terrorists or may be the source of accidental exposure. A tiered approach has been recommended for response to a terrorist event wherein local, regional, state and federal assets become involved sequentially, as the magnitude in severity of the incident increases. State-wide hospital plans have been developed and published for Connecticut, New York and California. These plans address delineation of responsibilities of various categories of health professionals, protection of healthcare providers, identification and classification of individuals who might have been exposed to and/or contaminated by radiation and, in the case of Connecticut response plan, early management of victims. Regional response programs such as the New England Regional Health Compact (consisting of 6 member states) have been developed to manage consequences of radiation injury. The Department of Homeland Security is ultimately responsible for managing both health consequences and the crisis. Multiple US national response assets may be called upon for use in radiological incidents. These include agencies and programs that have been developed by the Department of Energy, the Environmental Protection Agency and the Department of Defense. Coordination of national, regional and state assets with local response efforts is necessary to provide a timely and efficient response.

First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation.

OBJECTIVE: Hematopoietic syndrome (HS) is a clinical diagnosis assigned to people who present with ≥ 1 new-onset cytopenias in the setting of acute radiation exposure. The World Health Organization convened a panel of experts to evaluate the evidence and develop recommendations for medical countermeasures for the management of HS in a hypothetical scenario involving the hospitalization of 100 to 200 individuals exposed to radiation. The objective of this consultancy was to develop recommendations for treatment of the HS based upon the quality of evidence. METHODS: English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to panel members before the meeting and updated during the meeting. Published case series and case reports of individuals with HS, published randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation (GRADE) system. In cases in which data were limited or incomplete, a narrative review of the observations was made. No randomized controlled trials of medical countermeasures have been completed for individuals with radiation-associated HS. The use of GRADE analysis of countermeasures for injury to hematopoietic tissue was restricted by the lack of comparator groups in humans. Reliance on data generated in nonirradiated humans and experimental animals was necessary. RESULTS: Based upon GRADE analysis and narrative review, a strong recommendation was made for the administration of granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor and a weak recommendation was made for the use of erythropoiesis-stimulating agents or hematopoietic stem cell transplantation. CONCLUSIONS: Assessment of therapeutic interventions for HS in humans exposed to nontherapeutic radiation is difficult because of the limits of the evidence.

Literature review and global consensus on management of acute radiation syndrome affecting nonhematopoietic organ systems.

OBJECTIVES: The World Health Organization convened a panel of experts to rank the evidence for medical countermeasures for management of acute radiation syndrome (ARS) in a hypothetical scenario involving the hospitalization of 100 to 200 victims. The goal of this panel was to achieve consensus on optimal management of ARS affecting nonhematopoietic organ systems based upon evidence in the published literature. METHODS: English-language articles were identified in MEDLINE and PubMed. Reference lists of retrieved articles were distributed to conferees in advance of and updated during the meeting. Published case series and case reports of ARS, publications of randomized controlled trials of relevant interventions used to treat nonirradiated individuals, reports of studies in irradiated animals, and prior recommendations of subject matter experts were selected. Studies were extracted using the Grading of Recommendations Assessment Development and Evaluation system. In cases in which data were limited or incomplete, a narrative review of the observations was made. RESULTS: No randomized controlled trials of medical countermeasures have been completed for individuals with ARS. Reports of countermeasures were often incompletely described, making it necessary to rely on data generated in nonirradiated humans and in experimental animals. A strong recommendation is made for the administration of a serotonin-receptor antagonist prophylactically when the suspected exposure is >2 Gy and topical steroids, antibiotics, and antihistamines for radiation burns, ulcers, or blisters; excision and grafting of radiation ulcers or necrosis with intractable pain; provision of supportive care to individuals with neurovascular syndrome; and administration of electrolyte replacement therapy and sedatives to individuals with significant burns, hypovolemia, and/or shock. A strong recommendation is made against the use of systemic steroids in the absence of a specific indication. A weak recommendation is made for the use of fluoroquinolones, bowel decontamination, loperamide, and enteral nutrition, and for selective oropharyngeal/digestive decontamination, blood glucose maintenance, and stress ulcer prophylaxis in critically ill patients. CONCLUSIONS: High-quality studies of therapeutic interventions in humans exposed to nontherapeutic radiation are not available, and because of ethical concerns regarding the conduct of controlled studies in humans, such studies are unlikely to emerge in the near future.