Radiation-induced multi-organ injury.

PURPOSE: Natural history studies have been informative in dissecting radiation injury, isolating its effects, and compartmentalizing injury based on the extent of exposure and the elapsed time post-irradiation. Although radiation injury models are useful for investigating the mechanism of action in isolated subsyndromes and development of medical countermeasures (MCMs), it is clear that ionizing radiation exposure leads to multi-organ injury (MOI). METHODS: The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases partnered with the Biomedical Advanced Research and Development Authority to convene a virtual two-day meeting titled 'Radiation-Induced Multi-Organ Injury' on June 7-8, 2022. Invited subject matter experts presented their research findings in MOI, including study of mechanisms and possible MCMs to address complex radiation-induced injuries. RESULTS: This workshop report summarizes key information from each presentation and discussion by the speakers and audience participants. CONCLUSIONS: Understanding the mechanisms that lead to radiation-induced MOI is critical to advancing candidate MCMs that could mitigate the injury and reduce associated morbidity and mortality. The observation that some of these mechanisms associated with MOI include systemic injuries, such as inflammation and vascular damage, suggests that MCMs that address systemic pathways could be effective against multiple organ systems.

Blood product use for radiological/nuclear trauma: product development and US regulatory considerations.

Blood products are likely to be critical components of the medical response to nuclear detonation, as the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) includes depletion of platelets and red blood cells that can lead to lethal hemorrhage and anemia. There is, however, only limited clinical information on the use of blood products to treat H-ARS. As currently configured, the US blood supply cannot meet the predicted surge in blood product demand that is likely to occur short-term and possibly long-term in the event of a large nuclear detonation. As part of the Administration for Strategic Preparedness and Response within the US Department of Health and Human Services, the Biomedical Advanced Research and Development Authority (BARDA) is addressing this preparedness gap by supporting the development of novel blood products and devices with characteristics that improve blood product storage and use in austere operational environments. The US Food and Drug Administration's Center for Drug Evaluation and Research (CDER) recently issued draft guidance on the development of drugs and biologics regulated by CDER to prevent or treat Acute Radiation Syndrome under the provisions of the "Animal Rule." The commentary provided here discusses the unique regulatory scheme for transfusion components and blood products regulated as biological drugs by Center for Biologics Evaluation and Research, including the ambiguity surrounding the evidentiary requirements for their approval for H-ARS, and whether, under certain circumstances, a specific H-ARS indication is necessary if relevant commercial indications are approved.

Animal Care in Radiation Medical Countermeasures Studies.

Animal models are necessary to demonstrate the efficacy of medical countermeasures (MCM) to mitigate/treat acute radiation syndrome and the delayed effects of acute radiation exposure and develop biodosimetry signatures for use in triage and to guide medical management. The use of animal models in radiation research allows for the simulation of the biological effects of exposure in humans. Robust and well-controlled animal studies provide a platform to address basic mechanistic and safety questions that cannot be conducted in humans. The U.S. Department of Health and Human Services has tasked the National Institute of Allergy and Infectious Diseases (NIAID) with identifying and funding early- through advanced-stage MCM development for radiation-induced injuries; and advancement of biodosimetry platforms and exploration of biomarkers for triage, definitive dose, and predictive purposes. Some of these NIAID-funded projects may transition to the Biomedical Advanced Research and Development Authority (BARDA), a component of the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services, which is tasked with the advanced development of MCMs to include pharmacokinetic, exposure, and safety assessments in humans. Guided by the U.S. Food and Drug Administration's (FDA) Animal Rule, both NIAID and BARDA work closely with researchers to advance product and device development, setting them on a course for eventual licensure/approval/clearance of their approaches by the FDA. In August 2020, NIAID partnered with BARDA to conduct a workshop to discuss currently accepted animal care protocols and examine aspects of animal models that can influence outcomes of studies to explore MCM efficacy for potential harmonization. This report provides an overview of the two-day workshop, which includes a series of special topic presentations followed by panel discussions with subject-matter experts from academia, industry partners, and select governmental agencies.

Balancing potential risks and benefits of hemoglobin-based oxygen carriers.

Hemoglobin-based oxygen carriers (HBOCs) are thought to have an adverse risk:benefit profile when compared to that of transfusing stored red blood cells (RBCs). However, there are clinical circumstances when RBC transfusion is not an option (e.g., patient refusal, unavailability owing to issues of compatibility or remote location). For these circumstances assessment of the risks of an HBOC should be compared to the risks of untransfused acute anemia. In this article we compare the risk of allowing a patient with severe anemia to have a further small decrease in hemoglobin (Hb) concentration to the risk of infusing an HBOC. We conclude that at Hb concentrations less than 6 g/dL, the risk of a further decrease in Hb concentration greatly exceeds the risk of HBOC infusion. Thus, we suggest that there may be a place for use of HBOCs when RBC transfusion is not an option.