Introduction
Disasters occur in many forms. Natural hazards include climatological events, such as floods, tornadoes, and hurricanes, as well as geological incidents, such as earthquakes, volcanic eruptions, and landslides.1 There are also technological hazards, such as power outages, cybersecurity breaches, and hazardous materials incidents that include nuclear and radiological disasters.1 Recent events in Ukraine and the Middle East highlight the fact that warfare and terrorism remain ongoing challenges for disaster planning and response. Nowhere are these challenges more daunting than for chemical, biological, radiological, and nuclear (CBRN) incidents, or when CBRN agents are used in terrorism attacks or warfare. Preparing for and managing radiological and nuclear casualties is particularly problematic because of the following: (1) There are a large number of radionuclides with which individuals might be externally or internally contaminated. (2) There are few antidotes for internal contamination with radionuclides, and relatively few countermeasures for those exposed to radioactive sources. (3) CBRN incidents are low-probability, high-consequence events. (4) Planners and responders lack familiarity and experience with CBRN threats. We hypothesized that the multiple standard references relied upon for these events have inconsistencies between them, with a lack of clarity that supports rapid and accurate utilization.
The unique management problems posed by pediatric casualties during a disaster motivated our previous study.Reference Maciulewicz, Kazzi, Navis, Nelsen, Cieslak, Newton, Lin, Grimm and Walter2 However, the United Nations, its Children’s Fund (UNICEF), and the World Health Organization (WHO), along with other national and international bodies and experts, recognize that children are best cared for in a holistic manner, integrating care with their parents, families, and caregivers. This holistic approach keeps families united as much as possible during a disaster, enhancing family adaptation to and recovery from disasters.Reference Cieslak, Lillibridge, Sharp, Christopher, Eitzen and Wallace3–Reference Pfefferbaum and North5 Therefore, WRAP-EM (https://wrap-em.org/) conducted this study to assess existing, standard references detailing adult medical countermeasures and antidotes for radiological and nuclear incidents, including acts of war and terrorism, to complement the previously published pediatric study on this topic.Reference Maciulewicz, Kazzi, Navis, Nelsen, Cieslak, Newton, Lin, Grimm and Walter2
WRAP-EM is an alliance of pediatric preparedness and response experts from 6 states (Arizona, California, Nevada, Oregon, Utah, and Washington). WRAP-EM initially received federal grant support from the Administration for Preparedness and Response (ASPR) in 2019 to focus on regional pediatric capacity and capabilities for all hazards. During gap analysis of selected references, the WRAP-EM program identified the need for medical countermeasures with pediatric considerations for dosing and administration during a CBRN incident. This gap included the need for a quick reference with pediatric dosing and administration guidance. Therefore, WRAP-EM assembled an interdisciplinary group of health care practitioners and national CBRN subject matter experts (SMEs) called the CBRN Focus Group, a working group with administrative support. As well as collaboration with participants from the HRSA-funded pediatric Pandemic network. This team includes individuals with experience and/or training in CBRN response, disaster preparedness, emergency medicine, epidemiology, trauma surgery, hospital medicine, clinical pharmacy, pharmacology, poison control center response, public health, medical toxicology, and related disciplines.
WRAP-EM’s CBRN Focus Group formed a Countermeasures Sub-Group to study medications for radiological and nuclear incidents with the following objectives: (1) to perform a search of standard references available for adult dosing and administration considerations, (2) to compare these standard references, detailing adult indications and dosing, and assessing the differences among them, (3) to collect, tabulate and then disseminate adult dosing and administration recommendations from these references to health care professionals caring for families, specifically for adults in this study, and (4) to document whether each countermeasure or antidote is U.S. Food and Drug Administration (FDA) approved for use in adults.
Materials and Methods
This paper is a comparative analysis of standard references that address adult indications and dosing for medical countermeasures and antidotes for radiological and nuclear incidents. The databases and medical references were selected by expert consensus to represent those that would be likely to be accessed during a radiological or nuclear emergency. These selected standard references include U.S. civilian and military governmental, open-access resources; proprietary medical and pharmaceutical databases; and continuing education courses that responders commonly attend to prepare for radiological and nuclear incidents. The selected standard references are listed alphabetically below:
Advanced Hazmat Life Support (AHLS) for Radiological Incidents and Terrorism (https://www.ahls.org/site/take-a-course/radiological-incidents-and-terrorism-course/) is an interdisciplinary, international, 4-hour, continuing education course whose textbook is in its fifth edition (2020), that is copresented by the American Academy of Clinical Toxicology (AACT) (https://www.clintox.org/) and AHLS (https://www.ahls.org/site/) within the Arizona Emergency Medicine Research Center (https://emergencymed.arizona.edu/aemrc) at the University of Arizona College of Medicine.Reference Kazzi, Nemhauser, Feldman and Walter6 The AACT is an international multi-disciplinary organization uniting scientists and clinicians to promote research, education, prevention, and treatment of diseases caused by chemicals, drugs, and toxins.
DailyMed (https://dailymed.nlm.nih.gov/dailymed/) is a U.S. National Library of Medicine (NLM), National Institutes of Health (NIH) searchable database.7 It contains 148,970 of the most recent labels for medications and medical products submitted to the FDA. DailyMed presents the labeling and prescribing information in an easy-to-read format.
Internal Contamination Clinical Reference (ICCR) (https://www.cdc.gov/nceh/radiation/emergencies/iccr.htm) is an app from the U.S. Centers for Disease Control and Prevention (CDC).8
The Medical Aspects of Radiation Incidents (https://orise.orau.gov/resources/reacts/documents/medical-aspects-of-radiation-incidents.pdf) is a handbook in its fourth edition (2017), produced by the Radiation Emergency Assistance Center/Training Site (REAC/TS) (https://orise.orau.gov/reacts/index.html).9 REAC/TS is a radiation emergency medical response asset of the U.S. Department of Energy/National Nuclear Security Administration (DOE/NNSA). REAC/TS provides emergency response and subject matter expertise for medical management of patients from radiation incidents. REAC/TS is operated for the DOE by the Oak Ridge Associated Universities (ORAU) (https://www.orau.org/). REAC/TS also teaches a number of continuing medical education courses (https://orise.orau.gov/reacts/continuing-medical-education/index.html), including Radiation Emergency Medicine (https://orise.orau.gov/reacts/continuing-medical-education/radiation-emergency-medicine.html).
Medical Management of Radiological Casualties (https://afrri.usuhs.edu/sites/default/files/media/documents/affri_-_medical_management_of_rad_casualties_5th_edition_0.pdf) is a handbook in its fifth edition (2022), produced by the Armed Forces Radiobiology Research Institute (AFRRI) (https://afrri.usuhs.edu/home).10 AFRRI is responsible for preserving and protecting the health and performance of U.S. military personnel operating in potentially radiologically contaminated environments. AFRRI provides rapidly deployable radiation medicine expertise to radiological or nuclear events, domestically or abroad, through its Medical Radiobiology Advisory Team (MRAT) (https://afrri.usuhs.edu/education-mrat). AFFRI also teaches the Medical Effects of Ionizing Radiation (MEIR) Course (https://afrri.usuhs.edu/meir-course). From January to June 2024, the MEIR course has a precourse asynchronous lecture set (4.5 hours) completed prior to the live, 2-day MEIR course that is taught at major U.S. military bases throughout the United States and abroad. Starting in July 2024, the MEIR course will be virtual learning, conducted through the Canvas Learning Management System with 40 continuing education hours of synchronous and asynchronous learning over 5 days. This will be offered quarterly and will replace most live MEIR courses globally.
Micromedex® (https://www.merative.com/clinical-decision-support) is a database that provides access to full-text, tertiary literature, including referenced information about pharmaceuticals and toxicology.11
National Stockpiles for Radiological and Nuclear Emergencies: Policy Advice (https://iris.who.int/bitstream/handle/10665/365681/9789240067875-eng.pdf?sequence=1) is a publication of the World Health Organization (WHO) (https://www.who.int/publications/i/item/9789240067875).12 It is available in 3 languages: English, Japanese, and Ukrainian. This monograph describes protocols and practices regarding national stockpiles of medical countermeasures for radiation emergencies, especially medications to treat people affected by radiological and nuclear emergencies. This monograph details guidelines for establishing and managing a formulary for a national stockpile of medications to care for affected people. It includes examples from Argentina, Brazil, France, Germany, Japan, the Republic of Korea, the Russian Federation, and the United States of America.
Poisindex® (https://www.aapcc.org/npds-FAQs) is a database (supported by Merative Micromedex® software) sponsored by the America’s Poison Centers (APC) and used by poison center staff to code and respond to calls for assistance. Poisindex® has information on more than 445,000 chemical and household products to assist in the management of calls.13
Radiation Medical Emergency Management (REMM) (https://remm.hhs.gov/) is a website produced by the US Department of Health and Human Services (HHS), Administration for Strategic Preparedness and Response (ASPR).14 It provides guidance for health care providers, primarily physicians, about the clinical diagnosis and treatment of radiation injury during radiological and nuclear emergencies. Its guidance is evidence-based, usable information that is understandable to those without formal radiation medicine expertise. It also provides guidance for the wider health care community to plan for and respond to radiation mass casualty incidents. REMM is also available as an app, Mobile REMM (https://remm.hhs.gov/downloadmremm.htm).
We considered including Management of Persons Contaminated with Radionuclides: Recommendations of the National Council on Radiation Protection and Measurements (NCRP Report No. 161); however, we decided not to because it consists of 2 volumes, totaling 1032 pages, and is incorporated by reference into many of the standard references above.15
If a medical countermeasure or antidote for radiological and nuclear incidents was listed in any of the selected standard references, we included it in this study. This was done to identify which references did or did not include each of the countermeasures and antidotes.
We conducted a literature search with a medical librarian to see if any previous similar human study had been published in the English medical literature. Embase was searched from 1947 through January 2024 and PubMed was searched from 1996 through January 2024 with the search details in Table 1. We further delineated whether each standard reference was (1) a U.S. governmental, open-access resource, (2) available as an app, or (3) associated with continuing education courses (Table 2).
Literature search
Reference characteristics
We identified pharmaceutical countermeasures or antidotes for radiological and nuclear incidents and terrorism in each standard reference listed above. Then we systematically abstracted and tabularized the following information for each medication: generic name, indication(s), FDA approval status for use in adults, mechanism of action, dosage, and route of administration (Table 3). We also standardized the format for each medication’s dosage and route in Table 3, while maintaining the specific dosage and route as originally listed in each standard reference. While all medications in Table 3 are countermeasures for radiological and nuclear incidents and terrorism, we divided them into 3 major sections for clarity: (1) antidotes for internal contamination with radionuclides, (2) cytokines to treat the hematopoietic subsyndrome of the acute radiation syndrome (ARS), and (3) a topical dressing for ionizing radiation burns (Table 3). Once the data was collated and standardized, we performed a comparison analysis for each of the medications listed. This study is Institutional Review Board (IRB) exempt.
Adult medical countermeasures: antidotes and cytokines for radiological and nuclear incidents and terrorism
Results
Our literature search (Table 1) found no similar published study other than WRAP-EM’s recently published pediatric study on this topic.Reference Maciulewicz, Kazzi, Navis, Nelsen, Cieslak, Newton, Lin, Grimm and Walter2 Of the 9 selected standard references for adult medical countermeasures for radiological and nuclear incidents and terrorism, 5 (55.6%) are governmental, open-access resources (Table 2). Of the 9 references, 3 (33.3%) offer an app (ICCR and REMM without purchase and Micromedex® with subscription), and 4 (44.4%) of the sponsoring organizations offer continuing education courses for health care professionals to teach details of using these antidotes and cytokines (Table 2).
We found 24 medical countermeasures for radiological and nuclear incidents and terrorism (Table 3). Types of countermeasures and antidotal mechanisms of action (pharmacokinetic versus pharmacodynamic) are depicted in Figure 1. Of the 24 countermeasures, 15 (62.5%) have FDA approval for specific radiological threats. Nine selected standard references had no listed adult indication or dosing for Silverlon (Table 3). Nine countermeasures with adult dosing or administration recommendations did not have FDA approval for the cited indications.
Adult Medical Countermeasures, Including Antidotes (dark blue), Cytokines (orange), a Thrombopoietin Receptor Agonist Mimetic (green), and an Antimicrobial Dressing (light blue) for Radiological and Nuclear Incidents and Terrorism and FDA Approval Status.
Discussion
WRAP-EM recently published a summary of medical countermeasures and antidotes used to treat children affected by radiological and nuclear incidents.Reference Maciulewicz, Kazzi, Navis, Nelsen, Cieslak, Newton, Lin, Grimm and Walter2 Given increasing recognition that children are best cared for holistically with their families, we recognized the need for a companion study addressing adults affected by radiological and nuclear incidents. To our knowledge, this is the first study comparing indication and dosing recommendations from recognized sources for adult countermeasures and antidotes for radiological and nuclear incidents. The 9 standard references selected for this study varied in which countermeasures or antidotes they included, indications and dosing, media (app, database, pdf, printed book and/or eBook, or website), accessibility (proprietary or governmental), and whether the sponsoring organization provided continuing education. Adult indications and dosing in the selected standard references stem from FDA-approved labeling (62.5%) or NCRP Report No. 161 (37.5%).15
Nuclear and radiation exposure incidents constitute low probability but potentially high-consequence events. Radiological and nuclear threat scenarios fall into 3 broad categories: (1) nuclear detonations, (2) nuclear power plant incidents, and (3) radiation exposure accidents, as well as “dirty bombs” and other radiological dispersal devices. To date, nuclear and radiation exposure incidents have been uncommon. Most clinicians, public health officials, and preparedness and response personnel thus have little, if any, experience in dealing with these events. Specifically, they are likely to be unfamiliar with the medical countermeasures available to mitigate against health hazards caused by exposure to the isotopes involved in such events.
Fortunately, of the >8000 isotopes known to exist, about a dozen constitute the greatest threats, versus the rarity of a nuclear detonation resulting in exposure to numerous aerosolized and gaseous radioisotopes.9–10 The types of isotope exposure risk by source are highlighted in Table 4.
As the number of problematic isotopes involved in any of the 3 broad threat scenarios is quite limited, the provision of specific medical countermeasures against illness caused by exposure to these isotopes is a distinct possibility. Our review found that 24 such countermeasures have been deemed potentially useful by the authors of the 9 standard references considered in our study. Fifteen of these have indications approved for such use by the FDA (Figure 1).
Our study compares recommendations provided in 9 standard references. These references vary in the number of countermeasures they include as well as their indications, dosing, and accessibility. Recommendations vary somewhat among these 9 references and, in some cases, derive from “expert opinion” (Table 3).
Our study aims to provide clinicians and responders with information to make well-reasoned decisions regarding the use of radiation countermeasures and antidotes in adults affected by a radiation threat. Moreover, we sought to harmonize this information with what WRAP-EM recently published regarding children affected by radiological and nuclear incidents and terrorism. It is hoped that, by doing so, we can foster holistic care for families affected by nuclear or radiation threats.
Limitations
This study analyzed selected standard references for countermeasures for radiological incidents and terrorism but did not assess the primary literature for the basis of the listed indications and dosing (safety and efficacy). The standard references are continually updated, and this study captured recommendations at the time of the study. New information may have been incorporated into the references since data was abstracted for this study. The consensus panel chose 9 standard references; however, other sources are possible. This study only included English language references for human studies, not animal studies.
Conclusions
Gaps remain in countermeasures for radiological incidents and terrorism. This study analyzed 9 standard references to identify these gaps as areas for future research and development.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1017/dmp.2025.10190.
Acknowledgements
The authors would like to thank the members of the WRAP-EM Countermeasures Group for their invaluable contributions and commitment to this publication. Research reported in this publication was supported by the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response under award number 6 U3REP190616-01-06. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response.
The authors gratefully acknowledge April L. Aguinaga, Librarian, Health Sciences Library, The University of Arizona Libraries. Her hard work, dedication, and expertise were essential for the literature search.
Author contribution
The CBRN Focus Group, Pediatric Countermeasures Sub-Group of WRAP-EM, conceived this study. All authors helped design the study. All authors helped acquire, analyze, and interpret the data. All authors helped draft and revise the work and approved this submitted manuscript for publication and are accountable for this work.
Competing interests
This study was partially funded by these sources:
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1) The Western Regional Alliance for Pediatric Emergency Management (WRAP-EM) that is supported by Award Number 6 U3REP190616-01-02 from the Administration for Strategic Preparedness and Response (ASPR) of the U.S. Department of Health & Human Services (HHS).
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2) The Southern Regional Disaster Response System (SRDRS) that is supported by Award Number HITEP 210054-01-00 from the Administration for Strategic Preparedness and Response (ASPR) of the U.S. Department of Health & Human Services (HHS).
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3) The Pediatric Pandemic Network that is supported by grant awards U1IMC43532 and U1IMC45814 from the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS).
This study and its manuscript are solely the responsibility of the authors and do not represent the official views of, nor an endorsement by the ASPR, HRSA, HHS, or the U.S. Government.
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