Pediatric Medical Countermeasures: Antidotes and Cytokines for Radiological and Nuclear Incidents and Terrorism

Abstract The war in Ukraine raises concerns for potential hazards of radiological and nuclear incidents. Children are particularly vulnerable in these incidents and may need pharmaceutical countermeasures, including antidotes and cytokines. Searches found no published study comparing pediatric indications and dosing among standard references detailing pediatric medications for these incidents. This study addresses this gap by collecting, tabulating, and disseminating this information to healthcare professionals caring for children. Expert consensus chose the following references to compare their pediatric indications and dosing of medical countermeasures for radiation exposure and internal contamination with radioactive materials: Advanced Hazmat Life Support (AHLS) for Radiological Incidents and Terrorism, DailyMed, Internal Contamination Clinical Reference, Medical Aspects of Radiation Incidents, and Medical Management of Radiological Casualties, as well as Micromedex, POISINDEX, and Radiation Emergency Medical Management (REMM). This is the first study comparing pediatric indications and dosing for medical countermeasures among commonly used references for radiological and nuclear incidents.

Alliance for Pediatric Emergency Management (WRAP-EM) 1 conducted this study to assess existing, standard references detailing pediatric medical countermeasures and antidotes for radiological and nuclear incidents, including acts of war and terrorism.
WRAP-EM is an alliance of pediatric preparedness and response experts from 6 states (Arizona, California, Nevada, Oregon, Utah, Washington).WRAP-EM received federal grant support from the Administration for Strategic Preparedness and Response (ASPR) in 2019 to focus on regional pediatric capacity and capabilities for all hazards.One large gap identified in early WRAP-EM program assessments was the need for pediatric 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 healthcare practitioners, and national CBRN subject matter experts (SMEs) called the CBRN Focus Group; a working group with administrative support.This team includes individuals with experience and/or training in CBRN response, disaster preparedness, emergency medicine, and epidemiology, as well as pediatric emergency medicine, pediatric trauma surgery, pediatric hospital medicine, and clinical pharmacy.It also includes pharmacology, poison control center response, public health, and medical toxicology, as well as related disciplines.
The initial SME review of medical countermeasures and antidotes for radiological and nuclear incidents found that resources with pediatric-specific considerations were not readily apparent nor easy to find.WRAP-EM's CBRN Focus Group formed a Pediatric 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 pediatric dosing and administration considerations, (2) to compare these standard references detailing pediatric indications and dosing, assessing the differences among them, (3) to collect, tabulate, and then disseminate pediatric dosing and administration recommendations from these references to healthcare professionals caring for children, and (4) to document whether each countermeasure or antidote is US Food and Drug Administration (FDA) approved for use in children.

Materials and Methods
This paper is a comparative analysis of standard references that address pediatric 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 US 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: 1) Advanced Hazmat Life Support (AHLS) for Radiological Incidents and Terrorism 2 : This is an interdisciplinary, international, 4-hour, continuing education course whose textbook is in its fifth edition (2020), that is co-presented by the American Academy of Clinical Toxicology (AACT) 3 and AHLS 4 within the Arizona Emergency Medicine Research Center 5 at the University of Arizona College of Medicine. 8he 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.2) DailyMed6 : This is a US National Library of Medicine (NLM), National Institutes of Health (NIH) searchable database.9It contains 146 843 of the most recent labels for medications and medical products submitted to the FDA.REAC/TS also teaches a number of continuing medical education courses 11 , including Radiation Emergency Medicine.125) Medical Management of Radiological Casualties13 : is a handbook in its fourth edition (2013), produced by the Armed Forces Radiobiology Research Institute (AFRRI). 14,12FRRI is responsible for preserving and protecting the health and performance of US 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). 15AFFRI also teaches the Medical Effects of Ionizing Radiation (MEIR) Course 16 which is an on-site, three-day course taught at major U.S. military bases throughout the United States and abroad.
Micromedex® (Merative, Ann Arbor, MI, USA 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.Poisindex® (Merative Micromedex®, Ann Arbor, MI, USA 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. 14adiation Medical Emergency Management (REMM) (US Department of Health and Human Services, Washington DC, USA https://remm.hhs.gov/) is a website produced by the US Department of Health and Human Services Administration for Strategic Preparedness & Response (ASPR). 15It 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 healthcare 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 two-volumes, totaling 1,032 pages, and is incorporated by reference into many of the resources above. 16f 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, even if it only had adult dosing and administration information.This was done to identify gaps in pediatric indications and dosing.
During this study, the FDA gave a 510(k) clearance to use Silverlon (Argentum Medical, Geneva, IL, USA) as an antimicrobial dressing for radiation dermatitis and cutaneous radiation injury with dry desquamation. 17Therefore, with expert consensus, Silverlon was included in this study.
We conducted a literature search with a medical librarian to see if any previous similar study had been published in the English medical literature.Embase was searched from 1947 through August 2022 and PubMed was searched from 1996 through August 2022 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).
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 children, 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 it into three 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.

Results
Our literature search found no similar published study (Table 1).Of the eight selected standard references for pediatric medical countermeasures for radiological and nuclear incidents and terrorism, five (62.5%) are governmental, open-access resources (Table 2).Of the eight references, three (37.5%)offer an app (ICCR and REMM without purchase and Micromedex® with subscription), and four (50.0%) of the sponsoring organizations offer continuing education courses for healthcare 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.Eight selected standard references had no listed pediatric indication or dosing for eight countermeasures for radiological and nuclear incidents and terrorism, as follows: acetylcysteine, calcium gluconate, calcium chloride, propylthiouracil, sodium alginate, sodium bicarbonate, water diuresis, and Silverlon (Table 3).Three countermeasures with pediatric dosing or administration recommendations did not have FDA approval for the cited indications.

Discussion
To our knowledge, this is the first study comparing indication and dosing recommendations for pediatric countermeasures and antidotes for radiological and nuclear incidents.The eight 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.Pediatric indications and dosing in the selected standard references stem from FDAapproved labeling (62.5%) or NCRP Report No. 161 (37.5%). 16adiological illness is caused by exposures involving radioisotopes or prompt gamma/neutron irradiation.Given this constitutes a low incidence event (but potentially high consequence), most clinicians and responders are unfamiliar with the medical countermeasures and antidotes available to mitigate against illness caused by exposure to involved radioisotopes.
2] Incidents involving exposure accidents and dirty bombs derived from medical and academic sources risk exposure to 14 C, 252 Cf, 60 Co, 3 H, 125 I, 131 I, and 32 P. [11][12] Those derived from industrial sources risk exposure to 60 Co, 137 Cs, and 192 Ir, while those derived from military sources are likely to involve 241 Am, 3 H, 239 Pu, 235 U, and 238 U. [11][12] Accidental releases from damaged fission reactors risk exposure to 137 Cs, 131 I, 133 Xe and other noble gas radioisotopes. 11,12Finally, a nuclear detonation would result in exposure to numerous aerosolized and gaseous radioisotopes. 11,12iven the limited number of problematic radioisotopes, procuring and administering specific medical countermeasures against illnesses caused by internal contamination with these isotopes is distinctly possible.In fact, 24 such countermeasures (15 of which are FDA-approved) are widely regarded as useful in certain circumstances.Of the 24 countermeasures, eight (33%) have no listed pediatric indications or dosing (Table 3).Of note, half of the organizations that produce the eight standard references that are cited in this study provide education regarding the use of these countermeasures, while half do not.Pediatric dosing for countermeasures varies from no dosing recommendations to recommendations derived from "expert opinion" without datadriven support, to FDA-approved recommendations.Additionally, there remains a need to determine if radiation biodosimetry would be age dependent, with children responding differently than adults to biomarkers that suggest or predict injuries.This is certainly outside the scope of this work and future research is needed.
In providing this comparison, we hope to give clinicians, responders, and emergency planners robust information with which to make well-reasoned decisions regarding the use of radiation countermeasures and antidotes in children involved in these threat scenarios.We also seek to lay the groundwork for future efforts that should focus on providing uniform, easily accessible, data-driven, pediatric-specific recommendations, whenever possible.Additional continuing education is needed for healthcare professionals caring for children with exposure to radiological incidents or terrorism.NCRP Report No. 161 could be enhanced with an update that includes expanded pediatric indications and dosing for countermeasures and antidotes. 16he mission of the U.S. Dept. of Health and Human Services' Biomedical Advanced Research and Development Authority (BARDA) is to develop medical countermeasures to address public health and medical consequences of CBRN incidents, pandemic influenza, and emerging infectious diseases (https:// aspr.hhs.gov/AboutASPR/ProgramOffices/BARDA/Pages/default.aspx).BARDA, the FDA, and the National Institute of Allergy and Infectious Diseases (NIAID) Radiation and Nuclear Countermeasures Program could play critical roles to address gaps in pediatric indications and dosing for countermeasures and antidotes identified in this study.These agencies could collaborate with teams of experts within academic health sciences centers to address these gaps in pediatric care.

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.For example, newly approved generics or biosimilars of medical countermeasures.The consensus panel chose eight references; however, other sources are possible.This study only included English language references.

Conclusions
Gaps remain in pediatric countermeasures for radiological incidents and terrorism.This study analyzed eight standard references to identify these gaps as areas for future research and development.
10 Internal Contamination Clinical Reference (ICCR)7: The ICRC is an app from the US Centers for Disease Control and Prevention (CDC).104)The Medical Aspects of Radiation Incidents 8: This is a handbook in its fourth edition (2017), produced by the Radiation Emergency Assistance Center/Training Site (REAC/TS). 11,9REAC/TS is a radiation emergency medical response asset of the US 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 Affiliated Universities (ORAU). 13 1 https://wrap-em.org/ 2 https://www.ahls.org/site/take-a-course/radiological-incidents-and-terrorismcourse/

Table 1 .
Literature search

Table 2 .
Reference characteristics

Table 3 .
Pediatric medical countermeasures and antidotes for radiological and nuclear incidents and terrorism Ca-DTPA preferred ≤ 24 hours after suspected or confirmed internal contamination.Safety & effectiveness of the nebulized route have not been established in children.< 12 years: 14 mg/kg initial IV dose, max. 1 g Administer initial dose during 1st 24 hours after internal contamination Slow IV push over 3 -4 minutes or by infusion diluted in 100 -250 mL of D5W, LR, or NS