Abstract:This article is part of a collaborativeeffort by experts in the field ofemergency preparedness to com-plete an overview begun by the lateMichael Shannon, MD, MPH, on thecurrent challenges and future direc-tions in pediatric disaster readi-ness. This particular article,"Preparation for Terrorist Threats:Radiation Injury," will address perti-nent clinical management issuesrelating to radioactive agents andthe unique vulnerabilities and careneeds of children as potential vic-tims of such terrorism.

Reprint requests and correspondence:David Siegel, MD, FAAP, National Instituteof Child Health, and Human Development,National Institutes of Health, USDepartment of Health and HumanServices, 6100 Executive Blvd, Room4A01, MSC 2440, Bethesda, MD20892-2440.david.siegel@nih.hhs.gov

1522-8401/$ - see front matter© 2009 Published by Elsevier Inc.

136 VOL. 10, NO. 3 • PREPARATION FOR TERRORIST

Preparation forTerrorist Threats:Radiation Injury

THREATS: RADIATION INJURY / S

David Siegel, MD, FAAP

itigating the effects of radiation injury, whether at thepolitical or patient care level, is one of the highest

Mpriorities for those that are entrusted with theresponsibility of taking care of our children. Radi-

ologic and nuclear threats come from a variety of sourcesincluding nuclear detonation, radiologic dispersive devices(dirty bombs), radiologic exposure devices (concealed source),and industrial and shipping accidents (power plant releases, foodand medical irradiators). Ionizing radiation injures tissuesthrough energy transfer. Potential exposure outcomes includecell death, cell malfunction, and delayed effects. In cell malfunc-tion, the cell survives but is altered and is incapable of self-repair,potentially causing tissue and organ malfunction. With delayedeffects, the cell's genetic material is altered, which creates thepotential for subsequent malignancy and birth defects.

The amount of radiation absorbed by the body determineshow sick a patient will be. Biodosimetry is the laboratory orclinical methodology used to measure or estimate the exposuredose and is used for triage as well as the development ofdefinitive treatment plans. Emerging biodosimetric technolo-gies may further refine triage and dose assessment strategies.A key component of current radiation countermeasuresresearch is the development of biodosimetry tools includingbioassays to evaluate the extent of radiation exposure andinjury. Particular attention to pediatric appropriate biomarkerresearch is needed.

The current treatment goals for radiation sickness are toprevent further radioactive contamination, treat damaged organs,reduce symptoms, and manage pain. Internal decontaminationtargets material that has been inhaled, ingested, and depositedand typically requires medical and/or surgical removal (usuallydone after initial stabilization). Examples of these medicalcountermeasures (MCMs) include radionuclide chelating (decor-poration) agents that reduce the body burden of an isotope (ie,

IEGEL

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diethylenetriamine pentaacetic acid, Prussian blue)and blocking agents that reduce organ uptake of anisotope (potassium iodide).

Survival is possible with mild-moderate exposures(0.5-3.5 Gy) with higher exposures increasing thelikelihood of death. With 3.5 Gy, there is approxi-mately a 50% mortality 30 days postexposure. TheRadiation Event Medical Management Web site(http://www.remm.nlm.gov/) produced by theDepartment of Health and Human Services/Officeof the Assistant Secretary for Preparedness/NationalLibrary of Medicine is an excellent resource for thediagnosis and management of acute radiationsyndrome (ARS). The Radiation Event MedicalManagement's algorithms are very comprehensivefor adults and for children; they provide an excellentfoundation for a pediatric approach to acute radia-tion injury.

Low levels of radiation (such as that occurringthrough natural background radiation and medicaldiagnostic procedures) are routinely managed bythe body's normal repair mechanism. When largeradiation exposures occur over short periods, thebody's ability to manage the damage can beoverwhelmed, leading to a spectrum of clinicalchanges that are collectively known as ARS. Theseclinical symptoms occur in stages during a periodof hours to weeks after whole-body radiationexposure, as injury to various tissues and organsis expressed. Acute radiation syndrome mayinvolve hematologic, gastrointestinal, cutaneous,and neurovascular systems. Long-term exposureoutcomes may also include renal failure andpulmonary fibrosis. Secondary malignancies mayappear decades later.

Acute radiation syndrome typically encompasses4 phases:

Prodromal phase: this is a nonspecific response toacute high-dose radiation exposure. The earlierthe onset of nausea, vomiting, and malaise, thegreater the exposure dose of radiation. Time toemesis (TE) correlates with dose absorbed: TEless than 4 hours suggests a whole body dose of3.5 Gy (350 rad) and a TE less than 1 hoursuggests a whole body dose of 65 Gy. This phasecan occur without later “manifest illness” (seebelow) if the dose is low enough.Latent phase: after recovery from the prodromalphase, there will be a length of time during whichthe exposed individual will be relatively symp-tom free. The duration of the phase is hours ordays. Declining absolute lymphocyte count isbest predictor of whether further injury maymanifest itself.

Manifest illness: this presents with the clinicalsymptoms of major the organ system(s) injured,with the time of onset decreasing as the exposuredose is increased. The 3 major organ systemsare affected relatively acutely: hematopoieticsystem, gastrointestinal system, and the centralnervous system.Recovery/death: chronic renal failure and pul-monary fibrosis may follow.1

The hematopoietic syndrome begins to manifest afterradiation exposures of 1.5 to 2.0 Gy in children andcan take weeks to manifest. The hematopoieticsyndrome is composed of neutropenia, lymphope-nia, thrombocytopenia, and anemia. There is con-sensus that agents that could prevent or reduce theseverity of neutropenia, thrombocytopenia, andanemia should be administered to those victimsthat have received 2 to 6 Gy. Currently, there are noexposure screening mechanisms to delineate a needfor the above treatment; therefore, any patientdisplaying the signs of ARS could be a candidatefor treatment.

• Lymphopenia: a drop in absolute lymphocytecount of 50% in 24 hours indicates a sig-nificant exposure. At the present time, thereis no known treatment for lymphopenia, andthe recovery of immunity is, in manyinstances, prolonged and incomplete.

• Neutropenia: the loss of progenitor cells andthe unusual kinetics of neutrophil productionand release account for the delayed onset ofthe hematopoietic syndrome.2 Human gran-ulocyte colony-stimulating factor are glyco-proteins that act on hematopoietic cells bybinding to specific cell receptors that stimu-late proliferation and differentiation as well assome end-cell function (based on the degreeof radiation exposure, these cytokines wouldbe initiated prophylactically). Keratinocytegrowth factor has been shown to reduce theperiod of febrile neutropenia secondary tototal body irradiation.

• Thrombocytopenia: the loss of progenitorcells with radiation exposure also results in adecrease in platelets. Thrombocytopeniatreatment challenges include the need forrecurrent platelet transfusions, which can beextremely difficult in the mass casualtysetting. Thrombopoietin is a cytokine thathas been isolated and identified as the primarygrowth factor responsible for regulation ofmegakaryopoiesis and thrombopoiesis. Sec-ond-generation thrombopoietin drugs such as

138 VOL. 10, NO. 3 • PREPARATION FOR TERRORIST THREATS: RADIATION INJURY / SIEGEL

Romiplostim, recently licensed for idiopathicthrombocytopenic purpura, hold promise forthe treatment of radiation induced injury.

• Anemia: the long half-life of red cells makesthis less of an immediate problem within thehematopoietic syndrome. Two erythropoie-tin-stimulating agents (epoetin alfa, darbe-poetin alfa) have been approved by the Foodand Drug Administration for other indicationsand may be useful in the management ofradiation-induced anemia.

• Stem cell transplantation is a considerationwith significant exposures. Many recom-mend following the Radiation Injury Treat-ment Network-National Marrow DonorProgram/American Society for Bone andMarrow Transplantation (RITN-NMDP/ASBMT) guidelines.

The gastrointestinal system is affected with doses inthe range of 6 to 20 Gy1 and always occurs inconjunction with hematopoietic injury and isassociated with a high mortality rate. The patho-physiology involves disruption of the villous mem-brane by reducing expression of endothelialthrombomodulin, a transmembrane protein recep-tor that regulates inflammation and is found onendothelial cells, with resultant diarrhea (fluidlosses may be severe enough to cause shock),infection (with membrane integrity lost opportunis-tic gram-negative organisms invade), and bleedingfrom injury to the submucosal vasculature.3,4

Treatment aims to restore fluid losses as well astreat opportunistic infections in a neutropenic host.Additional treatment modalities include statins,which increase the levels of endothelial thrombo-modulin, thus reducing radiation effects anddecreasing gastrointestinal injury. Palifermin(recombinant keratinocyte growth factor) hasbeen approved for use in prevention of oralmucositis, and animal studies suggest that it mayprevent intestinal mucositis.3,4

The neurovascular syndrome is less well definedthan other syndromes, and its stages are com-pressed. Individuals presenting with fever, hypoten-sion, and major impairment of cognitive functionwill most likely have had a supralethal exposure.5

These symptomsmay be observed in those receivingmore than 20 to 30 Gy of radiation.2 The prodromalphase is characterized by disorientation, confusion,and prostration and may be accompanied by loss ofbalance and seizures. The physical examinationmay show papilledema, ataxia, and reduced orabsent deep tendon and corneal reflexes. Duringthe latent period, apparent improvement occurs for

a few hours and is followed by severe manifestillness. Within 5 to 6 hours, watery diarrhea,respiratory distress, hyperpyrexia, and cardiovas-cular shock can occur. This rapid decline mimicsthe clinical course of acute sepsis and septic shock,both of which must be considered. The ensuingcirculatory complications of hypotension, cerebraledema, increased intracranial pressure, and cere-bral anoxia can bring death within 2 days.

Cutaneous injury from thermal or radiation burns ischaracterized by loss of epidermis and, at times,dermis. Injuries to the skin may cover small areasbut extend deeply into the soft tissue, even reachingunderlying muscle and bone.6 They may be accom-panied by profound local edema and place thepatient at risk for a compartment syndrome.Patients presenting with burns immediately afterexposure have thermal rather than radiation burns.Treatment protocols have not been standardized,but clinicians have used corticosteroids, interferon,pentoxiflylline, α-tocopherol, and superoxide dis-mutase for treatment of their patients.

Lung injury may manifest 1 to 6 months afterexposure to therapeutic doses of radiation to thechest. Acute pneumonitis may occur with symptomsof shortness of breath, cough, and sometimes fever. Inpatients and animal models, pneumonitis is asso-ciated with cell loss in the alveolar lining, alveolarhemorrhage, breathlessness, pulmonary edema, andleukocyte infiltration. Within 3 weeks of radiationexposure, there is an increase in mucous-secretinggoblet cells and ciliary dysfunction. Within 3 to 12weeks, radiation-induced pneumonia occurs. Thismanifestation of radiation injury is often fatal. Ifrecovery occurs, fibrosis develops, which is thereplacement of the normal alveolar architecturewith abnormal scar tissue. Pentoxifylline has beenfound to be effective inmitigating pulmonary toxicity,and the combination of pentoxifylline combined withα-tocopherol has been shown useful for the treatmentof radiation-induced fibrosis.7-10

Delayed radiation-induced kidney injury occursmonths to years after exposure to radiation doses of10 to 20 Gy. The higher the dose, the sooner theonset and progression of injury. In animal models,ultrastructural damage to the glomerular endothe-lium is evident within approximately a month.Tubular epithelial cells manifest evidence of injurysoon after, followed by interstitial scarring. Struc-tural damage and renal function worsen with time.High levels of protein and nitrogen are observed inthe urine, and hypertension occurs. Mechanisticstudies have suggested the involvement of the renin-angiotensin system in the development of radiation-induced renal effects.11,12 Treatment may include

PREPARATION FOR TERRORIST THREATS: RADIATION INJURY / SIEGEL • VOL. 10, NO. 3 139

suppression of the renin-angiotensin system usingangiotensin-converting enzyme inhibitors, angiotensinII receptor antogonists (based on anecdotal evi-dence of efficacy).

FUTURE PEDIATRIC RESEARCH NEEDSIn the years after the September 11, 2001 terrorist

attacks, the federal government in collaboration withacademia and industry has prioritized developmentand stockpiling of MCMs to deal with the conse-quences of weapons of mass destruction. Unfortu-nately, for a multitude of reasons, regulatory, fiscal,ethical, and the lack of a pediatric voice, children donot have the same protective resources available forthem as the adults in our community do. In addition,many of the MCMs undergoing research and devel-opment at this point in time are not being adequatelystudied to benefit children. To bring attention to thisproblem and to provide a starting point for resolu-tion, a meeting of government and academicpediatric biodefense experts was held at the EuniceKennedy Shriver National Institute of Child Healthand Human Development on September 8 to 9, 2008.The goals of this meeting were to:

• Identify what additional studies may beneeded to help ensure that the currenttherapeutic agents in the Strategic NationalStockpile are properly formulated, dosed,safe, and effective for the care of childrenand pregnant women.

• Review and provide input into further devel-opment of therapeutic countermeasures forchildren and pregnant women in selectiveongoing basic science and clinical biodefense-related research studies.

Visit the National Institute of Child Health andHuman Development–Best Pharmaceuticals forChildren Act13 Web site for an overview of thecontents of the meeting. Further continuous pedia-tric input is crucial at all levels of biodefenseresearch and development as well as subsequent

deployment of future MCMs. Mechanisms arecurrently being developed to assist in this process.

REFERENCES1. Quinn M. Pediatric emergency training program: radiological

incidents. Washington DC: Children's National MedicalCenter; 2004.

2. Walker RI, Willemze R. Neutrophil kinetics and regulation ofgranulopoiesis. Rev Infect Dis 1980;2:282-93.

3. Blijlevens N, Sonis S. Palifermin (recombinant keratinocytegrowth factor-1): a pleiotropic growth factor with multiplebiological activities in preventing chemotherapy- and radio-therapy-induced mucositis. Ann Oncol 2007;18:817-26.

4. Nasilowska-Adamska B, Rzepecki P, Manko J, et al. Theinfluence of palifermin on oral mucositis and acute graftversus host disease in patients with hematological disordersundergoing hematopoietic stem cell transplant. Bone MarrowTransplant 2007;40:983-8.

5. Hall EJ, Garcia AJ. Acute effects of total body irradiation.Radiobiology for the radiologist. Philadelphia (Pa): LippincottWilliams & Wilkins; 2006. p. 117-28.

6. Barabanova AV. Acute radiation syndrome with cutaneoussyndrome. In: Ricks RC, Berger ME, O'Hara FM, editors. Themedical basis for radiation accident preparedness: theclinical care of victims. Boca Raton, FL: CRC Press-Parthenon Publishers; 2002.

7. Marks LB, Yu X, Vujaskovic Z, Small W, et al. Radiation-induced lung injury. Semin Radiat Oncol 2003;13:333-45.

8. Abratt RP, Morgan GW, Silvestri G, et al. Pulmonarycomplications of radiation therapy. Clin Chest Med 2004;25:167-77.

9. Hill RP. Radiation effects on the respiratory system. BJRSuppl 2005;27:75-81.

10. Molteni A, Moulder JE, Cohen EF, et al. Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1receptor blocker. Int J Radiat Biol 2000;76:523-32.

11. Cohen EP, Bonsib SA, Whitehouse E, et al. Mediators andmechanisms of radiation nephropathy. Proc Soc Exper BiolMed 2000;223:218-25.

12. Robbins ME, Diz DI. Pathogenic role of the renin-angiotensinsystem in modulating radiation-induced late effects. Int JRadiat Oncol Biol Phys 2006;64:6-12.

13. Siegel D, Shannon M, Henretig F, et al. Biodefense meeting:Best Pharmaceuticals for Children Act (BPCA). EuniceKennedy Shriver National Institute of Child Health andHuman Development. Available at: http://bpca.nichd.nih.gov/outreach/upload/Biodefense-09-08.pdf. Accessed 7/14/09.