TopicsTopicsAcute Radiation Syndrome (ARS)y ( )• Definition and diagnosis• TreatmentTreatment

External and Internal ContaminationExternal and Internal Contamination• Definition and diagnosis• Treatment• Treatment

Examples Follow Up Care and ResearchExamples, Follow-Up Care and Research

56

Radiation InjuryRadiation Injury

• EXPOSURE– Acute Radiation Syndrome (Hematopoietic /Acute Radiation Syndrome (Hematopoietic /

GI / CV-CNS / Cutaneous Subsyndromes

• EXTERNAL CONTAMINATIONINTERNAL CONTAMINATION• INTERNAL CONTAMINATION

57

Radiation InjuryRadiation InjuryEXPOSURE

EXPOSURE DUE TO CONTAMINATION

EXTERNAL

58Modified from AFRRI

Radiation InjuryRadiation InjuryEXPOSURE

EXPOSURE DUE TO CONTAMINATION

inhalation

EXTERNAL INTERNAL

59Modified from AFRRI

Radiation InjuryRadiation InjuryEXPOSURE

EXPOSURE DUE TO CONTAMINATION

ingestion

EXTERNAL INTERNAL

60Modified from AFRRI

Radiation InjuryRadiation InjuryEXPOSURE

EXPOSURE DUE TO CONTAMINATION

EXTERNAL INTERNAL

trauma, injection, absorptionabsorption

61Modified from AFRRI

Medical EffectsMedical Effects

Acute:Acute:Usually none. ARS possible with large i t k hi h i t (intake or high energy isotopes (e.g. Polonium)

Chronic:Carcinogenesis, chronic radiation injury in target organ, e.g. kidney, lung, bone

62AFRRI

Alexander LitvinenkoAlexander Litvinenko

Died Nov 2006Died Nov 2006 from Polonium-210

63Photo Source: www.msnbc.msn.com

Major Pathways of Releasej y

CloudInhalation (Inhalation (γγ,,αα,,ββ))

Shine (γ)Deposition

Skin (β)

Release GroundShine (γ)

Inhalation (Inhalation (γγ,,αα,,ββ))from resuspended materialfrom resuspended materialGround

Courtesy: F. Harper

Contamination withCutaneous Radiation InjuryCutaneous Radiation Injury

Superficial & partial thickness:Increased permeability

Full thickness contamination:Remains in burn escharRemains in burn eschar

65AFRRI

Major Pathways of Releasej y

CloudInhalation (Inhalation (γγ,,αα,,ββ))

Shine (γ)Deposition

Skin (β)

Release GroundShine (γ)

Inhalation (Inhalation (γγ,,αα,,ββ))from resuspended materialfrom resuspended materialGround

Courtesy: F. Harper

Amount of Internal HazardAmount of Internal Hazard (acts as a poison)

• Amount of radionuclide• Radiation characteristics

T t• Target organ• Radiation biological half-life

67AFRRI

Possible Contaminating Agents

Nuclide

Primary Radiation Type

(half-life)Primary Form Application that Forms the

Basis for Size of Source Deposition

Sr-90 Beta (28 6 y) Ceramic (SrTiO3) Large radioisotopic thermal BoneSr 90 Beta (28.6 y) Ceramic (SrTiO3) Large radioisotopic thermal generator (RTG)

Bone

Cs-137 Beta + Ba-137m Gamma (30.17 y)

Salt (CsCl) Irradiator Whole body

I-131 Beta, Gamma (8.02 d)

Salt Fission product, nuclear weapons testing, nuclear medicine

Thyroid

H-3 Beta (12.3 y) Gas/liquid Gun sights, nuclear warheads Kidney

U-238 Alpha (4.5x1012 y) Metal Depleted munitions Kidney

Pu-238 Alpha (87.75 y) Ceramic (PuO2) RTG used for the Cassini Saturn Lung (inhaled)space probe Bone

Am-241 Alpha (432.2 y) Pressed ceramic powder (AmO2)

Single well-logging source LiverBone

Ra 226 Alpha (1600 y) Salt Old medical therapy sources BoneRa-226 Alpha (1600 y) Salt(RaSO4)

Old medical therapy sources Bone

68

Large source scenarios

Large

Large

MediumMedium

Large

69Modified from AFRRI

Biological Half-LifeBiological Half LifeDefinition:Definition:

The time for half the atoms of a substance to be removed from the body.

Examples:– Cesium (137Cs): 12 – 165 days (shortest in infants)( ) y ( )– Tritium (3H): 10 - 12 days– Plutonium (Pu): bone = 100 yrs, liver = 40 yrs

Uranium (U): bone = 300 days kidney = 15 days– Uranium (U): bone = 300 days, kidney = 15 dayslung = 120-1470 days (size/solubility)

NCRP 65, pp 78, 108, 90, 111, 1980. 70

Inhalation PathwayInhalation Pathway

• Most efficient route• Inhale radiation-emitting particulate matter (we• Inhale radiation-emitting particulate matter (we

do not “inhale radiation”)• Particle size — key factor (0 1 – 5 microns)Particle size key factor (0.1 5 microns)• Secondary source for ingestion • Solubility — important• Solubility — important

71AFRRI

Clearance Times from theClearance Times from the Respiratory Tract

Structure Clearance Time

Trachea 6 minBronchi 1 hrBronchioles 4 hrTerminal Bronchioles 10 hrAl li 100 1500 dAlveoli 100 - 1500+ days

NCRP 65, p. 23, 1980. 72

TopicsTopicsAcute Radiation Syndrome (ARS)y ( )• Definition and diagnosis• TreatmentTreatment

External and Internal ContaminationExternal and Internal Contamination• Definition and diagnosis• Treatment• Treatment

Examples Follow Up Care and ResearchExamples, Follow-Up Care and Research

73

Initial Patient ManagementInitial Patient Management

Fi t dd lif th t i• First address life-threatening conditions / injuries — the ABC’s

• Initial survey (frisk with RADIACs)N l b d l• Nasal swabs-do early

Health care workers have never been hurt caring for contaminated patients

74AFRRI

First Steps:

External Decontamination

1. Remove patient’s clothing.

2. Wash patient with mild soap and

( )water (or take a shower).

95+%EFFECTIVE

75AFRRI

General Management toReduce Internal Dose

(Consider as a Poison)

a. Reduce intake, uptake, depositionb. Increase excretionb. Increase excretionc. Decide “Risk versus Benefit” for treatment

76AFRRI

Classes of Some Drugs for Treatment of Internal

Contamination

Bl ki t t i i did• Blocking agents, e.g. potassium iodide• Chelating agents, e.g. DTPA• Diluting agents, e.g. water• Ion exchange resins e g Prussian BlueIon exchange resins, e.g. Prussian Blue

77NCRP Report 65, 1980, Section 7

Potassium Iodide (KI) forR di ti I di (RAI) P t tiRadioactive Iodine (RAI) Protection

• Indication: Protection against RAI to reduce risk ofthyroid cancer

• Contraindication: Iodine hypersensitivity• Availability: over the counterAvailability: over the counter• Possible side effects:

— Allergic reaction, GI upset, thyrotoxicosis— Hypothyroidism in neonates: Get TSH

• Use:— Administer NLT 4 hours after exposure to RAI— Administer NLT 4 hours after exposure to RAI— Prioritize sheltering for pregnant and lactating

females and those allergic to KI

FDA Guidance 2001. 78

Threshold Thyroid Radioactive Exposures and Recommended DosesExposures and Recommended Doses

of Potassium Iodide (KI)P di t d KI dPredicted

Thyroid ExposureKI dose daily mg

Adults > 40 yrs > 500 cGy (5 Gy) 130Adults > 40 yrs > 500 cGy (5 Gy) 130

Adults 18-40 yrs > 10 cGy 130

Pregnant / lactating females

> 5 cGy 130

Age 3 -18 yrs > 5 cGy 65 (130 if large)Age 3 18 yrs > 5 cGy 65 (130 if large)

1 month – 3 yrs > 5 cGy 32

Birth – 1 month > 5 cGy 16

FDA Guidance 2001. 79

Potassium Iodide (KI)Potassium Iodide (KI)

130 mg/tablet

65 mg/ml 1000 mg/ml

80AFRRI

Chelating Agents: e.g. DTPAChelating Agents: e.g. DTPADiethylenetriaminepentaacetate(Trisodium Calcium / Zinc Salts)

• FDA approved, 2004– For plutonium (Pu)

( )

For plutonium (Pu), americium (Am), curium (Cu)

– Available in StrategicNational Stockpile (SNS)National Stockpile (SNS)

– Prescription, injection

• May remove 60-90% of ysoluble plutonium– When started early

81AFRRI

Other Chelating AgentsOther Chelating Agents

• Defarasirox (FDA 2005 oral for Fe*)• Defarasirox (FDA 2005, oral for Fe )• Deferoxamine (Fe*, Pu)• Dimercaprol (As*, Au*, Hg*, Cr Ni, Pb)p ( , , g , , )• EDTA (Pb*, other metals)• Penicillamine (Cu*, Au, Hg, Pb)• Sevelamer (P*)• Succimer (Pb*)* FDA approved for these indications only

82

Ion Exchange Resins: e g Prussian Bluee.g. Prussian Blue

(ferric ferrocyanide)• FDA approved, 2003

– Prescription drug available in Strategic National StockpileStrategic National Stockpile

• Indicated for Cesium and Thallium• Dosage

– Oral, adults 3 grams tid (18 capsules) per day; ages 2-12, 1 gram tid (6 capsules) per day, possibly for weeks

• Side Effect: Possible constipation• Reduces 137Cs biologicalReduces Cs biological

half-time to <30% previous value

83AFRRI

DILEMMASDILEMMAS

• Rapid diagnosis– Where to send specimens?Where to send specimens?– Location and use of whole body counters?

• When to treat? 5-10 x Annual Limit?• When to treat? 5-10 x Annual Limit? • When to stop treatment?• Special populations, e.g. children,

pregnant females, elderly

84

Remember FDA Indications ?Drug Indication Availability

Remember FDA Indications ?Drug Indication Availability

DTPA

Potassium Iodide (KI)Prussian Blue

85

Remember FDA Indications ?Drug Indication Availability

Remember FDA Indications ?Drug Indication Availability

DTPA Plutonium A i i

RxAmericium

CuriumSNS*

P t i R di i did OTCPotassium Iodide (KI)

Radioiodides OTCSNS

Prussian Blue CesiumThallium

RxSNS

* SNS is the Strategic National Stockpile86

Treatment of?Fission Products ?

• No specific drug since there may be dozens of isotopes present

• Prevent inhalation and ingestion• Shelter in placep• External decontamination• Consider irrigation cathartics andConsider irrigation, cathartics and

laxatives

87AFRRI

TopicsTopics

Acute Radiation Syndrome (ARS)Acute Radiation Syndrome (ARS)• Definition and diagnosis• TreatmentTreatment

External and Internal Contamination• Definition and diagnosis• Treatment

Examples, Follow-Up Care, Research Areas

E l f M di l RExamples of Medical Responseto Radiation Accidents

• 1986 Chernobyl, Ukraine (former USSR)• 1987 Goiânia, Brazil• 1999 Tokaimura, Japan

89

CHERNOBYLApril 1986

Worst Radiation Accidentin Historyin History

Photo: Monitoring ChernobylPhoto: Monitoring ChernobylReactor from Helicopter

Adapted from AFRRI 90

Chernobyl M di l RMedical Response

• 500 personnel hospitalized– > 100 personnel received > 1 Grayp y

• Intensive Supportive Care– Clean environment / isolation– Prophylactic and therapeutic antimicrobials– Transfused RBC and platelets– “High rate of survival up to 6 Gray”– High rate of survival up to 6 Gray

Gale, R.P., “Lessons from Chernobyl”, JAMA, Aug 1987. 91

Chernobyl:

13 transplants for victims with doses 5 6 13 Gy

Bone Marrow Transplants• 13 transplants for victims with doses 5.6 – 13 Gy• 2 survivors (as of 1989 after doses of 8.7 & 5.6 Gy)• Causes of DeathCauses of Death

– Burns 5– Interstitial pneumonitis 3– Graft versus Host Disease 2– Renal failure & ARDS 1

11 deaths11 deaths

• Conclusion: No clear evidence that bone marrow transplants were beneficialtransplants were beneficial

Gale et al, NEJM, 1989; 321: 205-212 / UNSCEAR 2000 Appendix J. 92

Chernobyl at 20+ YearsChernobyl at 20+ Years

• About 50 deaths due to radiation injury• About 50 deaths due to radiation injury• 4000+ childhood thyroid cancer• Long term psycho social impact• Long-term psycho-social impact

– Evacuation of 135,000– Victim mentalityVictim mentality– Expecting medical problems– Socio-economic problemsp

93Chernobyl Forum, 2005.

Goiânia, Brazil, September 1987

“ Worst radiation accident inin

the Western Hemisphere”p

Science, 1987Source: Science, 1987~ 2.5 cm diameter~ 1400 Ci, Cesium-137as CsCl salt (powder)as CsCl salt (powder)

94Adapted from AFRRI

Goiânia Cesium-137 Incident: Di t b b i ?Dirty bomb scenario ?

• 130,000 people (10%) came to ER /temporary screening locations

• 250 (0.2%) were t i t dcontaminated

• 20 (0.01%) required t t ttreatment

95

IAEA Pub “The Radiological Accident in Goiania”, 1988available at www-pub.iaea.org

Goiânia Cesium-137 Incident: D /Th I f ti

• 20 patients ARS dose exposure: 1 - 7 1 Gy

Dose/Therapy Information• 20 patients, ARS dose exposure: 1 - 7.1 Gy• Internal contamination: + urine

+ stool+ perspiration+ perspiration

• TreatmentChelation therapy: Prussian BluepyInfection/sepsis: antibiotics, antifungal, antiviral Bone marrow stimulation: GM-CSF

• Outcome: 4 deaths (4-6 Gy)

96

IAEA Pub “The Radiological Accident in Goiania”, 1988available at www-pub.iaea.org

Tokaimura, Japan 1999Incident: Criticality accident

B B

A

A

97Endo & Yamaguchi, Radiat Res 159, 2003.

Tokaimura, Japan:P ti t APatient A

• Patient A holding funnel• Estimated dose 16-25 Gy-Equivalent

f• Rapid loss of consciousness• Suffered from cutaneous radiation burns, and

intestinal renal and respiratory impairmentintestinal, renal and respiratory impairment• Numerous problems with vascular

hyperpermeabilityhyperpermeability

98Adapted from AFRRI

Patient A InterventionsPatient A Interventions

• Cytokines (G-CSF)• Peripheral stem cell transfusion from HLA-identical

sibling• Digestive tract decontamination• Crypt cell stimulation with L-glutamine• High dose pentoxyphylline to control vascular injury • Expired 84 days after exposure from cardiac event

99Adapted from AFRRI

Tokaimura, Japan:P ti t BPatient B

• Patient B pouring uranium• Estimated dose 6-10 Gy-Equivalent • GI tract decontamination• Crypt cell stimulation with L-glutamine• G-CSF cytokine bone marrow stimulation• Cord blood cell transfusion• Vascular injury control with high-dose

pentoxiphylline

100Adapted from AFRRI

Patient B Interventions (contd)Patient B Interventions (contd)

• Severe cutaneous burns required multiple skin grafts

• Developed radiation pneumonitis and pulmonary hemorrhagepulmonary hemorrhage

• Expired 7 months after incident in April 2000Expired 7 months after incident in April 2000

101Adapted from AFRRI

Long Term and Follow-Up CareLong Term and Follow Up Care

• Multiple Organ Dysfunction: pulmonary, p g y p yhepatic, renal and cardiac failure

• Possible late effectsPossible late effects– Malignancies: Leukemia early, then breast,

intestinal, lung, thyroid etc., g, y– Cataracts, sterility– In-utero and childhood effectsIn utero and childhood effects– Psychosocial

• Need long term screening• Need long term screening

102

Research AreasResearch Areas

• Biodosimetry• Biodosimetry– Genomic and proteomic predictors of dose

Hi h th h t– High through-put screens• Radiation mitigators and protectants

– Amifostine - no– Improved chelating agents– Captopril, statins, vitamins, etc.

103

Summary of Topics Covered:Acute Radiation Syndrome (ARS)• Definition and diagnosis• Definition and diagnosis• Treatment

External and Internal ContaminationD fi i i d di i• Definition and diagnosis

• Treatment

Examples, Follow-Up Care, Research Areas

104

Questions?