RITN Radiation Grand Rounds Rev. 2 2008

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Cullen Case | ccase@nmdp.org | 612.884.8402

David Weinstock, M.D. | DavidM_Weinstock@DFCI.HARVARD.EDU | 617.632.4245

Medical Response to Radiation Exposure: the Role of HematologistsPresenter

Affiliation

Date

RITN Radiation Grand Rounds Rev. 2 2008

Agenda

• Describe the Radiation Injury Treatment Network

• Radiological Event Scenarios

• Radiation Basics

• Radiation Biology/Acute Radiation Syndrome

• Biodosimetry

• Incident Response

• Treatment

• Available resources

RITN Radiation Grand Rounds Rev. 2 20084

Radiation Injury Treatment Network (RITN)

• Network of 36 stem cell transplant centers, 9

donor centers, and 7 umbilical cord blood banks

• Partnership between:

– National Marrow Donor Program

– American Society for Blood and Marrow

Transplantation

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Radiation Injury Treatment Network (RITN)

• The goals of RITN are to:– educate hematologists, oncologists, and stem cell

transplant practitioners about their potential involvement in the response to a radiation event

– provide treatment expertise in the aftermath of a radiation event

• RITN centers are NOT….– First responders– Victim triage experts– Decontamination specialists

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Not RITN

Source: http://www.wdhr.com/news/uploaded_images/100_3114-737293.JPG

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Location of RITN Centers

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Radiation Injury Treatment Network (RITN)

• In the aftermath of a radiological event, RITN centers may be asked to:– Accept patient transfers to their institutions– Provide treatment expertise to practitioners caring for

victims at other centers– Travel to other centers to provide medical expertise– Provide data on victims treated at their centers

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RITN Efforts

• Standard Operating Procedures

• Standardized admission and treatment orders

• Standardized data collection protocol

• Training

• Coordination with international organizations

• Conduct readiness exercises

• Emergency communications equipment

RITN Radiation Grand Rounds Rev. 2 2008

Radiological Event Scenarios

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RITN Radiation Grand Rounds Rev. 2 200811

Radiological Events

Weinstock et al. Blood 2008.

Events Description Anticipated deaths

Radioactive source accident

Loss or theft of a radiological source (e.g. Goiania)

0-100s

Nuclear reactor accident

Release of radioactive gas or material (e.g. Chernobyl)

0-1,000s

Radiological dispersal device

Device or scheme for dispersing radioactive isotope (e.g., dirty bomb or radioactive material in the food supply)

0-100s

Radiological exposure device

(open source)

Radioactive material intended to expose people in the vicinity (e.g. Cesium source on a train)

100s-1,000s

Improvised nuclear device

Incorporates radioactive material intended to produce a low yield nuclear explosion

1,000s-1,000,000s

Military-grade nuclear device

Incorporates radioactive material intended to produce a fusion detonation

1,000,000s

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Threat Planning by the U.S. Government

1) 10-Kiloton Improvised Nuclear Device 2) Aerosol Anthrax 3) Pandemic Influenza 4) Plague 5) Blister Agent 6) Toxic Industrial Chemicals 7) Neurotoxin8) Chlorine Tank Explosion 9) Major Earthquake10) Major Hurricane 11) Radiological Dispersal Devices 12) Improvised Explosive Devices 13) Food Contamination 14) Foreign Animal Disease (Foot and Mouth Disease)15) Cyber Attack

http://media.washingtonpost.com/wpsrv/nation/nationalsecurity/earlywarning/NationalPlanningScenariosApril2005.pdf

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• Alexander Litvinenko– Fell ill November 1, 2006– Died November 23, 2006– Ingestion of 1 mg of Polonium-210

Isotope Ingestion

RITN Radiation Grand Rounds Rev. 2 200814

Open Source Exposure

• Taiwanese graduate student

– October 1994 - February 1996

– Survived attempts by fellow student to poison with 32P

and other chemicals

• Taiwan scientist rivalry

– In 2003, a nuclear scientist planted Iridium-192 pellets

in the office of a business rival

– Sickened the rival and 74 other people

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Open Radiation Sources• Goiania, Brazil – 1987

– Cesium-137 source taken from vacant clinic

– Source opened to separate metals to sell to recycler

– Glowing blue Cesium handled by adults and children

– 28 cases of radiation sickness– 112,000 people screened

• Russia -2002 & 2003– Nuclear generators used to power

remote lighthouses– Generators are unguarded and

frequently stolen/vandalized by scrap metal hunters

– Russia has 1000 of these generators– Many incidents have occurred

resulting in exposed cores and injuries

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Contaminated soil for extended storage in

Goiania, Brazil

Temporary concrete storage of contaminated materials in

Goiania, Brazil

Decontamination

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Open Radiation Sources

• North America – 1984

– Cobalt-60 pellets from junked radiotherapy device

– Recycled into steel and used for construction

– >200 people exposed from Mexico to Illinois

– 1 fatality, 4 injuries

– 109 homes demolished as part of decontamination

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• Houston, TX – 1980 (7 fatalities)

• Columbus, OH – 1974-76 (10 fatalities, 78 injuries)

• Epinal, France – 2004-05 (1 fatality, 13 injuries)

• Panama City, Panama – 2000-01 (17 deaths, 11

injuries)

Miscalibrated Radiotherapy Devices

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Radiological Dispersal Device (RDD)

• Chechen Rebels, 1995– Planted cesium and

explosives device in a playground

– Notified local TV station– Never detonated

• Chechen Rebels 1998– Chechen Security Service

renders safe a dirty bomb

planted next to a railway line

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Theft or Loss of Radiological Materials Reported to the IAEA

Source of graph: IAEA 2006 Illicit Trafficking Database Report

10 million radiation sources worldwide

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Interpreted from the U.S. National Planning Scenarios found on www.washingtonpost.com

10 kiloton Improvised Nuclear Device detonation - Scenario planning

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Interpreted from the U.S. National Planning Scenarios found on www.washingtonpost.com

Limited survival due to:1) Overpressure (blast)2) Thermal damage3) Prompt radiation

10 kiloton Improvised Nuclear Device detonation - Scenario planning

0.5 mi

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Interpreted from the U.S. National Planning Scenarios found on www.washingtonpost.com

Limited survival due to:1) Overpressure (blast)2) Thermal damage3) Prompt radiation

Fallout over 24 hours 1) > 400 REM exposure2) 202,000 non-fatal casualties

(40,000 hospital beds in US)3) 180,000 fatalities

10 kiloton Improvised Nuclear Device detonation - Scenario planning

0.5 mi 9 miles

Comparison of Intensities of Detonations

Yield

He

igh

t (x

10

00

fee

t)H

eig

ht (x

100

0 mete

rs)

0 = Approximate altitude band commercial aircraft use1 = Fat Man 22.5 kilotons (Nagasaki). Little Boy (Hiroshima) was ~10-15 kilotons.2 = Castle Bravo 15 megatons (1st US nuclear bomb test on Bikini Atoll)

RITN Radiation Grand Rounds Rev. 2 2008

Radiation Basics

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Types of Ionizing Radiation

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Radioactive Contamination• Internal contamination requires medical

decorporation• 90% of external contamination can be cleansed by

removing clothing and washing exposed body parts

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Reducing Radiation Exposure

3 steps for protection:

1) Keep your DISTANCE

2) Limit your TIME

exposed

3) SHIELD yourself from

exposure

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Protection from Radiation

Protective Not protective

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Acute Radiation Syndrome

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Acute Radiation Syndrome

Weeks After Exposure1 2 3 4 5 6 7 80

0

2

4

6

8

10

0%

50%

100%

Prodromalnausea/vomiting

GIsymptoms

Onset of signs ofhematopoietic injury

Approximatetime of death

100% mortality(may be higher dose with HSCT)

>100CNS injury (100% mortality within days)

Mo

rtal

ity

Rad

iati

on

do

se (

Gy)

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Toxicity is Proportional to Dose

• LD50 for humans: LD50 is the level of exposure that is lethal to 50% of people exposed to that dose– 3.5 to 4 Gy

• Without supportive care• However the use of antibiotics and transfusions may

decrease the chance of morbidity

– 4.5 to 7 Gy• With antibiotics, transfusions and other supportive care

– Greater than 10 Gy• With HSCT

• In a radiation incident, shielding will result in heterogenous body dosing

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Acute Radiation Syndrome - Combined Injury

• Most victims with significant injury will have multi-organ dysfunction– Trauma/wounds/burns– Gastrointestinal– Hematologic– Neurologic– Psychiatric

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Acute Radiation Syndrome - Neurovascular

Symptoms Degree of severity 1 to 4

Nausea Mild to excruciating

Vomiting 1 per day to >10 times per day

Anorexia Able to drink to requiring parenteral nutrition

Fatigue Normal activity to prevents activity

Headache Minimal to intense

Neurological deficits No deficits to unarousable

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Symptoms Degree of severity 1 to 4Diarrhea - frequency Twice/day >10 times/day

Stool - consistency Bulky to watery

Blood in stools Occult to gross hemorrhage

Abdominal pain/cramps Minimal to excruciating

Nausea Mild to excruciating

Vomiting 1 per day to >10 times per day

Acute Radiation Syndrome - Gastrointestinal

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Acute Radiation Syndrome - CutaneousSymptoms Degree of severity 1 to 4Erythema Minimal to severe

Altered sensation/Itching Pruritis to severe

Edema Asymptomatic to total dysfunction

Blistering Rare to bullae with hemorrhage

Desquamation Absent to confluent

Ulcer/necrosis Epidermal only to muscle/bone

Hair loss Thinning to complete

Onycholysis Absent to complete

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Cutaneous Injuries from Open Sources

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Acute Radiation Syndrome - Hematopoietic

RITN Radiation Grand Rounds Rev. 2 2008

Biodosimetry

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Biodosimetry Tools

• Definition– Biodosimetry is the use of biological markers to estimate

dose– Dosing after radiological and nuclear events is

complicated by a variety of factors, including shielding

• Standard approaches– Lymphocyte Depletion Kinetics– Dicentric Chromosomes in Peripheral Blood

Lymphocytes

• Research approaches– Proteomics– Markers of DNA damage

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From: CDC Radiological Terrorism Emergency Management Pocket Guide for Clinicians Pocket Guide: www.bt.cdc.gov/radiation/pocket.asp

ARS – Time to vomiting as a marker of dose

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Acute Radiation Syndrome - Lymphocyte Kinetics

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Biodosimetry Tools

• AFRRI Biodosimetry Assessment Tool (BAT)– Downloadable software

• Radiation Event Medical Management (REMM) www.remm.nlm.gov– Web-based software– Provides suggested treatments based on estimated

dose– Standardized admission and treatment order

templates

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RITN Radiation Grand Rounds Rev. 2 2008

Incident Response

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RITN in Federal Response Planning:Improvised Nuclear Device

MC

MC

MC

ACAC

MC

Evacuationcenters

RTR3 (collection)

AC

RTR1 (collection)

AC

RITN centerModified from Weinstock et al. Blood 2008

RTR1 (blast)

RTR2 (plume)

MC

RTR2 (plume)

Ambulatory

Critical

RITN Radiation Grand Rounds Rev. 2 2008

Hematopoietic Stem Cell Transplantation After a

Radiological Event

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RITN Radiation Grand Rounds Rev. 2 2008

HSCT After a Radiological Event

Affected population

Marrow injury

• Potentially irreversible marrow injury• Salvageable• Minimal combined injury

Expedited HLA typing

• Myeloablation• Available donor• Acceptable pre-transplant condition

HSCT

Supportive care

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RIT

N T

reat

men

t S

up

po

rt

RITN Radiation Grand Rounds Rev. 2 2008

Management of Urgent Donor Searches

• NMDP-contracted HLA laboratories:

– Currently perform 5-6,000 HLA typings weekly but could

be increased to more than 10,000 assuming HLA is

prioritized over other work

– Data is transmitted directly from the labs to NMDP via

Internet

– Use automated matching of adult donors/CBUs to

potential transplant recipients

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RITN Radiation Grand Rounds Rev. 2 2008

Management of Urgent Donor Searches• NMDP-computer systems:

– Facilitate contact, communication and coordination with the adult donors/CBU banks

– Are available 24x7 to meet the demands of the increased search load

• HapLogic uses advanced logic to predict high-resolution matches– Easier identification of donors and/or CBUs most likely to

match patients – Reduction in the number of donors called for testing that

would be unlikely to match the patient – Faster matches for some patients, which may mean

getting to transplant sooner resulting in improved survival

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Hematopoietic Stem Cell Transplantation for Acute Radiation Syndrome

• 31 patients have undergone allogeneic HSCT after accidental radiation exposure

• Median survival after transplant ~ 1 month

• All four patients who survived one year reconstituted autologous hematopoiesis

• Graft-versus-host-disease contributed to mortality in >20%

Weinstock et al. Blood 2008.

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• Standardized RITN regimen:– Reduced intensity conditioning, based on the Blood and

Marrow Transplant Clinical Trials Network (BMT CTN Protocol 0301)

Weinstock et al. Blood 2008.

G-CSF

Mycophenolate, d -3 to +30

Cyclosporine or tacrolimus, days -3 to +100-3 -2 -1-4-7 -6 -5 30 1000

Cyclophosphamide 50 mg/kg Fludarabine 30 mg/m2

Anti-thymocyte globulin (Thymoglobulin®) 3 mg/kg

-3 -2 -1-4Day -7 -6 -5 +30 +1000

Allograft infusion

Hematopoietic Stem Cell Transplantation for Acute Radiation Syndrome

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Data Collection Protocol

• Incorporated into standard NMDP data

collection protocol

• Will feed consistent information for review

after an event

• Will track progress of victims

– Online data entry

– Real-time feedback of data

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What RITN is Doing to Prepare

• Standard Operating Procedures

• Standardized admission and treatment orders

• Training– Basic radiation training (over 700 completed in 2007)

– Training resources on the RITN Web site (www.RITN.net)

• Organize coordination with international organizations

• Conduct readiness exercises– Annual tabletop exercise

– Participate in national exercises (TOPOFF 4, Pinnacle 07)

• Emergency communications equipment– GETS cards and satellite telephones

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Summary

• There are a variety of event scenarios

• Hematologists, oncologists, and stem cell

transplant experts may be called upon to care

for victims

• Have a plan and get involved!

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Resources for further investigation• Incidents:

– IAEA nuclear events list: http://www-news.iaea.org/news/ – www.johnstonsarchive.net/nuclear/radevents/index.html

• Treatment:– Radiation Injury Treatment Network (RITN): www.RITN.net– Radiation Event Medical Management (REMM): www.remm.nlm.gov– Radiation Emergency Assistance Center/Training Site (REAC/TS):

www.orau.gov/reacts– Radiation Countermeasures Center of Research Excellence

(RadCCORE): www.radccore.org• Bio-dosimetry & Treatment:

– Armed Forces Radiobiology Research Institute (AFRRI): www.afrri.usuhs.mil

• Other:– IAEA Library:

http://www.iaea.org/DataCenter/Library/catresources.html

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For treatment guidelines, references:

www.REMM.NLM.gov

www.RITN.net