TREATMENT fTREATMENT ofEXPOSED PATIENTSEXPOSED PATIENTS
JACQUELINE WILLIAMS, Ph.D.,WILLIAM DICKERSON, M.D.
jackie [email protected][email protected]@gmail.comASTRO September 2008
Disclosure Information
Opinions presented are those of the authors. Any “off-label” use of medications is at the discretion of a licensed medical provider.
Any use of trade or brand names is for illustration purposes only and does not imply endorsement by the authors (or the Department of Defense)the authors (or the Department of Defense).
This lecture does not constitute official policy of the United States Department of Defense.
2
ObjectivesObjectives
After this session, attendees should be able to:
• Describe the diagnosis and treatment of the Acute Radiation Syndrome (ARS)the Acute Radiation Syndrome (ARS)
• Understand the differences in diagnosis and treatment following external andand treatment following external and internal contamination
• Identify possible late effects and explainIdentify possible late effects and explain appropriate medical follow-up.
3
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 Research AreasExamples, Follow-Up Care, Research Areas
4
Acute Radiation SyndromeMedical Effects of Ionizing RadiationMedical Effects of Ionizing Radiation
Acute Radiation Syndrome
A combination of clinical signs andsymptoms occurring in stages over aperiod of hours to weeks due to asignificant partial body or wholeg ybody exposure of >1 Gy (100 cGy), asinjury to various tissues and organs isj y gexpressed
5
What Happens After WBI?What Happens After WBI?
What is the most fundamental event following irradiation?
CELL DEATH
As dose increases, which cells are most susceptible?
CELL DEATH
DIVIDING CELLS
Which dividing cells are most radiosensitive?
STEM / PRECURSOR CELLSSTEM / PRECURSOR CELLS
6
Tolerance Doses (TD5/5 - TD50/5)Tolerance Doses (TD5/5 TD50/5)Single Dose (Gy)
Ovary 2 - 6 Kidney 10 - 20Bone marrow 2 - 10 Liver 15 - 20Eye (lens) 2 - 10 Skin 15 - 20Eye (lens) 2 - 10 Skin 15 - 20Testes 2 - 10 Spinal cord 15 - 20Lymphoid 2 - 20 Peripheral nerve 15 - 20Gastrointestinal 5 - 10 Brain 15 - 25Mucosa 5 - 20 Heart 18 - 20Lung 7 10 Bone and cartilage >30Lung 7 - 10 Bone and cartilage >30Colorectal 10 - 20 Muscle >70
Microvasculature (endothelial cells) / epithelial cellsMicrovasculature (endothelial cells) / epithelial cells
J.M. Vaeth: Clinical Radiation Pathology, 1988. 7
The Human Lethal Dose - LD50/60The Human Lethal Dose LD50/60
100 • No medical intervention
80
100 • No medical intervention• Homogenous & total• 60 days - expression of
ff h i i
lity
in %
60
effects on hematopoiesis
Note: surviving to 60 days
Mor
tal
40
g ydoes not ensure long-termsurvival
0
20
Sources:• Japanese atomic bomb
Dose (Gy)0 2 4 6 8
0 Japanese atomic bomb• Accidents (e.g. Chernobyl)• Therapeutic exposures
LD50/60 Estimates (DS86): Atomic BombSource City # persons
(deaths)Source of
sampleLD50/60(Gy)
Comments
RERF Hiroshima 7593 Master sample 2 7 3 1 LD / based onRERF Survey
Hiroshima 7593(1095)
Master sample 2.7 -- 3.1 LD50/60 based on linear fit, excluding first day deaths
Special Hiroshima 53 Female students, Shi t k hi h
4.0 Dose estimates b dsurvey (27) Shintoku high
schoolbased on chromosomal aberrations in survivors
Hiroshima University survey
Hiroshima 1216(201)
Persons located 600-1300m from hypocenter
2.44 Survey by RINMB and city authorities
Oak Ridge-Dikewood Nuclear Def Agy
Nagasaki 97(79)
Young adult occupants of Chinzei and Shiroyama Schs
2.9 Extension of study for Nuclear Defense Agency
Def AgyTOTALS 8959
(1402)3.1
Considerations - LD50/60Sources:Sources:•• Japanese atomic bombJapanese atomic bomb
Additional injuries from the bombAdditional injuries from the bombAdditional injuries from the bombAdditional injuries from the bombTyphoon (typhoid fever)Typhoon (typhoid fever)Disturbed environmentDisturbed environmentPoor nutritionPoor nutritionUnderUnder--representation of middlerepresentation of middle--aged menaged menDosimetry (also accidents)Dosimetry (also accidents)
•• Therapeutic exposuresTherapeutic exposuresP h lth liP h lth liPoor health + malignancyPoor health + malignancy
•• Other factorsOther factorsAge gender medical care (supportive)Age gender medical care (supportive)Age, gender, medical care (supportive)Age, gender, medical care (supportive)
10
Best Estimates - LD 0/60Best Estimates - LD50/60
LD50/60
Acute TBI, no medical support = 2.5-3.5 Gy
Acute TBI + supportive care = 4.5 Gy
Acute TBI + supportive care + CSFs = 6-8 Gy
A t TBI + BMT 8 10 GAcute TBI + BMT = 8-10 Gy
11
Whole Body Irradiation (WBI)Whole Body Irradiation (WBI)io
nur
e
Latentperiod
Prodromalphase
Manifestillness
Recoveryor death
Rad
iati
Expo
su
Time
time of onset dosetime of onsetseverityduration
dosedose rate
quality12
Prodromal PhaseGastrointestinal• Anorexia
Neuromuscular• Easy fatigability
• Nausea• Vomiting
Easy fatigability• Apathy or
listlessnessg• Diarrhea• Intestinal cramps
listlessness• SweatingIntestinal cramps
• Salivation• Fluid loss
• Fever• HeadacheFluid loss
• Dehydration• Weight loss
• HypotensionWeight loss
13
Prodromal PhaseGastrointestinal• Anorexia
Neuromuscular• Easy fatigability
• Nausea• Vomiting
Easy fatigability• Apathy or
listlessnessg• Diarrhea• Intestinal cramps
listlessness• SweatingIntestinal cramps
• Salivation• Fluid loss
• Fever• HeadacheFluid loss
• Dehydration• Weight loss
• HypotensionWeight loss
50% lethal dose50% lethal dose14
Prodromal PhaseGastrointestinal• Anorexia
Neuromuscular• Easy fatigability
• Nausea• Vomiting
Easy fatigability• Apathy or
listlessnessg• Immediate diarrhea• Intestinal cramps
listlessness• SweatingIntestinal cramps
• Salivation• Fluid loss
• Fever• HeadacheFluid loss
• Dehydration• Weight loss
• HypotensionWeight loss
Supralethal doseSupralethal dose15
Prodromal Phase
Nausea, vomiting
Time of onset
Duration Lymphocyte count
CNS function
0 - 1 Gy None Minimally affected
No impairment
1- 2 Gy 5 - 50% 3 - 6 hr <24 hr Minimally No decreased impairment
2- 6 Gy 50 - 100% 2 - 4 hr <24 hr <1000 at 24 hr
Impairment for 6 - 20 hr
6 - 8 Gy 75 - 100% 1 - 2 hr <48 hr <500 at 24 hr
Impairment for >24 hr
10 30 90 100% <1 hr <48 hr Decreases Rapid10 - 30 Gy
90 - 100% <1 hr <48 hr Decreases in hrs
Rapid incapacitation
>30 Gy 100% Minutes N/A Decreases i h
Rapid i it tiin hrs incapacitation
Adapted from Burnham and Franco: Crit Care Clin, 2005.
Prodromal Phase
Nausea, vomiting
Time of onset
Duration Lymphocyte count
CNS function
0 - 1 Gy None Minimally affected
No impairment
1- 2 Gy 5 - 50% 3 - 6 hr <24 hr Minimally No impairmentdecreased
2- 6 Gy 50 - 100% 2 - 4 hr <24 hr <1000 at 24 hr
Impairment for 6 - 20 hr
6 - 8 Gy 75 - 100% 1 - 2 hr <48 hr <500 at 24 hr
Impairment for >24 hr
10 30 90 100% <1 hr <48 hr Decreases Rapid10 - 30 Gy
90 - 100% <1 hr <48 hr Decreases in hrs
Rapid incapacitation
>30 Gy 100% Minutes N/A Decreases i h
Rapid i it tiin hrs incapacitation
Adapted from Burnham and Franco: Crit Care Clin, 2005.
Prodromal Phase
Nausea, vomiting
Time of onset
Duration Lymphocyte count
CNS function
0 - 1 Gy None Minimally affected
No impairment
1- 2 Gy 5 - 50% 3 - 6 hr <24 hr Minimally No impairmentdecreased
2- 6 Gy 50 - 100% 2 - 4 hr <24 hr <1000 at 24 hr
Impairment for 6 - 20 hr
6 - 8 Gy 75 - 100% 1 - 2 hr <48 hr <500 at 24 hr
Impairment for >24 hr
10 30 90 100% <1 hr <48 hr Decreases Rapid10 - 30 Gy
90 - 100% <1 hr <48 hr Decreases in hrs
Rapid incapacitation
>30 Gy 100% Minutes N/A Decreases i h
Rapid i it tiin hrs incapacitation
Adapted from Burnham and Franco: Crit Care Clin, 2005.
Onset of Vomiting
19AFRRI
Whole Body Irradiation (WBI)io
nur
e
Latentperiod
Prodromalphase
Manifestillness
Recoveryor death
Rad
iati
Expo
su
Time
20
Latent Phase of Acute Radiation Syndrome (ARS)
Degree of ARS and approximate dose of acute WBE (Gy)Mild
(1–2 Gy)Moderate(2–4 Gy)
Severe(4–6 Gy)
Very Severe(6–8 Gy)
Lethal(>8 Gy)
L tLatency period (d) 21–35 18–28 8–18 7 or less None
Lymphocytes (G/L) 0.8–1.5 0.5–0.8 0.3–0.5 0.1–0.3 0.0–0.1(days 3–6)Granulocytes (G/L) >2.0 1.5–2.0 1.0–1.5 ≤ 0.5 ≤ 0.1
A ADiarrhea None None Rare Appears on days 6–9
Appears on days 4–5
Epilation NoneModerate,
beginning on Moderate or complete on
Complete earlier than
Complete earlier than p g g
day 15 or laterp
days 11–21 day 11 day 10
Medical response
Hospitalization not necessary
Hospitalization recommended
Hospitalization necessary
Hospitalization urgently
necessary
Symptomatic treatment
onlynecessary only
Adapted from IAEA: Diagnosis and treatment of radiation injuries; 1998.
Whole Body Irradiation (WBI)io
nur
e
Latentperiod
Prodromalphase
Manifestillness
Recoveryor death
Rad
iati
Expo
su
Time
22
Acute Radiation Syndromes (ARS)
• Hematopoietic• Gastrointestinal• Gastrointestinal • Multiple organ failure• Cardiovascular/CNS
23
Hematopoietic Syndrome
Critical cells: Hematopoietic precursorll
Dose: 1-5 GyH k t lit t 30 d
cells
Humans: peak mortality at 30 days, to 60 days
LD 2 5 3 5 GLD50/60: 2.5 - 3.5 GySymptoms:y pProdromal phase: nausea, vomiting,
anorexia, malaise, possible pdiarrhea (onset 3-16 hours)
24
Human 4.5 Gy15
10
3.1
4.4
5 6Lymphocytes
5.6
7.75
00 10 20 30 40 50
Time (days)Andrews et al., 1967.
Goans et al., 2005.
26
Human 4.5 Gy15
1 week = granulocytopenia
Granulocytesabortive rise
10
abortive rise
5
00 10 20 30 40 50
Time (days)Andrews et al., 1967.
15 Human 4.5 Gy
DeathDeath
2 weeks = thrombocytopenia
10300
DeathDeath
PlateletsPlatelets
200
Haemoglobin
5
100
00 10 20 30 40 50
Time (days)Andrews et al., 1967.
Hematopoietic SyndromeSymptoms:ARS: chills, fatigue, petechial (3 weeks) hemorrhages in skin,
ulceration of mouth,epilation (2 weeks >3 Gy)bone marrow atrophy, infections, fever, bleeding, anemia
Death: infection important causeChernobyl: 134 personnel >1 Gy; 37 -
severe bone marrow failure; 28 died in first 4 months 29
GI Syndrome
Critical cells: Epithelial lining of the g.i.tract
30
GI Syndrome
0 Gy0 Gy
10 Gy
14 Gy
Courtesy Hauer-Jensen. 31
GI Syndrome
Critical cells: Epithelial lining of the g.i.
Dose: ≥6 Gytract
ySymptoms:Prodromal phase: nausea and vomitingProdromal phase: nausea and vomiting,
prolonged (watery) diarrhea(onset 1-4 hours)(onset 1 4 hours)
Latent phase: malaise, weaknessARS: severe vomiting diarrheaARS: severe vomiting, diarrhea
(bloody) + fever, shock, death32
CV/CNS SyndromeDose: >20 GySymptoms: severe nausea and vomitingSymptoms: severe nausea and vomiting
disorientationloss of coordinationloss of coordinationrespiratory distressdiarrheadiarrheaconvulsive seizurescomacoma
Cause of death: ?
33
CV/CNS SyndromeDose: >20 GySymptoms: severe nausea and vomitingSymptoms: severe nausea and vomiting
disorientationloss of coordinationloss of coordinationrespiratory distressdiarrheadiarrheaconvulsive seizurescomacoma
Cause of death: increased brain fluid content d t ll l l kdue to small vessel leakage
34
Cutaneous Syndrome
• Erythema (skin reddening) occurs hours to days depending on dosey p g
• Duration of 1-2 days• Body locationy• Target cells reside in epidermis, dermis,
hair follicles, subcutaneous tissues,
• Symptoms: pruritus, blisters, hair loss, y p pmoist desquamation, ulceration
• Epilation: 10-20 days after >3-4 Gyp y y
35
Cutaneous Syndrome• Acute erythema can occur 1-2 days after 2-6 Gy• Erythema and epilation can occur 2-3 weeks after 5 - 10
GyGy• Desquamation can occur 2-3 weeks after 15 - 20 Gy• Re-epithelialization takes place after 6 - 8 weeksp p
Erythema Moist desquamationy
Courtesy W. McBride/Boreham.
Epilation
Combined Injury
Biomedical consequences of radiation exposure are exacerbated by trauma and/orexposure are exacerbated by trauma and/or disease, including burns and wounds.
Radiation + burn: 820
9799
95Radiation: LD50/30 - 963
Radiation + burn: 820
Radiation + wound: 761
90
70
50
erce
nt s
urvi
val
5
30
10
3
Pe
1500 700 900 1000
60Co Dose (cGy)Modified from Pellmar & Ledney, 2005.
Dosimetry (State of the Science)
BIOLOGICALDOSIMETRY
PHYSICALDOSIMETRY
CLINICALDOSIMETRY
DOSE SYMPTOMSDOSERECONSTRUCTION
Biophysics
SYMPTOMSType
Time of onset
OTHEROTHERBIOINDICATORS
Cytology,protein changes,
CYTOGENETICSDicentrics
PERIPHERALBLOOD
Lymphocyte novel biomarkers
EPR
y p ydepletion
38
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
39
ARS - When Treatment is Too ARS - When Treatment is Too LateLate
HiroshimaHiroshimaARS VictimARS Victim
(~Day 20)(~Day 20)
40
Causes of death: Infection and bleedingPhoto: DOE, National Archives
First Action for Responders/First Action for Responders/Receivers – the ABCs
• Universal Precautions: Protect yourself with scrubs mask gloveswith scrubs, mask, gloves
• Standard medical emergency procedures
– Airway/ Breathing/ Circulation
• Decontaminate AFTER stabilized• Decontaminate AFTER stabilized
• Radiation injury NOT acutely life threatening
41AFRRI
ARS Treatment
• Supportive care
• Specific therapyy
42
Supportive Care
• Clean environment
• IV fluids, antiemetics, anti-di h ldiarrheals
P i di ti• Pain medication
43AFRRI
More on Supportive Care• Antiemetics
More on Supportive CareAntiemetics– KytrilTM (granisetron) and ZofranTM
(odansetron) Need should abate(odansetron). Need should abate within 48 hours
• Antidiarrheals– e.g. ImodiumTM (Ioperamide)
• Replace fluids, electrolytes, blood products and plateletsproducts, and platelets
44
ARS TreatmentARS TreatmentSpecific Therapyp py
A ti i bi l f t i f• Antimicrobials for neutropenic feverAnti-bacterial, anti-viral, anti-fungal
• Granulocyte Colony Stimulating FactorGranulocyte Colony Stimulating Factor
45
Antibiotics - Initial Management
Hughes WT. 2002 Guidelines for the Use of AntimicrobialAgents in Neutropenic Patients with Cancer Clin Infect Dis. 34:730-51, 2002. 46
Justification for Use of Colony Stimulating Factors (CSF) in
Radiation-Induced Neutropeniap
1. Oncology data with chemotherapy-Enhanced neutrophil recovery by 3-6 days
2. Pre-clinical animal data-Enhanced neutrophil recovery of radiationi d d t iinduced neutropenia
-Enhanced survival with early initiation
47
AFRRI / “Recommendations of the Strategic National Stockpile Radiation WorkingGroup”, Ann Intern Med 140: 1037-51, 2004.
Benefit of Supportive Care and G-CSF
LD 50/30 =260 cGy
LD 50/30 =260 cGy 338 cGy
LD 50/30 =LD 50/30 =488 cGy
MacVittie TJ, Health Phys, 2005. 48
FDA-Approved CSFsOnly 3 approved in USA for reducing neutropenia. None currently approved for radiation-induced neutropenia. y pp p
1. Granulocyte-colony stimulating factor, G-CSF, or filgrastim (Neupogen®)g ast ( eupoge )
2. Pegylated granulocyte-colony stimulating factor,PEG-G-CSF or pegfilgrastim (Neulasta®)PEG G CSF, or pegfilgrastim (Neulasta )
3. Granulocyte-macrophage-colony stimulating factor,GM CSF or sargramostim (Leukine®)GM-CSF, or sargramostim (Leukine®)
G-CSF is part of the US Strategic National Stockpile
49AFRRI
Granulocyte Colony Sti l ti F t (G CSF)Stimulating Factor (G-CSF)
• ASCO GUIDELINES* Includes• ASCO GUIDELINES*- Includes management of patients exposed to lethal doses of total body radiotherapy but notdoses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the j y g ,prompt administration of G-CSF or pegylated G-CSF
ASCO 2006 50
CSF Therapy for ARS
Cytokine Adults Pediatrics Pregnancy Precautions
G CSF or 5 µg/kg per 5 µg/kg per day Category C Sickle cell diseaseG-CSF orFilgrastim(Neupogen®)
5 µg/kg per day SQ injection started as early as
5 µg/kg per day SQ injection started as early as possible **
Category C Sickle cell disease,significant CAD,ARDS.
early as possible** Adverse reaction: bone
pain
C id di ti ti
Pegylated G-CSF or
6 mg SQ x 1 dose
For adolescents >45 kg: Give 6
Category C
Consider discontinuation if pulmonary infiltrates develop at neutrophil recovery
Pegfilgrastim(Neulasta®)
mg SQ x 1 dose
GM-CSF or 250 µg/m2 SQ 250 µg/m2 SQ Category C
**continued until ANC >1,000
Sargramostim(Leukine®)
per day started as early as possible**
per day started as early as possible**
AFRRI / “Recommendations of the Strategic National Stockpile Radiation Working Group”, Ann Intern Med 140: 1037-51, 2004. 51
Combined Effects of Whole Body Irradiation and Burns in Various
Animal ModelsCombined Injury
Animal Models
Model Injury Lethality20% Burn 12%Ref: AFRRI
SyndromeDog 100 cGy 0
Combined 73%10 15% B 0
Ref: AFRRI
Pig10-15% Burn 0
400 cGy 20%Combined 90%%
Rat31-35% Burn 50%
250 cGy 0Combined 95%
Guinea
1.5% Burn 9%250 cGy 11%Guinea
Pig250 cGy 11%
Combined 38%52
Combined Injury Patient Triage is Based on Traditional Triage MethodsBased on Traditional Triage Methods
Physical Expected changes in triage categories Physical injury without
irradiation
p g g gafter whole-body irradiation
<1.5 Gy 1.5~4.5 Gy 4.5~10 Gy5 Gy 5 5 Gy 5 0 Gy
Uninjured Ambulatory monitoring
Ambulatory monitoring, routine care and delayed
h it li timonitoring hospitalizationMinimal MinimalDelayed Delayed VariableDelayed Delayed
Immediate Immediate ExpectantExpectant
Variable
After: Ann Intern Med 2004;140:1037-1051Expectant
53
AFRRI / Recommendations of the Strategic National Stockpile Radiation Working Group, Ann Intern Med 140: 1037-51, 2004.
ARS TreatmentModerate Dose Exposure*Moderate-Dose Exposure
SyndromeEstimated Radiation Treatment
P iSyndrome RadiationDose (Gy) Summary
Fluids,
Prognosis
Excellent, Hematopoietic
syndrome(only)
1 - 4
,antimicrobials,
may require cytokines
continue therapy for 3-4 weeks
Hematopoietic (and GI?)
d4 - 7 Early cytokine Tx,
fluids, GI nutrition, Good with aggressive Tx,
syndromes, ,
antimicrobials, avoid infection
will require at least 4-5 weeks’ inpatient care
*Radiation injury only, no complicating trauma or chemical/biological weapons
54Modified from AFRRI
ARS TreatmentModerate Dose Exposure*Moderate-Dose Exposure
SyndromeEstimated Radiation Treatment Prognosisy
Severe
RadiationDose (Gy) Summary
Fluids,
Prognosis
Some survival with aggressiveSevere
Hematopoietic with GI
syndrome7 - 10
,symptomatic Tx,
cytokines, antimicrobials.
with aggressive Tx; will require weeks of inpatient Tx with
Hematopoietic GI and
Stem cell transplant?
inpatient Tx with barrier protection
GI and Cerebro-vascular
syndromes10 - 30
Aggressive treatment versus palliative care
Near 100% mortality
*Radiation injury only, no complicating trauma or chemical/biological weapons
55Modified from AFRRI