Medical Response to Nuclear Exposures

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1 Medical Response to Nuclear Exposures Boris Hristov, MD Radiation Oncology Wright-Patterson Medical Center WPAFB, OH

2 None Disclosures

3 Overview Biological Principles of Radiation Acute Health Effects Triage and Medical Management Preparedness Resources

4 Measuring Radiation Tissue absorbs the dose Different types of radiation have varying effects Different types of tissues have unique responses to radiation Quantity Measures SI Unit Activity Exposure Absorbed Dose Dose Equivalent Effective Dose Disintigrations per second Ion pairs in air from γ/x-rays Energy imparted to medium Equates imparted energy by radiation type Equates Dose Equivalent by tissue type Becquerel (Bq) - Gray (Gy) Sievert (Sv) Sievert (Sv)

Direct vs Indirect Effect Radiation harms living cells via two mechanisms: direct and indirect effects Direct Effects: Radiation directly ionizes an atom breaking a chemical bond, potentially

5 Direct vs Indirect Effect Radiation harms living cells via two mechanisms: direct and indirect effects Direct Effects: Radiation directly ionizes an atom breaking a chemical bond, potentially damaging/altering a molecule. Indirect Effects: Radiation produces an ion-pair (free radical), which goes on to break a chemical bond, potentially damaging/altering a molecule. Direct Indirect H 2 O HO -

7 Damage Propagation Changes multiply through cellular reproduction to effect the whole body Atoms Molecules Cells Tissue Organs Whole Body

8 Cellular Damage Lethal Damage Interphase death Cell dies immediately Reproductive death Cell dies during an attempt to divide or after a few cell divisions Cause of deterministic effects No chance of cancer or hereditary effects Sub-Lethal Damage Full repair No mutation or repaired mutation Impaired function Cell survives injury but at a cost Normal function, but mutations not repaired after cellular division

9 Acute vs Chronic Exposure Acute Exposure: Single, large dose received in a short period of time Effects observable within hours to weeks Central to decision to evacuate or shelter in place Chronic Exposure: Low dose received over lifetime Occupational exposure Effects observable years post-exposure Both acute and chronic exposures can have late or delayed effects

10 Physical Dose rate LET/RBE Fractionation Damage Modifiers Chemical Oxygen Effect Bystander Effect Temperature Radiosensitizers/protectants Biological Cell Cycle and Sensitivity Tissue Type

11 Dose Rate As dose rate increases, cellular damage increases As total dose increases, cellular damage increases Generally an exponential relationship Hall, 7 th Edition, p 74, Figure 5.10

12 Biological Modifiers Law of Bergonie and Tribondeau As early as 1903, researchers understood that tissues appear to be more radiosensitive if their cells are less-well differentiated, have a greater proliferative capacity, and divide more rapidly. Radiobiology for the Radiologist, 5th Ed., Eric Hall, p339

13 The Cell Cycle Cells that spend most of their lives in interphase (not reproducing) are less sensitive to radiation Cells that divide frequently spend a larger portion of their time in mitosis, the most radiosensitive portion of a cell s lifetime

14 Tissue Organization Stem cells Found in tissues that self-renew These cells are undifferentiated In tissues, these are the most sensitive to radiation Maturing cells Throughout life, some stem cells will begin to mature to perform functions of tissue Differentiated or mature cells Fully functioning; normal death throughout life (sloughed off). Usually don t divide further. Least sensitive to radiation.

15 Relative Sensitivity Sensitive 1. Spermatogonia 2. Lymphocytes 3. Hematopoietic stem cells 4. Intestinal crypt cells Less sensitive 5. Myelocytes (e.g. RBC precursors) 6. Epithelial cells Skin cells Cells of the vascular wall Least Sensitive 7. Nerve Cells 8. Muscle Cells Tissue/organ w T Gonads 0.20 Bone marrow, colon, lung, stomach Bladder, Breast, Liver, Esophagus, Thyroid, Remainder Bone Surface, Skin 0.01 ICRP 60/NCRP 116 Effective Dose = Tissue Weighting Factor w T Dose Equivalent Adapted from Hall, 5 th ed., p343

The villi lining the intestine contain immature

they migrate up the villi, differentiate and

16 The villi lining the intestine contain immature stem cells, maturing cells and mature cells GI Tract Example Stem cells are confined to the base or crypt of the villi As stem cells mature, they migrate up the villi, differentiate and become mature functioning cells at the top of the crypts

17 GI Tract Example Radiation ~ 10 Gy sterilizes the immature cells in the crypt, but does not completely kill the mature cells Function will disappear as the mature cells slough off and are not replaced

18 Exposure and Effect The timing of exposure and effect are two different things Examples: High dose, Acute Exp, Early Effect= ARS Acute Exp, Late Effect = DEARE Chronic, Low dose= Malignancy Acute dose high dose Exposure: Acute Chronic Mixed Dose: High vs Low Effect: Early Intermediate Late

19 Human Dose Response LD 50/60 the dose threshold that causes 50% death in a population at 60 days LD 50/60 with no treatment Gy ( rad) LD 50/60 with treatment 6-8 Gy ( rad) (NUREG/CR-6545, 1997)

20 Factors that Affect LD 50/60 Lower LD50/60 -- extremes of age -- coexisting trauma/infection -- chronic nutritional deficit/disease -- quality factor Raise LD50/60 -- good supportive care -- poorly penetrating radiation -- partial-body exposure -- divided radiation dose -- radiation countermeasures

21 Overview Biological Principles of Radiation Acute Health Effects Triage and Medical Management Preparedness Resources

22 Acute Radiation Syndrome A combination of clinical signs and symptoms, occurring in phases over a period of hours to weeks, due to a significant partial-body or whole body exposure of > 1 Gy (100 rad), as injury to various tissues and organs is expressed.

23 EXPOSURE Phases of ARS PRODROMAL LATENT MANIFEST ILLNESS Anorexia Nausea Vomiting Diarrhea Histamine response and cellular membrane TIME Asymptomatic Mild Symptoms Recovery Combat Effective? Return of Prodrome Infection Hemorrhage Sepsis Death or Recovery Effect of cellular and DNA damage

24 Key ARS Mechanisms Cell line depletion Cell lines regenerate at survivable doses Microvascular injury Currently not survivable with high doses

25 ARS Subsyndromes The effect of radiation on SYSTEMS Related to dose Hematopoietic Gastrointestinal Neurovascular

26 Hematopoietic Syndrome Radiation Dose (Gy) Performance Decrements Life- Threatening Injuries Survival of an Unsupported Patient Radiation Dose (rad) 1 Motivation loss Fatigue Weakness Anorexia Bone marrow damage Probable Nausea Emesis 4 5 Diarrhea Severe bone marrow damage Likely 300 LD 50/ (untreated) 500 Dose > Gy ( rad) Effects: Hematopoietic Stem and Progenitor Cells

27 Hematopoiesis

28 Stem Cell Damage Normal Marrow Irradiated Marrow

29 Radiation Effect on Blood

30 H: Prodromal Period Symptoms: nausea, vomiting, anorexia, malaise, possible diarrhea Onset at 3-16 hours, short duration Severity increases with dose H: Latent Period Mostly asymptomatic, except mild weakness 3-4 weeks Hair loss at 2 weeks if > 3 Gy (300 rad) Restrict duty! Immunosuppressed H: Manifest Illness Onset: 3-5 weeks Bone marrow atrophy infection and hemorrhage

31 Gastrointestinal Syndrome Radiation Dose (Gy) Performance Decrements Life- Threatening Injuries Survival, Unsupport ed Patient Radiation Dose (rad) 6 Prolonged reaction time, decrement of Moderate Death 700 performance intestinal 8 accuracy damage (2-3 weeks) Hypotension 10 Severe 1,000 Death Early transient gastrointestinal 12 (1-2 weeks) incapacitation damage 1,200 Dose > 6-8 Gy ( rad) Effects: GI stem cells Small vessels

32 GI Vascular Damage Normal GI Mucosa Irradiated GI Mucosa Mucosa Muscularis Mucosae Submucosa Circular Muscle Longitudinal Muscle Serosa

33 GI: Prodromal Period Symptoms: Severe nausea/vomiting; possible watery diarrhea and cramps (difficult to treat), fever Onset: 1-4 hours after exposure; degrades combat capability GI: Latent Period 5-7 days Malaise and weakness Continued, but diminishing, GI tract function GI: Manifest Illness Malabsorption / Malnutrition from Impaired Barrier / Tissue Sloughing Fluid and Electrolyte shifts (dehydration, acute renal failure, cardiovascular collapse) Paralytic Ilieus (abdominal distension, severe vomiting and bloody diarrhea) Infection / Sepsis/ Fever Death

34 Neurovascular Syndrome Radiation Dose (Gy) Performance Decrements Life- Threatening Injuries Survival of Supported Patient Radiation Dose (rad) 20 Confusion 30+ Loss of consciousness Neurovascular damage Death (5-12 days) Death (2-5 days) 2,000 3,000+ Dose > Gy (1,200-3,000 rad) Effects: Endothelial cell injury (small vessels), especially in brain Death expected

35 NV: Prodromal Period Burning skin sensation within minutes Vomiting and diarrhea, < 30 minutes Loss of balance and confusion with prostration NV: Latent Period Apparent improvement for a few hours Possible euphoria Weakness NV: Manifest Illness Within 6-24 hours: Severe CNS signs BP instability Respiratory distress CV collapse, death

36 Cutaneous Radiation Injury Not an ARS Subsyndrome High dose to skin, localized effect Final result hard to estimate based on initial presentation Microvascular injury Initially - Inflammatory exudative lesion Finally - Fibrotic (obliterative) endarteritis

37 Cutaneous Radiation Injury Prodrome Brief erythema Heat sensation, itching Manifest injury Secondary erythema, edema, blisters Moist desquamation Superficial and deep ulcers, necrosis Pain, fever Localized Epilation (after 2+ weeks) Telangiectasia, pigment changes

38 Cutaneous Radiation Injury Recovery/late Pigment changes Keratosis Atrophy, sclerosis Obliterative vasculitis Chronic pain

39 Skin changes Normal Irradiated

40 Cutaneous Injury Incident Industrial Radiation Facility Maryland (11 Dec 91) Overexposure to 3 MeV electron beam During maintenance, operator placed forehead, hands and feet in beam - thought beam was off Alarms were ignored and safety interlocks were either defeated or sidestepped by the operator Mean dose estimate by EPR of /- 3.5 Gy to left middle finger Dose rate in shoes approximately 40 rad/sec (40 cgy/sec)

41 Skin Erythema ~ 4 weeks post exposure ~ 6 weeks post exposure ~ 8 weeks post exposure

42 Epilation Two Weeks Post Exposure Six Weeks Post Exposure

43 Cutaneous Injury ~1 week post exp ~2 weeks post exp ~4 weeks post exp ~8 weeks post exp ~12 weeks post exp ~17 weeks post exp

44 Overview Biological Principles of Radiation Acute Health Effects Triage and Medical Management Preparedness Resources

45 Treatment Algorithm

46 Three phases: Medical Management Early (First 72 hours) Intermediate (72 hours to ~30 days) Late (>~30 days) Based on dose estimate and clinical presentation

47 Early Phase (0-72 hours) Triage Initial (primary) medical care Emergency care and initial stabilization Monitor for infection Determine degree of radiation injury Signs and Symptoms Dosimetry estimates Biodosimetry Develop care plan Early employment of G-CSF Consider combined injury

48 Triage Based on COMBINED injuries Decontaminate AFTER stabilized Traumatic injuries are more acutely life threatening than radiation injuries Removal of clothing and washing of patient >90% effective Requirement for some medical providers to work in a radiation environment Risk to providers is very low

49 Triage w/ Radiation Incident Immediate Life threatening, non radiation injuries Combined Injuries Internal Contamination Delayed Evidence of radiation injuries [2-10 Gray (200-1,000 rad)] Emesis < 4 hours Lymphocytes drop > 50% w/in first 48 hours Minimal Radiation exposure with no evidence of injury Worried well Expectant - High dose[>20 Gy (>2,000 rad)]

50 Early Phase (0-72 hours) Triage Initial (primary) medical care Emergency care and initial stabilization Monitor for infection Determine degree of radiation injury Sign and Symptoms Dosimetry estimates Biodosimetry Develop care plan Early employment of G-CSF Consider combined injury

51 Initial Medical Care Standard medical emergency procedures CABs (Circulation, Airway, Breathing) Early surgical intervention Monitor for infection

52 Early Surgical Intervention Within the first 48 hours Risk of infection and bleeding increase due to hematopoietic subsyndrome Immunosuppression Decreased platelets Delayed wound healing Reestablish integument to protect against infection

53 Combined Injury Mortality

54 Surgery Within 48 Hours

55 Monitor/Treat for Infection Oral absorbable quinolone (Ciprofloxacin) Well-tolerated Broad spectrum Proven to decrease gram negatives Maintain normal flora, especially anaerobes When: Absolute neutrophil count (ANC) falls < 500 Or, profound Neutropenia expected

56 Selective Decontamination

57 Monitor for Infection In addition to quinolones, also consider: Fluconazole Acyclovir In a mass casualty scenario, medications may be the only therapy readily available Consider broad use Plan for patient dosing at home

58 Early Phase (0-72 hours) Triage Initial (primary) medical care Emergency care and initial stabilization Monitor for infection Determine degree of radiation injury Sign and Symptoms Dosimetry estimates Biodosimetry Develop care plan Early employment of G-CSF Consider combined injury

59 Acute Radiation Syndrome A combination of clinical signs and symptoms, occurring in phases over a period of hours to weeks, due to a significant partial-body or whole body exposure of > 1 Gy (100 rad), as injury to various tissues and organs is expressed.

60 Determine Degree of Injury Clinical Data Time to Emesis Signs and Symptoms Dosimetry Dosimeters Equipment/clothing Biodosimetry Basic (in medical facility) Advanced (at DoD/DOE Lab)

61 Dose Estimate

62 ARS- S/S of Good Prognosis Vomiting starts > 4 hours after incident No significant change in serial lymphocyte counts within 48 hours after an incident No other significant injuries

63 ARS- S/S of Poor Prognosis Coma, Seizures Vomiting < 4 hours after incident Serial Lymphocytes drop more than 50% w/in 48 hours Bloody vomitus or stool Other serious injuries

64 Degree of Injury Concept Dose (actual or estimated) Numerical designation Clinical outcome based on population data Easy to categorize patients Less accurate for individual patient planning vs. Clinical category Designation based on individual patient clinical course More accurate for individual Harder to categorize patients More difficult (time, equipment, and resource consuming)

65 Clinical Evaluation - 1 History: Who, what, when, where, how, & why? Location, Time, and Duration of exposure Activity at time of exposure Occupation Other (e.g. reported time of onset emesis, erythema, diarrhea, alopecia)

66 Clinical Evaluation -2 Physical Exam: Vital signs (fever, hypotension, orthostasis) Skin (edema, erythema, blistering, desquamation) Gastrointestinal (abdominal swelling or pain) Neurological (papilledema, reflexes, motor, sensory, cognitive function) Hyperthermia Hypotension Erythema CNS dysfunction Other (fever, fatigue parotid pain)

67 Biodosimetry Basic (in medical facility) Lymphocyte Depletion Kinetics q 6 hours C-Reactive Protein Serum Amylase Activity Complete Blood Count Advanced (at DoD Lab) Dicentric Assay EPR Lymphocyte Depletion Kinetics Premature Chromosome Condensation Translocation Analysis (FISH)

68 Basic Biodosimetry Can be completed within a Role 1/2/3 medical facility and managed by operational and general medical staff Point of care equipment to expedite these tests is in development

69 Lymphocyte Kinetics Lymphocyte response is dose dependent Large depletion indicates larger doses Absolute Lymphocyte Count Can be used to estimate doses between 3-7 Gy Qualitative response otherwise Drops greater than 50% in 48 hours indicate poor prognosis (> 4 Gy) Draw blood every 6 hours Gy 4.4 Gy 5.6 Gy 7.1 Gy Time (days) Lymphocyte Depletion Curves Andrews, 1965

70 Advanced Biodosimetry Requires delivery of samples to Role 4 lab Blood, tissue, etc Significant processing time (days vs. minutes) Generally more accurate than basic techniques More useful for non-acute patients Dose of record Medical decisionmaking in intermediate and late phases Contact Role 4 labs for sampling instructions

71 Early Phase (0-72 hours) Triage Initial (primary) medical care Emergency care and initial stabilization Monitor for infection Determine degree of radiation injury Sign and Symptoms Dosimetry estimates Biodosimetry Develop care plan Early employment of G-CSF Consider combined injury

72 Colony Stimulating Factors A class of cytokines (small proteins that are important in cell signaling) Play a major role in the proliferation, differentiation, and survival of primitive hematopoietic stem and progenitor cells Increase function of some mature cells

73 FDA Approved CSFs Granulocyte-colony stimulating factor G-CSF/ filgrastim (Neupogen ) Pegylated granulocyte-colony stimulating factor PEG-G-CSF /pegfilgrastim (Neulasta ) Prospective, randomized trials in humans are not feasible Approved under animal model rules

74 CSF Justification Oncology data - CSF enhances neutrophil recovery after chemotherapy by 3-6 days Pre-clinical animal data- CSF also enhances neutrophil recovery from radiation-induced neutropenia Enhanced survival with early initiation and aggressive supportive care Note: possible severe side effects: Pegylated forms should be avoided because of long half-lives. Therapy can be terminated more rapidly with non-pegylated forms.

76 Primate Shielding Experiment

77 Effect After 8 Gy (800 rad)

78 Intermediate Phase (3-30 days) Surgery completed Burn care Supportive care Infectious Disease Hematology Intensive Care Consider Stem Cell Transplant

79 Stem Cell Transplantation Consideration for minority of victims. Must be sick enough to require it, but not so sick they are likely to die 1. Irreversible marrow injury (dose > 3 Gy) Myeloablated complete depletion of bone marrow cells Neutrophil count < 100/ l by day 6 Rapid drop of platelets 2. Acceptable pre-transplant condition (combined injury) No Significant thermal/radiation burns No Significant lung, CNS, or liver injury No Other severe active radiation induced toxicity 3. Available donor

80 Late Phase (>30 days) Hematopoietic reconstitution Dose dependent deficits in cellular mediated immunity lymphocyte recovery Continued risk for acquisition of new infections and reactivation of previous viruses possible Need for revaccination at 1 year No live vaccine for 24 months

81 Late Phase (>30 days) Multiple organ system failures may require ICU care Long-term sequelae of radiation injury Skin injury, cataracts, infertility, risk of secondary malignancy Consider special populations Geriatric Children Pregnancy

82 Late Phase Recovery Resolution of Neutropenia When ANC >500 cells/mm3 and rising, may stop prophylactic antibiotics and antifungals Antiviral coverage- Acyclovir Continue until 30 days post-exposure Longer if coverage for Varicella Zoster Virus (VZV) desired Consult Infectious Disease For any patient with persistent or recurrent fever Cellular mediated immunity may still be severely abnormal

83 Summary CABs are the first priority Dosimetry paramount after initial triage Beware of Infections: Surgery should be completed within 48 hours Exposure likely to be non-uniform, so populations of stem cells may survive and benefit from early use of cytokines Combined injuries extremely common Mortality multiplier

84 Resources Centers for Disease Control and Prevention (CDC), Emergency Preparedness and Response Radiation Emergency Assistance Center/Training Site (REAC/TS) Based at Tennessee's Oak Ridge Institute for Science and Education (ORISE), REAC/TS provides 24/7 availability to deploy and provide emergency medical services at incidents involving radiation anywhere in the world.

85 Questions?

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