Radiation Injury Transplant Network. Acute Radiation Syndrome Treatment Guidelines

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Edgar Brooks
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1 Radiation Injury Transplant Network Acute Radiation Syndrome Treatment Guidelines November 16, 2006

2 Assumption: Mass casualty event Scenario 1: Healthy adult (Scenario 2: Pediatric patients TBD) EMS Field Triage^ Home Comfort Care No acute follow up First 24 to 72 hours Keep in hospital Return for F/U 2 Triage to medical centers* Diagnosis of Acute Radiation Syndrome (ARS) Supportive Care (page 2) Non survivable injuries Consider stem cell Support (page 3) Comfort Care Triage based on the AFRRI Biodosimetry Assessment Tool (BAT) schema or on the Response Category (RC) until a better dosimetry system is available. Give KI if radioactive iodine is present, decontaminate patient if external contamination. Activate National Response Plan (NRP), National Incident Management System (NIMS): Transfer to medical centers with expertise in ICU care, burn and trauma center, hematology/oncology, and stem cell transplantation A collaboration of the NMDP and ASBMT Sponsored by the Office of Naval Research

3 Supportive Care: Decisions based on clinical parameters and estimated biological effects FIRST - Treat complex injuries requiring wound/surgical care - FIRST Complex injuries Wound/surgical care ARS with Nuetropenia Hematopoietic support: 1. Start G-CSF (300 mcg/m 2 /d) 2. Consider PICC line 3. Blood product support: irradiated and leukoreduced (keep Hgb > 7 g/dl, platelets > 10,000µL). 4. HLA type victim 1 5. Search for donors 2 Anti-microbial support: 1. Reverse isolation 2. When neutropenic,start fluconazole 3 3. If HSV+ start acyclovir 4. PCP prophylaxis (pentamidine) 5. Start fluoroquinolone 3 6. Consider coverage for skin flora if burns are present. GI support: 1. 5HT3 inhibitor, lorazepam for nausea/vomiting 2. Proton pump inhibitor 3. Imodium, diphenoxylate/atropine for diarrhea or somatostatin 3 1 if estimated whole body radiation dose 3-10 Gy 3 Agents may vary by center depending on availability 2 if neutrophils <100/µL by day 6 and at physicians discretion A collaboration of the NMDP and ASBMT Sponsored by the Office of Naval Research

4 Clinical decision to Consider stem cell support (similar to non-myeloablative CTN aplastic anemia protocol 0301) 4 Neutrophil < 100/μl by day 6 (see RC criteria) Rapid drop of lymphocytes (see BAT schema - link on next page) Rapid drop of platelets Severely aplastic marrow or evidence of marrow necrosis at 2-3 sites (posterior iliac crests, sternum) Estimated whole body radiation dose at least 3 Gy and less than 10 Gy Suitable HLA compatible donor available A collaboration of the NMDP and ASBMT Sponsored by the Office of Naval Research

5 Dosimetry (BAT) Armed Forces Radiobiology Research Institute, Biodosimetry Assessment Tool (BAT): dostools.htm#batregister 5 A collaboration of the NMDP and ASBMT Sponsored by the Office of Naval Research

6 Dosimetry (Response Criteria [RC]) Purpose: assess clinical damage to critical organs (neurovascular, hematopoietic, cutaneous and GI) Grading: semi quantitative organ specific Cummulative overall grading code Summation of Response Criteria 6 Fliedner TM, Dorr HD, Meineke V. Multi-organ involvement as a pathogenetic principle on the radiation syndrome: a study involving 110 case histories documented in SEARCH and classified as the bases of haematopoietic indicators of effect. Brit J. Radiology 78:1-8, 2005 Fliedner TM, Friesecke I and Beyrer K. Manual on the Acute Radiation Syndrome. British Institute of Radiology. A collaboration of the NMDP and ASBMT Sponsored by the Office of Naval Research

7 Radiation Incident Triage phase Triage primary* / extended Referral Acute TBI / PBI Possible Flow Chart Diagnosis * If, due to additional trauma, immediate invasive intervention is necessary (e.g. surgery), this should be performed as fast as possible prior or in parallel with the diagnostic phase. In accordance to specific requirements in ARS surgical measures should be definitive. Diagnostic phase Therapeutic phase Work flow Information flow Feed back Case history + Physical examination Laboratory tests + Additional diagnostic measures + Organ specific grading Grading code RC Referral? Therapy (initial) Grading-based specific therapeutic approaches RC-based general therapeutic approaches Documentation

8 Symptoms Grading (organ specific) Grading code Response Category Nausea Vomiting Anorexia Fatigue syndrome Fever Headache Hypotension Neurological deficits Cognitive deficits Lymphocytes changes Granulocyte changes Thrombocyte changes Blood loss Infection Erythema Sensation / Itching Swelling and Edema Blistering Desquamation Ulcer / Necrosis Hair loss Onycholysis Diarrhea Abdominal Cramps/ Pain N H C G N = Neurovascular System H = Haematopoietic System C = Cutaneous System G = Gastrointestinal System i = Degree of severity 1-4 xd = Time point (x) at which RC was established; measured in days (d) after begin of exposure. N i H i C i G i Capital letter for the organ system, e.g. neurovascular system N 2 N i H i C i G i Degree of severity to describe the extent of damage Example : N2 H3 C1 G2 RC=? x d RC=3 2d An RC equal to 3 was determined on the second day after exposure

9 Evaluate as many of the 4 Acute Radiation Syndrome (ARS) subsyndromes as you have information for, by degree of severity. RC is assigned to patient based on highest degree of severity in any subsyndrome: NEUROVASCULAR SUBSYNDROME i Sign/Symptom/Test Degree 1 Degree 2 Degree 3 Degree 4 Nausea Mild Tolerable Intense Excruciating Vomiting Occasional: 1/day Intermittent, 2-5/day Persistent, 6-10/day Refactory>10/day or parenteral nutrition Anorexia Able to eat and drrink; reasonable intake Significantly decreased intake but able to eat No significant intake parenteral nutrition Fatigue Able to work or perform normal activity Able to work or perform normal activity Needs assistance for self-care Headache Minimal Minimal Intense Intense Vital signs Neurological deficits Temp < 38 degree C HR > 100 BP > 100/70 No major neurological deficit; Able to perform normal activities Temp degree C BP < 100/70 unstable vital signs Easily detectable mild neurological deficit; No significant interference with normal activity HEMATOPOIETIC SUBSYNDROME i Temp > 40 degree C for less than 24 hours; BP < 90/60; transient or intermittent drop or unstable Prominent neurological deficit; Significant interference with normal activity Prevents daily activity Temp > 40 degree C for more than 24 hours; hypotension: BP < 80/? Life threatening neurological signs; Possible loss of consciousness Sign/Symptom/Test Degree 1 Degree 2 Degree 3 Degree HOURS Serial CBCs recommended to improve estimation of severity. (Lymphocyte kinetics and dose, How frequent?) Lymphocyte count < 0.5 (10 9 cells/l) Granulocyte count (10 9 cells/l) > 2 4-6, mild granulocytosis 6-10, moderate granulocytosis > 10, marked granulocytosis Platelet count (10 9 cells/l) DAYS Serial CBCs recommended to improve estimation of severity. (Lymphocyte kinetics and dose, How frequent?) Lymphocyte count < 0.1 (10 9 cells/l) Granulocyte count > 2 > 2 > 5 > 5 (10 9 cells/l) (note the high granulocyte with low platelets is a poor prognostic sign) Platelet count < 20 (10 9 cells/l) CUTANEOUS SUBSYNDROME i Sign/Symptom/Test Degree 1 Degree 2 Degree 3 Degree 4 Erythema (hours - 30 days) Altered sensation/ Itching (hours - 30 days) Edema (5 days - 8 weeks) Blistering (5 days - 8 weeks) Desquamation (5 days - 8 weeks) Ulcer/necrosis (5 days - 8 weeks) Hair loss (2-8 weeks) Onycholysis (2-8 weeks) Minimal and transient; Moderate; Marked; isolated patches <10 cm2; not isolated patches or confluent; 10- more than 10% of body surface 40% of BSA area (BSA) Severe; isolated patches or confluent; >40% of BSA; Pruritus Slight and intermittent pain Moderate and persistent pain Severe and persistent pain Present; asymptomatic; Symptomatic; tension Secondary dysfunction Total dysfunction Rare, with sterile fluid Rare with hemorrhage Bullae with sterile fluid Bullae with hemorrhage Absent Patchy dry Patchy moist Confluent moist Epidermal only Dermal Subcutaneous Muscle/bone involvement Thinning, not striking Patchy, visible Complete and most likely reversible Complete and most likely irreversible Absent Partial Partial Complete GASTROINTESTINAL SUBSYNDROME i Sign/Symptom/Test Degree 1 Degree 2 Degree 3 Degree 4 Diarrhea - frequency 2-3 stools/d 4-6 stools/d 7-9 stools/d >= 10 stools/d Refactory diarrhea; Stool - consistency Bulky or normal Loose Very lose Watery Blood in stool Occult Intermittent Persistent Gross hemorrhage Abdominal cramps / Minimal Tolerable Intense Excruciating pain Vomit See Neurovascular System Nausea See Neurovascular System 1. Modified from the NIH REMM draft ARS treatment website, which created the original by modifying from Fliedner, TM, Friesecke, I, Beyrer K. Medical Management of Radiation Accidents: Manual on the Acute Radiation Syndrome. Oxford: British Institute of Radiology; 2001.

10 Images copied from the NIH REMM draft ARS treatment website.

11 Different level of complexity based on RC With permission: Fliedner TM, Dorr HD, Meineke V. Multi-organ involvement as a pathogenetic principle on the radiation syndrome: a study involving 110 case histories documented in SEARCH and classified as the bases of haematopoietic indicators of effect. Brit J. Radiology 78:1-8, A collaboration of the NMDP and ASBMT Sponsored by the Office of Naval Research

12 Clinical tasks Triage Early radiation specific information Subsequent radiation specific information Assessment of overall health condition External trauma, burns Diagnosis Observation Diarrhea Vomiting Consciousness Repeated review Routine history Chief complaints Past medical history Past medication Allergies Accident description Interrogation Vomiting Diarrhea Fatigue syndrome Consciousness Nausea Vomiting Anorexia Diarrhea Fatigue syndrome Neurological deficits Headache Abdom. Cramps/Pain Cognitive deficits Blood loss Sensation/Itching Hair loss Inspection of skin from head to toe Inspection Erythema Erythema Blistering Swelling/Oedema Desquamation Ulcer/Necrosis Petechia Hair loss Onycholysis Routine physical exam. (head to toe) EEG ECG Imaging tests Dosimetry Examination Fever Neurological deficits Fever Neurological deficits Hypotension Sensation/Itching Cognitive deficits Infection Blood loss Haematological tests Blood counts Differential blood HLA type Cytogenetics BM smears Bio-chemical tests Microbiological tests Laboratory tests Lymphocyte changes Granulocyte changes Lymphocyte changes Granulocyte changes Thrombocyte changes Stool characteristics Occult blood Organ specific grading Grading code RC (initial) Therapy

13 Hematologic Indicators of H3 Grading Granulocytes [G/l] H3, Granulocytes 1005 Chernobyl 1011 Chernobyl 3008 Moscow Shanghai Days after exposure Platelets [G/l] H3, Platelets 1005 Chernobyl 1011 Chernobyl 3008 Moscow Shanghai Days after exposure Lymphocytes [G/l] H3, Lymphocytes 1005 Chernobyl 1011 Chernobyl 3008 Moscow Shanghai Days after exposure Reversible Injury: Indicators Granulocytes: moderate granulocytosis, decline between day 4. and 10., abortive recovery followed by nadir: days Lymphocytes: decline to nadirlevels within 2 days, thereafter slow recovery Platelets: initial 10-day-shoulder followed by decline towards day 20., nadir: days

14 Hematologic Indicators of H4 Grading Granulocytes [G/l] H4, Granulocytes 17 Los Alamos 3106 Chelyabinsk 3107 Chelyabinsk Sor-Van 500 Tokaimura 501 Tokaimura Platelets [G/l] H4, Platelets 17 Los Alamos 3106 Chelyabinsk 3107 Chelyabinsk Sor-Van 500 Tokaimura 501 Tokaimura Day after exposure Day after exposure Lymphocytes [G/l] H4, Lymphocytes 17 Los Alamos 3106 Chelyabinsk 3107 Chelyabinsk Sor-Van 500 Tokaimura 501 Tokaimura Day after exposure Irreversible Injury: Indicators Granulocytes: initial granulocytosis and progressive decline of cell counts between day 4. and 6. Lymphocytes: progressive decline within 24 h Platelets: progressive decline within the first 10 days

15 Radiation Injury Transplant Network Acute Radiation Syndrome - Treatment Schedule of Events - RC Grading Quick Reference November 16, 2006

16 Radiation Injury Transplant Network ARS Schedule of Events TIME COURSE Time zero Immediate 1-2 hours,?doable Within 24 hours Event Occurs Event Assessment EMS Triage (AFRRI-BAT) Activate NRP and NIMS EMS-Patient Specific Assessment Initial health/trauma/burn complete Initial RC Assessment Complete Appropriate decontamination begun Patient -Home or Patient - Comfort care or Patient transferred to Hospital Patient in Hospital History, PE, Labs-see ARS tab Patient - Comfort Care or Patient - to be treated Appropriate trauma and surgical care Diagnosis ARS Dose of Irradiation known

17 Radiation Injury Transplant Network ARS Schedule of Events ARS Triage to medical center and dx of ARS Day 1 Day 2 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Case History Physical Examination Evaluation by surgery, if indicated Evaluation by burn team, if indicated Appropriate Decontamination Complete Blood Count w/diff Reticulocyte Count PT/PTT/INR Type and Scren Comprehensive Panel HLA typing of Patient HLA typing of Siblings Standard pre - SCT serologies- patient Standard pre - SCT serologies- siblings Urinalysis Bone Marrow Aspirate and Biopsy Place central triple lumen line Chest -Ray EKG Echo Wound/surgical Care Reverse isolation Nothing by Mouth Start GCSF if indicated Start Fungal Coverage Start quinolone Start Acyclovir, for all Start 5Ht3 inhibitor Start Proton Pump Inhibitor Start Imodium, if indicated Skin Care Consider KI therapy, if indicated a Consider Stem Cell Support Start donor search, if indicated

18 Radiation Injury Transplant Network ARS Schedule of Events Organ Specific Assessment Day 1 Day 2 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Neurologic Assessment Nausea Vomiting Anorexia Fatigue Fever Headache Hypotension Neurologic Assessment NEURO GRADE Hematopoietic Assessment Absolute Lymphocyte Count Absolute Granulocyte Count Platelet Count (untransfused) Blood Loss Infection HEME GRADE Cutaneous Assessment Erythema Sensation Edema Blisters Desquamation Ulcer/necrosis Hair Loss Onycholysis SKIN GRADE Gastrointestinal Assessment Diarrhea Abdomial Pain GI GRADE RC GRADING OVERALL RC GRADE

Medical Management of Radiation Accidents: Management of the Acute Radiation Syndrome The British Institute of Radiology

Medical Management of Radiation Accidents: Management of the Acute Radiation Syndrome 2001 The British Institute of Radiology This publication is copyright under the Berne Convention and the Universal