ACUTE RADIATION SYNDROME CLINICAL PICTURE, DIAGNOSIS AND TREATMENT

Module XI Lecture organization

Introduction ARS manifestations Haematological syndrome Gastrointestinal syndrome Neurovascular syndrome Triage of injured persons Medical management Summary

Module Medical XI. 2 Introduction

Acute radiation syndrome (ARS): Combination of clinical syndromes occuring in stages hours to weeks after exposure as injury to various tissues and organs is expressed ARS threat Discharged medical irradiators Industrial radiography units Commercial irradiators Terrorist detonation Nuclear fuel processing Nuclear reactors

Module Medical XI. 3 Early deterministic effects

<0.1 Gy, whole body - No detectable difference in exposed vs non-exposed patients 0.1-0.2 Gy, whole body - Detectable increase in chromosome aberrations. No clinical signs or symptoms >0.12 Gy, whole body - Sperm count decreases to minimum about day 45 0.5 Gy, whole body - Detectable bone marrow depression with lymphopenia

Module Medical XI. 4 Exposure levels at which healthy adults are affected ______Health effects Acute dose (Gy) Blood count changes 0.50 Vomiting (threshold) 1.00 Mortality (threshold) 1.50

LD50/60 (minimal supportive care) 3.2-3.6 LD50/60 (supportive medical treatment) 4.8-5.4 LD50/60 (autologous bone marrow or

______stem cell transplant)______>5.4 Source: NCRP Report 98 "Guidance on Radiation Received in Space Activities", NCRP, Bethesda (MD) (1989). Module Medical XI. 5 Factors

decreasing LD50/60

Coexisting trauma combined injury Chronic nutritional deficit Coexisting infection Contribution of high LET radiation

Module Medical XI. 6 Phases of ARS

 Initial or prodromal phase

 Latent phase

 Manifest illness phase

 Recovery phase

Module Medical XI. 7 Manifestations of ARS

Haematopoietic syndrome (HPS) Gastrointestinal syndrome (GIS) Neurovascular syndrome (NVS)

Module Medical XI. 8 Haematopoietic syndrome

Normal bone marrow cells

Module Medical XI. 9 Survival potential

Bone marrow damaged by radiation injury

Module Medical XI. 10 Haematological response to 1 Gy, whole body exposure to ionizing radiation

Module Medical XI. 11 Haematological response to 3 Gy, whole body exposure

Module Medical XI. 12 Phases of haematopoietic syndrome (HPS)  Prodromal phase symptoms nausea and vomiting lasts only a few hours, with time of onset from later than one hour to about 24 hours after exposure  Latent phase lasts up to a month. Relatively asymptomatic except for some fatigue and weakness  Manifest illness phase, characterized by neutropenic fevers, systemic and localized infections, sepsis, and haemorrhage

Module Medical XI. 13 Gastrointestinal (GI) syndrome (8-30 Gy) Pathophysiology of the GI Syndrome  Depletion of the epithelial cells lining lumen of gastrointestinal tract Irradiated GI Mucosa  Intestinal bacteria gain free access to body  Haemorrhage through denuded areas  Loss of absorptive capacity

Module Medical XI. 14 Phases of Gl syndrome

Prodromal period: Severe nausea and vomiting, watery diarrhoea and cramps. Occurs within hours after exposure Latent (subacute) phase: Asymptomatic for hours to days, severe tiredness, weakness Manifest illness: Return of severe diarrhoea, vomiting with fever; progression to bloody diarrhoea, shock and death without aggressive medical intervention

Module Medical XI. 15 Systemic effects of GI syndrome Malabsorptionmalnutrition Fluid and electrolyte shiftsdehydration, acute renal failure, cardiovascular collapse GI bleedinganaemia Sepsis Paralytic ileusvomiting, abdominal distention

Module Medical XI. 16 Pulmonary effects

Irradiated lung tissue Pulmonary fibrosis

Module Medical XI. 17 Neurovascular syndrome (NVS)

 At 30 Gy and above

 Endothelial cell damage

Module Medical XI. 18 NVS prodromal perıod

 Burning sensation within minutes of exposure  Nausea and vomiting within first hour  Loss of balance, confusion with prostration  Hypotension, hyperpyrexia

Module Medical XI. 19 NVS latent period

Apparent improvement lasting several hours –Maybelucidandin no pain but weak

Module Medical XI. 20 NVS overt clinical picture

 Rapid onset  Watery diarrhoea  Respiratory distress  Gross CNS signs  Wide pulse pressure  Hypotension

Module Medical XI. 21 ARS Neurovascular Syndrome Life threatening Death of Radiation Symptoms injuries patients dose (Gy)

16 Loss of consciousness 5-12 days 20 25 Neurovascular 30 damage 2-5 days

Module Medical XI. 22 Trıage of ınjured persons

Module Medical XI. 23 Measurement of severity

 Prodromal effects  Time of onset  Degree of symptoms  Haematological changes  Lymphocyte counts  Biological dosimetry  Physical dosimetry  Attendant readable

Module Medical XI. 24 Radiation dose under 5 Gy

 No immediate life-threatening hazard exists

 Prodromal symptoms of moderate severity

 Onset > 1 hour

 Duration < 24 hours

Module Medical XI. 25 Fatal radiation

 Nausea and vomiting within minutes (during the first hour)

 Within hours (on the first day):

 Explosive bloody diarrhoea

 Hyperthermia  Hypotension  Erythema  Neurological signs

Module Medical XI. 26 Triage categories of radiation injuries according to early symptoms

Module Medical XI. 27 Guide for management of radiation injuries on the basis of early symptoms No vomiting < 1 Gy Outpatient with 5-week surveillance

Vomiting 2-3 h 1-2 Gy Surveillance in a general hospital (or after exposure outpatient for 3 weeks) followed by hospitalization Vomiting 1-2 h 2-4 Gy Hospitalization in a haematological after exposure department Vomiting > 4 Gy Hospitalization in a well equipped earlier than 1 h, haematological or surgical department other severe with transfer to a specialized centre symptoms, like hypotension for radiopathology hyperthermia, diarrhoea, oedema, erythema, CNS

Modulesymptoms Medical XI. 28 Lymphocytes

3Gy

4-5Gy

Module Medical XI. 29 Change of lymphocyte counts in initial days of ARS depending on dose of acute WB exposure Degree of Dose Lymphocyte counts ARS (Gy) (cells/L) 6 days after first exposure

Preclinical phase 0.1-1.0 1500-2500 Mild 1.0-2.0 700-1500 Moderate 2.0-4.0 500-800 Severe 4.0-6.0 300-500 Very severe 6.0-8.0 100-300 Lethal >8.0 0-50

Module Medical XI. 30 Granulocyte counts and dose relationship after irradiation

Module Medical XI. 31 Medical management of acute radiation syndrome

Module Medical XI. 32 Therapeutic support for haematopoietic syndrome patient Primary goal of haematopoietic support is reduction in both depth and duration of leukopenia  Prevention and management of infection is mainstay of therapy  Quantitative relationship between degree of neutropenia and increased risk of infectious complications. Absolute neutrophil count (ANC) < 100/L is greatest risk factor

Module Medical XI. 33 Infection managment General principles  Prophylaxis Direct therapy for infections  Barrier/isolation Culture specific  Gut decontamination antibiotics  Antiviral agents Therapy for  Antifungal agents leukopenia  Pneumocystis prophylaxis Cytokine administration  Early cytokine therapy  Close wounds  Avoid invasive procedures

Module Medical XI. 34 Isolation

Treat ARS patients with estimated WB >2Gy in isolated rooms. Warn nursing personnel of the need for rigorous environmental control including:  laminar flow isolation  strict hand washing before and after patient care  surgical scrubs for staff  gowns, caps, gloves, masks for staff  double bagging of all disposables

Module Medical XI. 35 Prevention of infection

 Reduction of microbial acquisition  Contact control (e.g. careful, frequent hand washing)  Low-microbial content food  Acceptable water supply  Air filtration to reduce aspergillus infection  Reduction of invasive procedures (e.g. nasogastric tubes, catheters)

Module Medical XI. 36 Approach to prevent infection in immunocompromised patients

Suppression of micro-organisms Selective gut decontamination Administration of oral non-absorbable antibacterial drugs (e.g.,Quinolones) that preserve anaerobic bacteria Awareness of resistant bacterial acquisition during clinical course Antivirals (Acyclovir) as guided by positive anti-HSV (herpes simplex virus) antibody or empirically if test not available

Module Medical XI. 37 Approach to prevent infection in immunocompromised patients

 Suppression of micro-organisms  Physiological interventions Maintenance of gastric acidity

Avoidance of antiacids and H2 blokers Use of sucralfate for stress ulcer prophylaxis when indicated to reduce gastric colonization and pneumonia Early oral enteral nutrition (when feasible)  Adequate personal hygiene  Povidone-iodine (Betadine) or chlorhexidine for skin disinfection, shampoo  Oral hygiene (brushing and flossing)

Module Medical XI. 38 Approach to prevent infection in immunocompromised patients

 Improvement of host defences  Active vaccination for expected pathogens (e.g. influenza)  Passive immunization with immunoglobulins (utility not yet established)  Cytokine G-CSF administered prophylactically to reduce duration of neutropenia and provide adequate numbers of functional neutrophils

Module Medical XI. 39 Management of infection

 Survey for possible source, pancultures  Administer antibiotics for absolute neutrophil count (ANC) <500/mm3  Use broad spectrum antibiotic coverage  Add amphotericin for prolonged fever lasting 5-7 days after starting standard antibiotics  Continue antibiotics for duration of ANC <1000

Module Medical XI. 40 Management of infection

 If there is evidence of resistant gram-positive infection, add vancomycin  If diarrhoea is present, examine stool cultures for salmonella, shigella, camphylobacter and yersinia  Oral and pharyngeal mucositis and oesophagitis suggest herpes simplex infection or candidiasis. Empiric acyclovir or antifungal therapy should be considered Module Medical XI. 41 Total parenteral nutrition vs enteral feeding Premise for early enteral feeding

Early enteral feeding Parenteral feeding

Nutrients stimulate villi growth Villi atrophy from enteral starvation Gut mucosal barrier remains Gut mucosal barrier breaks intact down Unhealthy mucosal allows Healthy mucosa limits translocation of translocation of bacteria bacterial/endotoxin Immune system clears limited Complementary activation volume of translocated bacteria occurs Results: lowered stress Results: increased stress response and risk of sepsis Module Medical XI. response and risk of sepsis 42 Comparison of enteral and parenteral nutrition results

Module Medical XI. 43 Cytokines

Module Medical XI. 44 Cytokines

 Granulocyte-macrophage stimulating factor (GM-CSF) - Sargramostim (Leukine(R))  Macrophage colony stimulating factor (M-CSF)  Granulocyte colony stimulating factor (G-CSF) - Filgastrim (Neupogen(R))  Stem cell factor (SCF)  Interleukin series (IL 1-16)

Module Medical XI. 45 Selected cytokines

 G-CSF and GM-CSF are potent stimulators of haematopoiesis and effective in reducing duration and degree of neutropenia  Additional benefit of CSFs ability to increase functional capacity of neutrophil and thereby contribute to prevention of infection as active part of cellular host defence

Module Medical XI. 46 Advantages of cytokine therapy

 Bone marrow  increase production of white cells  stimulate production of colony forming units  decrease maturation time  Mature cells  increase viability  prime neutrophils/macrophages  stimulate additional cytokine release  Many act in synergy to increase haematopoiesis

Module Medical XI. 47 Results of cytokine therapy GM-CSF Sargramostim (LeukineR)

 Proven efficacy for decreasing duration of absolute neutropenia

 Decreased length of hospital stay

 Decreased need for antibiotics

 Fewer fever days

Module Medical XI. 48 G-CSF at 3.5 Gy (canine experiment)

Module Medical XI. 49 Use of cytokines for treatment of ARS  G-CSF and GM-CSF increase rate of hemopoietic recovery in patients after radiation exposure and may obviate need for BMT, when stem cells are still viable. Interleukins (IL-1 and IL-3) act in synergism with GM-CSF  Successfully used for radiation victims after Goiânia, San Salvador, Israel and Belarus and Istanbul accidents

Module Medical XI. 50 Initiation and duration of cytokine administration

 Benchmark absolute lymphocyte count less than 500/l threshold for beginning cytokine therapy in first 2 days  Continue cytokine administration with daily injections to reach ANC of 1000/l

Module Medical XI. 51 Cytokine dosage

 G-CSF Filgrastim (NeupogenR)  2.5-5.0 µg/kg/day (100-200 µg/m2/day)  GM-CSF Sagramostim (LeukineR)  5.0-10.0 µg/kg/day (200-400 µg/m2/day)  Begin therapy as early as practical for maximum effect

Module Medical XI. 52 Comparative toxicity of CSFs

 Predominant side effect of G-CSF - medullary bone pain, observed shortly after initiation of G-CSF treatment and again just before onset of neutrophil recovery from nadir  G-CSF may exacerbate preexisting inflammatory conditions  Main side effects of GM-CSF - fever, nausea, fatigue, headache, bone pain, myalgia

Module Medical XI. 53 Contraindication for cytokine treatment

Possibly in cases where radiation exposure is continuing (e.g. via internally deposited radionuclides, chronic external irradiation)

Module Medical XI. 54 Conventional therapy for thrombocytopenia

 Transfusion of platelets remains primary therapy to maintain adequate platelet counts  Requirement for platelet support depends on patient's condition. In irradiated patients with or without other major medical problems, platelets should be maintained at greater than 20 000/L. If surgery is needed, platelet count should be greater than 75 000/L

Module Medical XI. 55 Conventional therapy for thrombocytopenia

 All blood products should receive 15-20 Gy of radiation before infusion to prevent graft-vs-host disease through infusion of present mononuclear cells  If transplant performed, avoid use of platelets from related donors

Module Medical XI. 56 Growth factor therapy for thrombocytopenia

 Use of thrombopoietic agents immediately after radiation injury is not currently recommended  Consider use of thrombopoietic agents megakaryocyte growth and development factor/thrombopoietin (MGDF/Tpo) or synthetic IL-3 receptor agonist Synthokine in patient with neutrophil recovery but still platelet transfusion dependent after accidental irradiation

Module Medical XI. 57 Therapy for anaemia

 Transfusion of peripheral red blood cells (PRBCs) remains primary therapy to maintain haemoglobin above 8 g/dl; PRBC transfusions should be irradiated  Erythropoietin (Epo) anaemia therapy: Use of Epo after radiation injury is not recommended even though probably safe as anaemia is not generally life-threatening in this situation

Module Medical XI. 58 Granulocyte transfusions (GTX) from CSF-stimulated donors

 G-CSF, when administered to normal individuals, increases granulocytes collected, resulting in significant circulating levels of granulocytes in neutropenic patients. Use of HLA-compatible donors may avoid the problem of alloimmunization  G-CSF additional benefit, enhancing phagocytic and microbicidal activity of stimulated PMNs  GTX of G-CSF-stimulated PMNs could prove effective therapy for severely neutropenic patients with sepsis who have failed to respond to appropriate antibiotic therapy Module Medical XI. 59 Bone marrow transplantation (BMT)

 Indication for BMT following radiation accidents is probably limited  Following reversible BM injury BMT may have a negative effect, development of high risk graft rejection

Module Medical XI. 60 Effect of shielding, dose inhomogenity and GM-CSF on bone marrow recovery

Module Medical XI. 61 Indications for BMT

Physicians should consider allo-BMT if:  fully matched sibling donor available  patient has absolute lymphocyte count (ALC) <100/l  radiation dose unknown or likely to be 8-12 Gy  no other injuries preclude survival or transplantation (e.g. severe burns)  irradiation is not continuing from internal source

Module Medical XI. 62 Timing of grafting

 Timing is important - grafting in peak period of immunosuppression may reduce chance of graft rejection. Early marrow transplantation desirable, even in first week after exposure  Note importance of reliable clinical, biological and dosimetric findings to assess dose level and distribution in the body. Without reliable physical dosimetry and haematological parameters, allogenic bone marrow transplant unjustified

Module Medical XI. 63 Limitations of BMT

 Identification of histocompatible donors  HLA typing in lymphogenic patients  Need for additional immunosuppression  Risk of graft versus host disease (GvHD)

Module Medical XI. 64 BMT: Medical lessons learned from other radiological accidents  Chernobyl and Soreq experience shows BMT has limited role in treatment of victims of radiation accidents, benefits very few exposed individuals and might be considered only for those: receiving doses in the range of 8-12 Gy  uniformly distributed  without serious skin injuries  without severe internal contamination and conventional injuries

Module Medical XI. 65 Peripheral blood stem cell transplantation (PBSCT)

 Increasing evidence that PBSCT of cells mobilized by growth factors enables reliable, rapid, and durable autologous haematopoietic engraftment  Autologous mobilized (primed) PBSCT offered more rapid recovery of granulocytes and platelets than BMTs derived from normal, resting marrow  Cautious use of allogeneic PBSCT based on unknown toxicities from cytokine administration in donors and increased risk of GVHD from the large number of t-cells infused

Module Medical XI. 66 Combination of allo-BMT and allo-PBSCT

 Potential advantage of dual engraftment properties available in PBSC grafts 1. Mobilized peripheral blood cells contain large quantities of committed progenitors in addition to haematopoietic stem cells. These committed progenitors would provide for an earlier, although unsustained, phase of engraftment 2. More primitive stem cells contained in both PB and BM graft would then provide for later, durable, long-term reconstitution

Module Medical XI. 67 Criteria for choice of therapy-I

 Therapeutic recommendations: If lymphocyte count during first week 200- 500 cells/µL, spontaneous recovery possible Therapy: Isolation, antibiotics, supportive therapy including platelet infusion. Growth factors (cytokines) can be used

Module Medical XI. 68 Criteria for choice of therapy-II

If lymphocyte count in first week below 200 cells/µL, stem cells probably irreversibly damaged Therapy: Isolation, antibiotics, supportive therapy including platelet infusion. Additional growth factor therapy method of choice

Module Medical XI. 69 Criteria for choice of therapy-III

If the lymphocyte count in first week below 100 cells/µL, consider treatment with growth factors and BMT Observe HLA compatibility at allogenic BMT. This therapy may be recommended for patients exposed to WB radiation doses exceeding 9 Gy

Module Medical XI. 70 Therapeutic support for severely irradiated patient: gastrointestinal syndrome

 Nausea,vomiting and diarrhoea associated with prodromal effects of radiation exposure most likely related to neurohumoral factors. Nausea and vomiting can be prevented/ameliorated by new generation of 5-HT3-receptor antagonists such as ondansetron and granisetron  Diarrhoea associated with prodromal and subacute phases of gastrointestinal injury most likely affects gastrointestinal motility and transport. Anticholinergics, metamucil, amphogel, and loperamide can be used

Module Medical XI. 71 Therapeutic support for severely irradiated patient: gastrointestinal syndrome

Module Medical XI. 72 Gastrointestinal syndrome

 Generally, exposure to dose range 8-30 Gy -causes reproductive death of mucosal crypt stem cell  In spite of considerable medical advances in treatment of radiation injury, no patient with full-scale gastrointestinal syndrome has survived ! GI system and possibly lungs can limit survival probability, assuming patient survives bone marrow damage

Module Medical XI. 73 Review - I

 Acute radiation syndrome is a complex of acute injury manifestations occurring after extensive exposure to high dose of ionizing radiation  Phases of acute radiation syndrome: prodromal, latent, manifest illness, recovery  Different ranges of whole body doses produce different manifestations of injury  Dose ranges producing the most characteristic manifestations: haematological, gastrointestinal, cardiovascular /central nervous system syndromes

Module Medical XI. 74 Review P - II

 Radiation doses in cardiovascular/central nervous system syndrome range uniformly fatal regardless of therapy  Doses in gastrointestinal syndrome range, which also produce life-threatening pulmonary effects, usually fatal  Doses in the haematopoietic syndrome range are survivable. Therapeutic goal: lessen the severity of thrombocytopenia and neutropenia while minimizing and treating infection

Module Medical XI. 75 Review - III

 Cytokine therapy: powerful tool for treating patients with life threatening but survivable radiation injury  Consideration of peripheral stem cell transfusion and BMT should be reserved for patients with potentially survivable damage but whose bone marrow does not respond to cytokines

Module Medical XI. 76 Review - IV

 Because aggressive control of infectious agents necessary, use selective gut decontamination, prompt therapy of neutropenic fever, prophylactic antiviral and antifungal agents, and stringent nursing environmental control  Aggressive fluid, blood product, and symptomatic therapies are indicated

Module Medical XI. 77