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ACUTE RADIATION SYNDROME CL I N I CAL PI CTURE , DI AGNOS I S AND T REATMENT

ACUTE RADIATION SYNDROME CL I N I CAL PI CTURE , DI AGNOS I S AND T REATMENT. Module XI. Lecture o rganization. Introduction ARS m anifestations H aematological s yndrome Gastrointestinal s yndrome Neuro v ascular s yndrome Triage of i njured p ersons Medical m anagement

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ACUTE RADIATION SYNDROME CL I N I CAL PI CTURE , DI AGNOS I S AND T REATMENT

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  1. ACUTE RADIATION SYNDROME CLINICALPICTURE, DIAGNOSIS AND TREATMENT Module XI

  2. Lecture organization • Introduction • ARS manifestations • Haematological syndrome • Gastrointestinal syndrome • Neurovascular syndrome • Triage of injured persons • Medical management • Summary Module Medical XI.

  3. 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.

  4. 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.

  5. 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.

  6. Factors decreasingLD50/60 • Coexisting trauma combined injury • Chronic nutritional deficit • Coexisting infection • Contribution of high LET radiation Module Medical XI.

  7. Phases of ARS • Initial or prodromal phase • Latent phase • Manifest illness phase • Recovery phase Module Medical XI.

  8. Manifestations of ARS Haematopoietic syndrome(HPS) Gastrointestinal syndrome(GIS) Neurovascular syndrome (NVS) Module Medical XI.

  9. Haematopoietic syndrome Normal bone marrow cells Module Medical XI.

  10. Survival potential Bone marrow damaged by radiation injury Module Medical XI.

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

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

  13. Phases of haematopoietic syndrome (HPS) • Prodromal phasesymptoms nausea and vomitinglasts 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.

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

  15. 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.

  16. 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.

  17. Pulmonaryeffects Pulmonary fibrosis Irradiated lung tissue Module Medical XI.

  18. Neurovascular syndrome (NVS) • At 30 Gy and above • Endothelial cell damage Module Medical XI.

  19. NVSprodromal perıod • Burning sensation within minutes of exposure • Nausea and vomiting within first hour • Loss of balance, confusion with prostration • Hypotension, hyperpyrexia Module Medical XI.

  20. NVSlatent period • Apparent improvement lasting several hours • May be lucid and in no pain but weak Module Medical XI.

  21. NVSovert clinical picture • Rapid onset • Watery diarrhoea • Respiratory distress • Gross CNS signs • Wide pulse pressure • Hypotension Module Medical XI.

  22. ARSNeurovascular Syndrome Death of patients Life threatening injuries Symptoms Radiation dose (Gy) 16 20 25 30 Loss of consciousness 5-12 days 2-5 days Neurovascular damage Module Medical XI.

  23. Trıage of ınjured persons Module Medical XI.

  24. Measurement of severity • Prodromal effects • Time of onset • Degree of symptoms • Haematological changes • Lymphocyte counts • Biological dosimetry • Physical dosimetry • Attendant readable Module Medical XI.

  25. 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.

  26. 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.

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

  28. No vomiting Vomiting 2-3 h after exposure Vomiting 1-2 h after exposure  Vomiting earlier than 1 h, other severe symptoms, like hypotension hyperthermia, diarrhoea, oedema, erythema, CNS symptoms < 1 Gy 1-2 Gy 2-4 Gy  > 4 Gy Outpatient with 5-week surveillance Surveillance in a general hospital (or outpatient for 3 weeks) followed by hospitalization  Hospitalization in a haematological department  Hospitalization in a well equipped haematological or surgical department with transfer to a specialized centre for radiopathology Guide for management of radiation injuries on the basis of early symptoms Module Medical XI.

  29. Lymphocytes 3Gy 4-5Gy Module Medical XI.

  30. Degree of ARS Dose (Gy) Lymphocyte counts (cells/L) 6 days after first exposure Preclinical phase Mild Moderate Severe Very severe Lethal 0.1-1.0 1.0-2.0 2.0-4.0 4.0-6.0 6.0-8.0 >8.0 1500-2500 700-1500 500-800 300-500 100-300 0-50 Change of lymphocyte counts in initial days of ARS depending on dose of acute WB exposure Module Medical XI.

  31. Granulocyte counts and dose relationshipafterirradiation Module Medical XI.

  32. Medical management of acute radiation syndrome Module Medical XI.

  33. 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.

  34. Infection managmentGeneral principles • Direct therapy for infections • Culturespecific antibiotics • Therapy for leukopenia • Cytokine administration • Prophylaxis • Barrier/isolation • Gut decontamination • Antiviral agents • Antifungal agents • Pneumocystis prophylaxis • Early cytokine therapy • Close wounds • Avoid invasive procedures Module Medical XI.

  35. Isolation Treat ARS patients with estimated WB >2Gy in isolated rooms. Warnnursing 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.

  36. 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.

  37. 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.

  38. 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.

  39. 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.

  40. Management of infection • Survey for possible source, pancultures • Administer antibiotics for absolute neutrophil count (ANC) <500/mm3 • Use broad spectrum antibiotic coverage • Add amphotericinfor prolonged fever lasting 5-7 days after starting standard antibiotics • Continue antibiotics for duration of ANC <1000 Module Medical XI.

  41. 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.

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

  43. Comparison of enteral and parenteral nutrition results Module Medical XI.

  44. Cytokines Module Medical XI.

  45. 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 (IL1-16) Module Medical XI.

  46. 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.

  47. 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.

  48. Results of cytokine therapyGM-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.

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

  50. Use of cytokines for treatment of ARS • G-CSFand 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 Istanbulaccidents Module Medical XI.

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