ACUTE RADIATION SYNDROME CLINICAL PICTURE, DIAGNOSIS AND

TREATMENT

NAME : Mohammad Nour AlsaeedGROUP : 3

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Introduction

ARS threat Discharged medical irradiatorsIndustrial radiography unitsCommercial irradiatorsTerrorist detonationNuclear fuel processingNuclear reactors

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

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Early deterministic effects

<0.1 Gy, whole body - No detectable difference in exposed vs non-exposed patients0.1-0.2 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

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Exposure levels at which healthy adults are affected

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  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).

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Factors decreasing LD50/60

Coexisting trauma combined injuryChronic nutritional deficitCoexisting infectionContribution of high LET radiation

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Phases of ARS

Initial or prodromal phase Latent phase Manifest illness phase Recovery phase

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Manifestations of ARS

Haematopoietic syndrome (HPS)

Gastrointestinal syndrome (GIS) Neurovascular syndrome (NVS)

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Haematopoietic syndrome

Normal bone marrow cells

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Survival potential

Bone marrow damaged by radiation injury

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Haematological response to 1 Gy, whole body exposure to ionizing radiation

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Haematological response to 3 Gy, whole body exposure

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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

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Gastrointestinal (GI) syndrome (8-30 Gy)

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

Pathophysiology of the GI Syndrome

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Phases of Gl syndrome

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

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Systemic effects of GI syndrome

MalabsorptionmalnutritionFluid and electrolyte shiftsdehydration, acute renal failure, cardiovascular collapse GI bleedinganaemiaSepsisParalytic ileusvomiting, abdominal distention

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Pulmonary effects

Irradiated lung tissue Pulmonary fibrosis

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At 30 Gy and above

Endothelial cell damage

Neurovascular syndrome (NVS)

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NVSprodromal perıod

Burning sensation within minutes of exposure

Nausea and vomiting within first hour Loss of balance, confusion with

prostration Hypotension, hyperpyrexia

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NVSlatent period

Apparent improvement lasting several hours–May be lucid and in

no pain but weak

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NVSovert clinical picture

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

Hypotension

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ARSNeurovascular Syndrome

SymptomsRadiationdose (Gy)

Life threateninginjuries

Death of patients

16202530

Loss of consciousness

Neurovascular damage

5-12 days

2-5 days

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Triage of injured persons (degrees )

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Measurement of severity

Prodromal effects Time of onset Degree of symptoms

Haematological changes Lymphocyte counts Biological dosimetry

Physical dosimetry Attendant readable

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Radiation dose under 5 Gy

No immediate life-threatening hazard exists

Prodromal symptoms of moderate severity Onset > 1 hour Duration < 24 hours

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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

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Triage categories of radiation injuries according to early

symptoms

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Guide for management of radiation injuries on the basis of early symptoms

No vomiting Vomiting 2-3 hafter exposure Vomiting 1-2 hafter exposure Vomiting earlier than 1 h, other severe symptoms, like hypotensionhyperthermia,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 

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Lymphocytes

3Gy

4-5Gy

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Change of lymphocyte counts in initial days of ARS depending on dose of

acute WB exposureDegree of

ARSDose (Gy)

Lymphocyte counts (cells/L)6 days after first exposure

Preclinical phaseMildModerateSevereVery severeLethal

0.1-1.01.0-2.02.0-4.04.0-6.06.0-8.0

>8.0

1500-2500700-1500500-800300-500100-300 0-50

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Granulocyte counts and dose relationship after irradiation

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Medical management of

acute radiation syndrome

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Therapeutic support for haematopoietic syndrome patientPrimary 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

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Infection managmentGeneral principles

Prophylaxis Barrier/isolation Gut decontamination Antiviral agents Antifungal agents Pneumocystis prophylaxis Early cytokine therapy Close wounds Avoid invasive procedures

Direct therapy for infections

Culture specific antibiotics

Therapy for leukopenia

Cytokine administration

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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

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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)

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Approach to prevent infection in immunocompromised patients

Suppression of micro-organismsSelective 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

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Approach to prevent infection in immunocompromised patients

Suppression of micro-organisms Physiological interventions

Maintenance of gastric acidityAvoidance of antiacids and H2 blokersUse 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)

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Approach to prevent infection in immunocompromised patients

Improvement of host defencesActive 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

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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

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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

Management of infection

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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 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

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Cytokines

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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)

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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

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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

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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

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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, and Belarus and Istanbul accidents

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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

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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

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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

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Contraindication for cytokine treatment

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

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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

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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

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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

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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

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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

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Bone marrowtransplantation (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

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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

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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

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Limitations of BMT

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

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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

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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

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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

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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

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Criteria for choice of therapy-III

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

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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

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Therapeutic support forseverely irradiated patient:gastrointestinal syndrome

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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

Gastrointestinal syndrome