ACUTE RADIATION SYNDROME CLINICAL PICTURE, DIAGNOSIS AND TREATMENT

1
ACUTE RADIATION SYNDROME CLINICAL PICTURE,
DIAGNOSIS AND TREATMENT
Module XI
2
Lecture organization

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

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

4
Early deterministic effects

• lt0.1 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
• gt0.12 Gy, whole body - Sperm count decreases to
  minimum about day 45
• 0.5 Gy, whole body - Detectable bone marrow
  depression with lymphopenia

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)
gt5.4
__________________________________________________
___________________ Source NCRP Report 98
"Guidance on Radiation Received in Space
Activities", NCRP, Bethesda (MD) (1989).
6
Factors decreasing LD50/60

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

7
Phases of ARS

• Initial or prodromal phase
• Latent phase
• Manifest illness phase
• Recovery phase

8
Manifestations of ARS

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

9
Haematopoietic syndrome
Normal bone marrow cells
10
Survival potential
Bone marrow damaged by radiation injury
11
Haematological response to 1 Gy, whole body
exposure to ionizing radiation
12
Haematological response to 3 Gy, whole body
exposure
13
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

14
Gastrointestinal (GI) syndrome (8-30 Gy)
Pathophysiology of the GI Syndrome

• 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
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

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

17
Pulmonary effects
Pulmonary fibrosis
Irradiated lung tissue
18
Neurovascular syndrome (NVS)

• At 30 Gy and above
• Endothelial cell damage

19
NVSprodromal period

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

20
NVSlatent period

• Apparent improvement lasting several hours
• May be lucid and in no pain but weak

21
NVSovert clinical picture

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

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
23
Triage of injured persons
24
Measurement of severity

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

25
Radiation dose under 5 Gy

• No immediate life-threatening hazard exists
• Prodromal symptoms of moderate severity
• Onset gt 1 hour
• Duration lt 24 hours

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

27
Triage categories of radiation injuries
according to early symptoms
28
Guide for management of radiation injuries on
the basis of early symptoms
29
Lymphocytes
3Gy
4-5Gy
30
Change of lymphocyte counts in initial days of
ARS depending on dose of acute WB exposure
31
Granulocyte counts and dose relationship after
irradiation
32
Medical management of acute radiation syndrome
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) lt
  100/?L is greatest risk factor

34
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

35
Isolation

• Treat ARS patients with estimated WB gt2Gy 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

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)

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

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)

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

40
Management of infection

• Survey for possible source, pancultures
• Administer antibiotics for absolute neutrophil
  count (ANC) lt500/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 lt1000

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

42
Total parenteral nutrition vs enteral feeding
Premise for early enteral feeding
43
Comparison of enteral and parenteral nutrition
results
44
Cytokines
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 (IL 1-16)

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

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

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

49
G-CSF at 3.5 Gy (canine experiment)
50
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

51
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

52
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

53
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

54
Contraindication for cytokine treatment

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

55
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

56
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

57
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

58
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

59
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

60
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

61
Effect of shielding, dose inhomogenity and
GM-CSF on bone marrow recovery
62
Indications for BMT

• Physicians should consider allo-BMT if
• fully matched sibling donor available
• patient has absolute lymphocyte count
  (ALC) lt100/?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

63
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

64
Limitations of BMT

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

65
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

66
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

67
Combination of allo-BMT and allo-PBSCT

• Potential advantage of dual engraftment
  properties available in PBSC grafts
• 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
• More primitive stem cells contained in both PB
  and BM graft would then provide for later,
  durable, long-term reconstitution

68
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

69
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
70
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
71
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

72
Therapeutic support for severely irradiated
patient gastrointestinal syndrome
73
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

74
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

75
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

76
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

77
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