Radiation Injury: Critical Care

1
Radiation Injury Critical Care
Acute radiation syndrome (ARS) is an acute
illness caused by irradiation of the whole body
(or a significant portion of it). In general, the
higher the dose the greater the severity of early
effects and the greater the possibility of late
effects. Depending on dose, the following
syndromes can manifest
2

• Skin syndrome, characterized by loss of epidermis
  and possibly dermis, called radiation burns
  can occur with other syndromes.
• Hematopoietic syndrome, characterized by
  deficiencies of white blood count, lymphocytes
  and platelets, immunodeficiency, increased
  infectious complications, bleeding, anemia, and
  impaired wound healing total body exposure gt 2
  Gy (200 rads).
• Gastrointestinal syndrome - characterized by loss
  of cells lining intestinal crypts and loss of
  mucosal barrier, with alterations in intestinal
  motility, fluid and electrolyte loss with
  vomiting and diarrhea, loss of normal intestinal
  bacteria, sepsis, and damage to the intestinal
  microcirculation gt10 Gy
• Cerebrovascular/CNS syndrome - primarily
  associated with effects on the vasculature and
  resultant fluid shifts. Signs include vomiting
  and diarrhea within minutes of exposure,
  confusion, disorientation, cerebral edema,
  hypotension, and hyperpyrexia. Fatal in short
  time gt30 Gy

3
Acute Radiation Syndrome
Exposure Less Than 2 Gy (200 rad)

• Nausea and vomiting due to radiation are seldom
  experienced unless exposure is at least 0.75 Gy.
  Patients without symptoms in 24 hours will most
  certainly have had less than 0.75 Gy of
  whole-body exposure. Hospitalization is generally
  unnecessary if exposure is less than 2 Gy
  (200 rads).
• Management of ARS (dose less than 2 Gy)
• Observation and frequent CBC with differential.
• Outpatient management may be appropriate.
• Provide instructions regarding home care.

4
Acute Radiation Syndrome Exposure
Greater than 2 Gy (200 rads)

• Prevention and treatment of infections.
• Stimulation of hematopoiesis (use of growth
  factors, i.e., GCSF, GMCSF, interleukin 11).
• Stem cell transfusions cord blood, peripheral
  blood, or bone marrow. Platelet transfusions if
  bleeding occurs or if platelet count too low.
• Psychological support.
• Observe carefully for erythema, hair loss, skin
  injury, mucositis, parotitis, weight loss, and/or
  FEVER.
• Consultation with experts in radiation accident
  management is encouraged.

5
Hematopoietic Syndrome

• Prodromal phase nausea, vomiting and anorexia
  within a few hours at the higher dose levels,
  lasts 24 to 48 hours
• Latent Phase lasts a few days to 2-3 weeks
  depending on dose. Exhibits lymphocyte
  depression, and gradual decline of neutrophil and
  platelet counts
• Bone Marrow Depression Phase Infection and
  hemorrhage can occur when white cell and platelet
  become critically low
• Depending on exposure, Hematopoietic support can
  become critical within several days to three
  weeks

6
Chernobyl A Harsh Lesson

• At Chernobyl, some victims received bone marrow
  that was HLA matched or partially matched.
  However, donor marrows were difficult to obtain
  in adequate numbers.
• After exposure to between 2 to 16 Gy, 28 of 34
  service personnel died of acute bone-marrow
  failure, GVHD, or gastro-intestinal infection.
• Human umbilical cord blood, now considered an
  excellent source of hematopoietic stem cells, was
  not used at Chernobyl.

7
Bone Marrow Transplantation practical
limitations and clinical hurdles

• Finding matched donors for numerous casualties on
  short notice
• Rejection of donor marrow by residual immune
  functions
• Graft Versus Host Disease (GVHD) transplanted
  cells attack the host
• Increased risk of infection through
  immunosuppression.

8
Cord Blood for Hematopoietic Syndrome Benefits

• Greater genetic diversity and availability
• Reduced need for HLA-matching
• Less prone to GVHD, or host rejection
• Reduced need for immunosuppression
• Extensive clincial experience (for hematopoietic
  restoration following radiation and/or chemo for
  cancer)
• Easy to collect, analyze, store, and use

9
Unique Points
Single units of cord blood engraft more more
slowly than bone marrow from an HLA-matched
bone marrow donor, however

• Cord bloods speed of engraftment and event-free
  success is directly related to the number of
  transplanted nucleated cells.
• Pooling unmatched units of cord blood increases
  densities of nucleated blood cells, primitive
  (Berashis) stem cells, CD34, CD117, and GPA
  cells, and increases mitotic activity
• Without raising risks of rejection, pooling
  unmatched cord blood substancially reduces
  reactivity of CB responder cells to fresh
  allogenic CB stimulator cells, likewise reducing
  CB responder cell reactivity to host stimulator
  cells (GVHD)
• In addition to offering replacement of
  hematopoietic systems destroyed by radiation,
  cord blood-derived hematopoietic cells co-exist
  with surviving marrow cells, encouraging
  endogenous hematopoietic recovery, while
  providing transitional support

10
Human evidence suggestive of the previous points
Four patients with advanced solid tumors were
treated by means of high-dose chemotherapy and
HLA-mismatched and unrelated multi-cord blood
transfusion. Of these patients, three achieved
complete remission and one achieved a partial
remission. Little or no graft vs. host disease
(GVHD) was observed. These results suggest the
possibility that HLA-mismatched and unrelated
multi-cord blood transfusion may engraft with
little or no GVHD and hasten recovery from marrow
suppression.
Shen B.-J. et.al., Blood Cells Volume 20,
Issue 2-3 , 1994, Pages 285-292
11
Cord Blood Treated Radiation Casualty Japanese
Tokaimura Facility
Although the transplanted cord blood cells
engrafted, the patients bone marrow functions
eventually returned two months later. During this
period, there existed a mixed chimerism between
donor cells and recipient cells.
From Radiation-Accident Preparedness The
Clinical Care of Victims, Fourth International
REAC/TS Conference on the Medical Basis for
Radiation Accident Preparedness, March 2001,
Orlando FL
12
Cord Blood vs. Bone Marrow

• 68 adult human study using single units of
  mismatched cord blood compared to HLA-matched
  bone marrow use

Cord Blood Bone Marrow
Engraftement success Acute severe GVHD Chronic
GVHD
90 92
20 35-55
38 55-75
M. J. Laughlin, M.D., et.al., Hematopoietic
Engraftment and Survival in Adult Recipients of
Umbilical Cord Blood from Unrelated Donors. New
England Journal of Medicine Volume 3441815-1822
June 14, 2001 Number 24
13
In Conclusion
In the event of large-scale exposure, some
persons are likely to be exposed to a dose of
total-body radiation (approximately 6 to 15 Gy)
that would result in death from bone marrow
failure without other life-threatening
complications. The only effective treatment for
bone marrow failure caused by lethal doses of
radiation is hematopoietic-cell transplantation.

Continued
14
Units of cryopreserved umbilical-cord blood
can be identified in registries and made
available for transplantation within days. When
umbilical-cord blood is used, less stringent HLA
matching is required. A bank of approximately
200,000 units could provide 90 percent of the
population with cord blood matched at four or
five of six HLA loci the type of matches most
commonly used in cord-blood transplantation.
Continued
15
Stephen J. Forman, M.D. Lawrence D. Petz, M.D.
Major Radiation Exposure, Letters
New England Journal of Medicine, Volume
347944-947 September 19, 2002 Number 12
Shortening the turnaround time for
searching donor registries, providing an
umbilical-cordblood bank of appropriate size,
and developing a consortium of transplantation
programs should be part of the plan for
national preparedness for radiological disaster.
16
Referenced Literature Ricks RC, Berger ME,
OHara FM Jr., Radiation-Accident Preparedness
The Clinical Care of Victims, Fourth
International REAC/TS Conference on the Medical
Basis for Radiation Accident Preparedness, March
2001, Orlando FL Rubinstein, et.al., Outcomes
among 562 Recipients of Placental-Blood
Transplants from unrelated donors. New England
Journal of Medicine, Vol. 339, Nov. 26th, 1998,
no.22 1565-77 Laughlin, et.al., Hematopoietic
Engraftment and survival in adult recipients of
umbilical cord blood from unrelated donors. New
England Journal of Medicine Volume 3441815-1822
June 14, 2001 Number 24 Ende, et.al., Potential
effectiveness of stored cord blood (non-frozen)
for emergency use. The Journal of Emergency
Medicine Vol 14, no.6, pp673-677 (1996) Ende,
et.al., Pooled umbilical cord blood as a possible
universal donor for marrow reconstitution and use
in nuclear accidents. Life Sciences 69 (2001)
1531-1539 Shen et.al., Unrelated, HLA-mismatched
multiple human umbilical cord blood transfusion
in four cases with advanced solid tumors Initial
studies. Blood Cells Volume 20, Issue 2-3 , 1994,
Pages 285-292
17
Ende et.al., The feasibility of using blood
bank-stored (4C) cord blood, unmatched for HLA
for marrow transplantation. Am J. Clin. Pathol.
(1999) 111 6 773-781. Gluckman, Hematopoietic
Stem-Cell Transplants using umbilical-cord blood,
The New England Journal of Medicine, Vol. 344,
No. 24 June 14, 2001, pg. 1860-61 Ende, et.al.,
Murine survival of lethal irradiation with the
use of human umbilical cord blood. Life Sci.
511249-1253. (1992) Ende, N. Use of human
umbilical cord blood for stem-cell
transplantation (HLA-matched, unmatched.
Clinical, ethical, and legal aspects). In
Hematopoietic Stem Cells. (1995) Edited by D.
Levitt and Mertelsmann. 333-347. Ende et.al., The
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clinical significance Immunological
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Accident Management Radiation Emergency
Assistance Center/Training Site REAC/TS