Hyperbaric Oxygen Therapy for Radiation Injuries

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Hyperbaric Oxygen Therapy for Radiation Injuries
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HBO What is it?

• 100 oxygen is administered to a patient at
  higher then normal atmospheric pressue.
• 2 -2.5 ATA is typical
• Treatments average approximately 2 hours.

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Domicilium1662
Henshaw, British clergyman built a sealed chamber
called a Domicilium. (O2 discovered 1775).
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Fontaines mobile operating room 1879
French surgeon named J.A. Fontaine built a
pressurized mobile operating room.
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Cunninghams chamber in 1921
Orville J. Cunningham, a professor at the
University of Kansas built a chamber that was 10
feet in diameter and 88 feet in length
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Steel Ball Hospital 1928

• .

However, one patient that Cunningham treated, Mr
Timkin of the Timkin Rollerbearing Company, felt
that the time he spent in Cunningham's chamber
cured his uremia. In 1928 as a show of gratitude,
Timkin built a steel sphere, which was 6 stories
tall, and 64 feet in diameter, the largest
hyperbaric chamber ever built. Cunningham used
this hospital, located in Cleveland, to treat
patients with a number of ailments. It was well
appointed, with dining rooms, private patient
rooms, plush carpets, and even a smoking room on
the top floor! Without any scientific rationale
for his work, he was forced to close down by the
AMA and the Cleveland Medical Society in 1930,
and the steel ball hospital was cut up for scrap
during World War II. This essentially ended the
era of compressed-air hyperbaric therapy
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Today
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Today
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Today
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UHMS INDICATIONS

• 1. Air or Gas Embolism.
• 2. Carbon Monoxide Poisoning/Cyanide Poisoning.
• 3. Clostridial Myositis and Myonecrosis (Gas
  Gangrene).
• 4. Crush Injury, Compartment Syndrome and other
  Acute Traumatic
• Ischemias.
• 5. Decompression Sickness.
• 6. Arterial Insufficiencies Enhancement of
  Healing in Selected Problem
• Wounds and Central Retinal Artery Occlusion.
• 7. Severe Anemia.
• 8. Intracranial Abscess.
• 9. Necrotizing Soft Tissue Infections.
• 10. Osteomyelitis (Refractory).
• 11. Delayed Radiation Injury (Soft Tissue and
  Bony Necrosis).
• 12. Compromised Grafts and Flaps.
• 13. Acute Thermal Burn Injury.
• 14. Idiopathic Sudden Sensorineural Hearing Loss.

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Definition Radiation Tissue Injuries

• Radiation injuries can be divided into two
  categories on a time basis
• Acute injuries are those that present shortly
  after irradiationgenerally within weeks1
• Osteoradionecrosis and soft tissue radionecrosis
  are those conditions that present several months
  or even years after irradiation.1,2

1Feldmeier JJ. Undersea Hyperbaric Med
200431133-45. 2Pasquier D, Hoelscher T, Schmutz
J, et al. Radiother Oncol 2004721-13.
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Radiation Dosing
Rads Grays
1 rad 1 centi Gray (cGy)
The effect causes damage to the DNA, lipids, and
proteins
Causes cell dysfunction and death
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Incidence of ORN and STRN

• The incidence of osteoradionecrosis (ORN) and
  soft tissue radionecrosis (STRN) is not known
  with any certainty
• In the U.S., approximately 1.5 million new cancer
  cases are diagnosed every year1
• Data suggest that 750,000 patients with cancer
  receive radiotherapy every year, and if
  two-thirds are long-term survivors and 10 of
  these patients experience ORN or STRN in their
  lifetime,2,3 this would be about 50,000
  individuals per year (0.017 of U.S. population)
• Another way of looking at the statistics More
  than 200,000 patients receive abdominal or pelvic
  radiation therapy each year, and there are
  approximately 1.7 million survivors of this
  treatment who have or have had intestinal
  dysfunction as a result of STRN.4

1Jemal A, Siegel R, Ward E, et al. CA Cancer J
Clin 200959225-49. 2Feldmeier JJ, Hampson NB.
Undersea Hyperb Med 2002294-30. 3Rubin P,
Casarrett GW. Clinical Radiation Pathology. Vol
1. Philadelphia WB Saunders, 196858-61. 4Hauer-J
ensen M, Wang J, Boerma M, et al. Curr Opin
Support Palliat Care 2007123-9.
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ORN/STRN Tissue Injury Sites
Where can ORN or STRN occur? Any tissue that has
been irradiated!

• Jaw (osteoradionecrosis inadequate bone repair)1
• Neck area (e.g., chondroradionecrosis of the
  larynx)2
• Chest wall radionecrosis (result of treatment for
  breast, lung, or esophageal cancers)1
• Hemorrhagic radiation-induced cystitis1
• Chronic radiation-induced proctitis/enteritis1
• Spinal cord, brain, optic nerve, brachial plexus
  (myelitis or radiation-induced necrosis/injury).1

1Feldmeier JJ. Undersea Hyperbaric Med
200431133-45. 2Hunter SE, Scher RL. Curr Opin
Otolaryngol Head Neck Surg 200311103-6.
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Risk Factors for ORN/STRN
Radiation dose1
Location and size of original tumor1

• Risk Factors

Infection in irradiated area1
Trauma or surgery in irradiated area1
Prior ischemia (local hypoxia)3

• Immunodeficiency1
• Diabetes
• Steroids
• Immune suppression

Patient age2
1Chrcanovic BR, Reher P, Sousa AA, et al. Oral
Maxillofac Surg 2010143-16. 2Lye KW, Wee J, Gao
F, et al. Int J Oral Maxillofac Surg 2007
36315-20. 3Hoffman KE, Horowitz NS, Russell AH.
Gynecol Oncol 2007106262-4.
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Tissue Oxygen Levels Needed for Healing
Tissues require oxygen to survive We can measure
tissue oxygenation levels with a TcPo2 A
minimum of 20 mmhg partial pressure of oxygen is
required for cells that aide in wound healing
(fibroblast proliferation and collagen
production) to function Levels are far below
this 20 mmhg in tissue that has received radiation
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• HBO stimulates collagen synthesis, vascular
  networking, metabolism of bone, and may increase
  stem cells.

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In normal tissue in normobaric (room air or 1
ata) conditions, the tension of oxygen in the
tissues is only 30 microns away from the
damaged capillary wall

• 1.0 ATA Air

5 10 15 20 35 40 55
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In hyperbaric conditions, the oxygen tension in
the tissues can be up to 280 microns away
allowing for a rich collagen matrix to form

• HBO - 2.5 ATA

50 50 90 120-350 350
Capillary buds invade and form a new vascular
network (angiogenesis)-- Oxygen tension returns
to normal. Wounds can HEAL!
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Typically after 20 treatments, the new vascular
network is laid.

• Plateau Phase

280 300 320 350
Increased oxygen tension allows cells to function
normally and aide in healing
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General Causes of ORN/STRN

• ORN or STRN actually begins when radiation is
  first given1
• Levels of pro-inflammatory cytokines rise (e.g.,
  IL-1, IL-6, TNF-alpha)
• In some cases, the levels of cytokines associated
  with inflammatory actions stay elevated leading
  to further injury
• The levels of these same cytokines may subside
  but the cytokines may be affected later by
  another surgery, trauma, or infection years
  later.
• Radiation causes the lining of small blood
  vessels to become inflamed and then occluded,
  leading to tissue ischemia2
• Some researchers postulate increased thrombin
  levels and vascular permeability with subsequent
  fibrin and collagen deposition between cells.
  Fibrosis, dysfunction, and even obliteration of
  the local vasculature (especially capillaries)
  then follow.3

1Brush J, Lipnick SL, Phillips T, et al. Semin
Radiat Oncol 200717121-30. 2American College of
Hyperbaric Medicine. Osteoradionecrosis.
2010. 3Wang J, Boerma M, Fu Q, et al. World J
Gastroenterol 2007133047-55.
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Pattern of Injury to Tissues
Tumor - treated as a mass of cells
A boost dose of radiation is given to the center
of this mass of cells
The further away from the center of that mass,
the less the dose of radiation
Additional injury can occur to tissues around the
mass of cells (called a diffusion injury)
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Radiation Effects
Radiation effect on tissues
(highest effect to lowest)
Tumor
Endothelium
Fibroblasts
Muscle
Nerve
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RADIATION
Continues to cause damage to tissues even after
therapy stops
Basically obliterates the vessels
Destroys the blood supply to the tissues
Leaves tissue hypoxic and very fibrotic (hard,
woody tissue)
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Radiation Effects
Early (acute) Effects to the skin
Redness (erythema)
Changes in the pigment of the skin
Hair loss
Skin erosion
Supportive care
Antibiotics if skin tissues become infected
(cellulitis)
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Radiation Effects
Delayed Effects of Radiation
Typically seen after 6 months and up to years
later
Endarteritis (inflammation of the lining of the
artery is what causes the problem)
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Radiation Effects
It is difficult to provide adequate nutrients
oxygen to tissues without a good blood supply.
This leads to delayed healing.
There is no satisfactory treatment of radiation
necrosis using conventional therapies. HBO is the
only intervention that has shown to increase the
number of blood vessels in irradiated tissue.
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Radiation Effects to Bone
Bone is 1.8 x more denes than soft tissues so it
absorbs more of the radiation energy
Radiation affects both the vascular cellular
components of bone.
Mandible (jaw) is very susceptible greater bone
density lower vascularity
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Blood flow in bone that has NOT received radiation
Granstrom G 1993 XIXth Annual EUBS Meeting
ml/mg x 100g tissue
14
12
10
8
6
4
2
0
Frontal Zygoma Maxilla
Mandible
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Blood flow in bone that HAS received radiation
Granstrom G 1993 XIXth Annual EUBS Meeting
ml/mg x 100g tissue
14
12
10
8
6
4
2
0
Frontal Zygoma Maxilla Mandible
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Osteoradionecrosis vs Time
Clinical Damage
Clinical Threshold
Acute
Surgical Trauma
Mechanical Trauma
Nutrition Infection
Subclinical Damage
Recovery
Years
Rubin P, Casarett GW 1968
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OSTEORADIONECROSIS of the mandible (ORN)

• Incidence 0 below 6,000 cGy,1.8 6,000-7,000
  cGy, and 9 gt7,000 cGy.
• Pathophysiology hypoxia, hypovascularity, and
  hypocellularity.
• Marx Protocol prophylaxis, stages 1-111R all at
  2.5 ATA for 90 minutes.
• Evidence 1975-2001(14 case series using HBO and
  surgery) 13/14 found benefit and 86 patients
  improved.
• Cost saving in 2006 168,000 without HBO and
  53,000 with HBO.
• Feldmeier JJ, Hampson NB Undersea Hyperbaric
  Med 2002, Marx RE, 1999 www.westegg.com/inflation.
  

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MARX PROTOCOL2.
Osteoradionecrosis is defined as the presence of
exposed bone without healing. Marx creating
staging according to wound healing treatment and
hyperbaric oxygen response. Stage I (A)
Chronically exposed bone or rapidly progressive
ORN without any serious manifestations found in
stage III. 30 HBO presurgical treatments followed
by minor bony debridement followed by 10 HBO
postsurgical treatments.
1Marx RE. J Oral Maxillofac Surg
. 198341352-7. 2American College of Hyperbaric
Medicine. Osteoradionecrosis. 2010
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MARX PROTOCOL2.
Stage II If patients are not progressing
appropriately at 30 HBO at Stage I or if they are
needing more major debridement, they are advanced
to this stage and receive a more radical surgical
debridement in the OR followed by 10
post-surgical HBO treatments. Surgery must
maintain mandibular continuity. If mandibular
resection is required they are advanced to Stage
III.

• 1Marx RE. J Oral Maxillofac Surg .
• 198341352-7.
• 2American College of Hyperbaric Medicine.
  Osteoradionecrosis. 2010

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MARX PROTOCOL2.
In addition to those failing treatment in Stage I
and II, grave prognostic signs such as pathologic
fracture, orocutaneous fistulae or lytic
involvement extending to the inferior mandibular
border. Mandibular resection is part of the
treatment plan. Patients receive 30 HBO
pre-surgical treatments and 10 HBO post-surgical
treatments.

• 1Marx RE. J Oral Maxillofac Surg .
• 198341352-7.
• 2American College of Hyperbaric Medicine.
  Osteoradionecrosis. 2010

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Prevention of Osteoradionecrosis
Timing of preoperative HBO therapy is not
critical
Delays of up to one year between HBO surgery
have not compromised results
O
2
- Marx 1991
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National Cancer Institute Monographs 1990 No 9

• "Osteoradionecrosis is best managed
• with hyperbaric oxygen alone, or in
• conjunction with surgery"

0
2
in high-risk patients, pre-extractionhyperbaric
oxygen should be considered
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HBO and ORN

• There have been 22 studies published that show
  hyperbarics is useful either alone or as an
  adjunctive therapy
• Improvement has been show in 78 of these cases
  Hyperbarics has also shown to be useful in
  preventing or reducing complications if done
  prior to surgical intervention

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Conventional Treatment of ORN

• Nutritional support is essential as many patients
  become nutritionally deficient1
• Antibiotics where infection is suspected1
• Debridement to remove sequestra where identified2
• Microvascular free tissue transfer for stage III
  patients and jaw resection as necessary.2
• There have been reports of treating stage I
  patients with pentoxifylline (to improve blood
  flow), bisphosphonates, and vitamin E, but
  success to date must be regarded as preliminary.3

1Blanchaert Jr RH, Harris CM. eMedicine
2010. 1Hao SP, Chen HC, Wei FC, et al.
Laryngoscope 19991091324-8. 3Delanian S,
Depondt J, Lefaix JL. Head Neck 200527114-23.
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Complications of Surgery in Irradiated Tissue

DEHISCENCE
38 (48) 4 (11)
Control
HBO
INFECTION
Total
19 (24) 5 ( 6)
Control
HBO
DELAYED HEALING
44 (55) 9 (11)
Control
HBO
Marx RE 1993
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RADIATION INJURY
Soft Tissue Radionecrosis
Radiation Cystitis
Radiation Proctitis
Laryngeal Radionecrosis
Chest Wall Radionecrosis
Abdominal and Pelvic Radionecrosis Radiation
injuries of the extremities Neurologic Injuries
Secondary to Radiation
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Indication of HBO Delayed Radiation Injuries

• RADIATION CYSTITIS
• Symptoms include - hematuria, nocturia, frequency
  and or urgency.
• 18/20 published reports showed significant
  improvement or resolution in 76.
• Undersea and Hyperbaric Board Review course for
  physicians Penn Medicine Aug 2010.

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Indication of HBODelayed Radiation Injuries

• RADIATION PROCTITIS
• Symptoms include rectal bleeding/pain,
  diarrhea, and tenesmus.
• Combined results from trials including a total of
  199 cases complete resolution in 41 and 86
  had at least partial response.
• Clark RE et al. Hyperbaric oxygen treatment of
  chronic refractory radiation proctitis a
  randomized and controlled double-blind crossover
  trial with long-term follow-up. Int. Journal
  Radiation Oncology /Biology Phys 2008.
• Undersea and Hyperbaric Board Review course for
  Physicians. Penn Medicine. August 2010.

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Laryngeal Necrosis

• Uncommon complication of radiation therapy for
  patients with head and neck cancer usually lt1.
• Often present with persistent edema, fetid
  breath, and or visible necrosis.
• Chandler grade 1-4 (1 and 2 usually resolve).
• 5 published reports out of 43 patients, only 6
  failed and required a laryngectomy, the other 37
  maintained their voice box and good voice quality
  with HBO.
• Hyperbaric Oxygen Therapy Indications. 12th
  edition.

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RADIATION INJURIES
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ONCERNS

Does HBO cause cancer or make cancer worse?
Extensive review of clinical and animal studies
showed no enhancement of cancer
growth. Hyperbaric Oxygen Therapy Indications
12th edition.

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Summary
HBO for the late effects of radiation is
supported by Prospective Randomized Trials
Deemed to be a Standard of Care by the National
Cancer Institute
The weight of current evidence favors use of HBO
Demonstrated financial effectiveness
No proven alternative therapies
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REFERENCES

• G, LB. HYPERBARIC OXYGEN THERAPY INDICATIONS.
  12TH EDITION.
• KINDWALL, EP., WHELAN, HT. HYPERBARIC MEDICINE
  PRACTICE. 3RD EDITION.
• HEALOGICS WOUND CARE CENTERS.

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