Hyperbaric Oxygen Therapy for Radiation Injuries

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.

DomiciliumDomicilium16621662

Henshaw, British clergyman built a sealed chamber called a Domicilium. (O2 discovered 1775).Henshaw, British clergyman built a sealed chamber called a Domicilium. (O2 discovered 1775).

Fontaine’s mobile operating Fontaine’s mobile operating room 1879room 1879

French surgeon named J.A. Fontaine built a pressurized mobile operating room.French surgeon named J.A. Fontaine built a pressurized mobile operating room.

Cunningham’s chamber in 1921Cunningham’s 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 lengthOrville J. Cunningham, a professor at the University of Kansas built a chamber that was 10 feet in diameter and 88 feet in length

Steel Ball Hospital 1928Steel Ball Hospital 1928

• ..

However, one patient that Cunningham treated, Mr Timkin of the Timkin Rollerbearing Company, felt that the time he 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 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, 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 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, 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 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 therapycut up for scrap during World War II. This essentially ended the era of compressed-air hyperbaric therapy

TodayToday

TodayToday

TodayToday

UHMS INDICATIONSUHMS INDICATIONS• 1. Air or Gas Embolism.1. Air or Gas Embolism.• 2. Carbon Monoxide Poisoning/Cyanide Poisoning.2. Carbon Monoxide Poisoning/Cyanide Poisoning.• 3. Clostridial Myositis and Myonecrosis (Gas Gangrene).3. Clostridial Myositis and Myonecrosis (Gas Gangrene).• 4. Crush Injury, Compartment Syndrome and other Acute Traumatic 4. Crush Injury, Compartment Syndrome and other Acute Traumatic

Ischemia’s.Ischemia’s.• 5. Decompression Sickness.5. Decompression Sickness.• 6. Arterial Insufficiencies – Enhancement of Healing in Selected Problem6. Arterial Insufficiencies – Enhancement of Healing in Selected Problem• Wounds and Central Retinal Artery Occlusion.Wounds and Central Retinal Artery Occlusion.• 7. Severe Anemia.7. Severe Anemia.• 8. Intracranial Abscess.8. Intracranial Abscess.• 9. Necrotizing Soft Tissue Infections.9. Necrotizing Soft Tissue Infections.• 10. Osteomyelitis (Refractory).10. Osteomyelitis (Refractory).• 11. Delayed Radiation Injury (Soft Tissue and Bony Necrosis).11. Delayed Radiation Injury (Soft Tissue and Bony Necrosis).• 12. Compromised Grafts and Flaps.12. Compromised Grafts and Flaps.• 13. Acute Thermal Burn Injury.13. Acute Thermal Burn Injury.• 14. Idiopathic Sudden Sensorineural Hearing Loss.14. Idiopathic Sudden Sensorineural Hearing Loss.

• Radiation injuries can be divided into two categories on a time basis:– Acute injuries are those that present shortly

after irradiation—generally within weeks1

– Osteoradionecrosis and soft tissue radionecrosis are those conditions that present several months or even years after irradiation.1,2

Definition: Radiation Tissue Injuries

1Feldmeier JJ. Undersea Hyperbaric Med 2004;31:133-45.2Pasquier D, Hoelscher T, Schmutz J, et al. Radiother Oncol 2004;72:1-13.

1 rad = 1 centi Gray (cGy)

The effect causes damage to the DNA, lipids, and proteins

Causes cell dysfunction and death

Rads & Grays

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 2009;59:225-49. 2Feldmeier JJ, Hampson NB. Undersea Hyperb Med 2002;29:4-30.3Rubin P, Casarrett GW. Clinical Radiation Pathology. Vol 1. Philadelphia: WB Saunders, 1968:58-61.4Hauer-Jensen M, Wang J, Boerma M, et al. Curr Opin Support Palliat Care 2007;1:23-9.

ORN/STRN Tissue Injury Sites

• 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

Where can ORN or STRN occur?Any tissue that has been irradiated!

1Feldmeier JJ. Undersea Hyperbaric Med 2004;31:133-45.2Hunter SE, Scher RL. Curr Opin Otolaryngol Head Neck Surg 2003;11:103-6.

Risk Factors for ORN/STRN

Risk Factors

Radiation dose1

Trauma or surgery in

irradiated area1

Patient age2

Immunodeficiency1

•Diabetes•Steroids•Immune suppression

Prior ischemia(local hypoxia)3

Infection in irradiated area1

Location and size of original tumor1

1Chrcanovic BR, Reher P, Sousa AA, et al. Oral Maxillofac Surg 2010;14:3-16.2Lye KW, Wee J, Gao F, et al. Int J Oral Maxillofac Surg 2007 36:315-20.3Hoffman KE, Horowitz NS, Russell AH. Gynecol Oncol 2007;106:262-4.

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

HBO stimulates collagen HBO stimulates collagen synthesis, vascular synthesis, vascular networking, metabolism of networking, metabolism of bone, and may increase bone, and may increase stem cells.stem cells.

1.0 ATA Air

5 10 15 20 35 40 55

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

HBO - 2.5 ATA

50 50 90 120-350 350

In hyperbaric conditions, the oxygen tension in the tissues can be up to 280 microns away allowing

for a rich collagen matrix to form

Capillary buds invade and form a new vascular

network (angiogenesis)-- Oxygen tension

returns to normal. Wounds

can HEAL!

Plateau Phase

280 300 320 350

Typically after 20 treatments, the new vascular network is

laid.

Increased oxygen tension allows cells to

function normally and

aide in healing

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 2007;17:121-30.2American College of Hyperbaric Medicine. Osteoradionecrosis. 2010.3Wang J, Boerma M, Fu Q, et al. World J Gastroenterol 2007;13:3047-55.

Tumor - treated as a mass of cells

Additional injury can occur to tissues around the mass of cells (called a “diffusion injury”)

The further away from the center of that mass, the less the dose of radiation

A boost dose of radiation is given to the center of this mass of cells

Radiation effect on tissues (highest effect to lowest)

Tumor

Endothelium

Muscle

Nerve

Fibroblasts

Basically obliterates the vesselsDestroys the blood supply to the tissues

Continues to cause damage to tissues even after therapy stops

Leaves tissue hypoxic and very fibrotic (hard, woody tissue)

Redness (erythema)Changes in the pigment of the skinHair loss

Skin erosion

Early (acute) Effects to the skin

Supportive care

Antibiotics if skin tissues become infected (cellulitis)

Typically seen after 6 months and up to years later

Endarteritis (inflammation of the lining of the artery is what causes the problem)

Delayed Effects of Radiation

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.

It is difficult to provide adequate nutrients & oxygen to tissues without a good blood supply. This leads to delayed healing.

Bone is 1.8 x more denes than soft tissues so it absorbs more of the radiation energy

Mandible (jaw) is very susceptible– greater bone density & lower vascularity

Radiation affects both the vascular & cellular components of bone.

Blood flow in bone that has NOT received radiationGranstrom G 1993 XIXth Annual EUBS Meeting Granstrom G 1993 XIXth Annual EUBS Meeting

Frontal Zygoma Maxilla Mandible

14

12

10

8

6

4

2

0

ml/mg x 100g tissue

Frontal Zygoma Maxilla Mandible

14

12

10

8

6

4

2

0

ml/mg x 100g tissue

Blood flow in bone that HAS received radiationGranstrom G 1993 XIXth Annual EUBS Meeting Granstrom G 1993 XIXth Annual EUBS Meeting

Rubin P, Casarett GW 1968Rubin P, Casarett GW 1968

ClinicalThreshold

SubclinicalDamage

Recovery

Years

Clinical DamageAcute Surgical

TraumaMechanical Trauma

Nutrition Infection

OSTEORADIONECROSIS of the mandible OSTEORADIONECROSIS of the mandible (ORN)(ORN)

• Incidence 0% below 6,000 cGy,1.8% 6,000-7,000 cGy, and 9% Incidence 0% below 6,000 cGy,1.8% 6,000-7,000 cGy, and 9% >7,000 cGy.>7,000 cGy.

• Pathophysiology – hypoxia, hypovascularity, and hypocellularity.Pathophysiology – hypoxia, hypovascularity, and hypocellularity.• Marx Protocol – prophylaxis, stages 1-111R all at 2.5 ATA for 90 Marx Protocol – prophylaxis, stages 1-111R all at 2.5 ATA for 90

minutes.minutes.• Evidence – 1975-2001(14 case series using HBO and surgery) – Evidence – 1975-2001(14 case series using HBO and surgery) –

13/14 found benefit and 86% patients improved.13/14 found benefit and 86% patients improved.

• Cost saving in 2006 – $168,000 without HBO and $53,000 with Cost saving in 2006 – $168,000 without HBO and $53,000 with

HBOHBO. . • Feldmeier JJ, Hampson NB: Undersea Hyperbaric Med 2002, Marx RE, 1999 www.westegg.com/inflation.Feldmeier JJ, Hampson NB: Undersea Hyperbaric Med 2002, Marx RE, 1999 www.westegg.com/inflation.

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 .1983;41:352-7.2American College of Hyperbaric Medicine. Osteoradionecrosis. 2010

MARX PROTOCOL2.

– 1Marx RE. J Oral Maxillofac Surg .

– 1983;41:352-7.

– 2American College of Hyperbaric Medicine. Osteoradionecrosis. 2010

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.

MARX PROTOCOL2.

– 1Marx RE. J Oral Maxillofac Surg .– 1983;41:352-7.– 2American College of Hyperbaric Medicine. Osteoradionecrosis. 2010

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.

Timing of preoperative HBO therapy is not critical “Delays of up to one year between HBO & surgery have not compromised results”

- Marx 1991

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

conjunction with surgery"

…in high-risk patients, pre-extractionhyperbaric oxygen should be considered

National Cancer Institute Monographs 1990: No 9

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

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 1999;109:1324-8.3Delanian S, Depondt J, Lefaix JL. Head Neck 2005;27:114-23.

38 (48%)

4 (11%)

19 (24%)

5 ( 6%)

44 (55%)

9 (11%) Marx RE 1993

Control

HBO

DEHISCENCE

TotalINFECTION

Control

HBO

DELAYED HEALING

Control

HBO

Complications of Surgery in Irradiated Tissue

Soft Tissue RadionecrosisRadiation Cystitis

Radiation Proctitis

Abdominal and Pelvic Radionecrosis

Radiation injuries of the extremities

Neurologic Injuries Secondary to Radiation

Laryngeal Radionecrosis

Chest Wall Radionecrosis

Indication of HBO Indication of HBO Delayed Radiation InjuriesDelayed Radiation Injuries

RADIATION CYSTITISRADIATION CYSTITIS• Symptoms include - hematuria, nocturia, Symptoms include - hematuria, nocturia,

frequency and or urgency.frequency and or urgency.• 18/20 published reports showed significant 18/20 published reports showed significant

improvement or resolution in 76%.improvement or resolution in 76%.

Undersea and Hyperbaric Board Review course for physicians – Penn Medicine Aug 2010Undersea and Hyperbaric Board Review course for physicians – Penn Medicine Aug 2010..

Indication of HBOIndication of HBODelayed Radiation InjuriesDelayed Radiation Injuries

RADIATION PROCTITISRADIATION PROCTITIS• Symptoms include – rectal bleeding/pain, diarrhea, and Symptoms include – rectal bleeding/pain, diarrhea, and

tenesmus.tenesmus.• Combined results from trials including a total of 199 cases Combined results from trials including a total of 199 cases

– complete resolution in 41% and 86% had at least partial – complete resolution in 41% and 86% had at least partial responseresponse..

• Clark RE et al. Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term 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. follow-up. Int. Journal Radiation Oncology /Biology Phys 2008.

• Undersea and Hyperbaric Board Review course for Physicians. Penn Medicine. August 2010Undersea and Hyperbaric Board Review course for Physicians. Penn Medicine. August 2010 ..

Laryngeal Necrosis

• Uncommon complication of radiation therapy for patients with head and neck cancer – usually <1%.

• 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.

RADIATION INJURIES

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.

HBO for the late effects of radiation is supported by Prospective Randomized Trials

The weight of current evidence favors use of HBO

Demonstrated “financial” effectiveness

Deemed to be a “Standard of Care” by the National Cancer Institute

No proven alternative therapies

REFERENCES

• G, LB. HYPERBARIC OXYGEN THERAPY INDICATIONS. 12TH EDITION.

• KINDWALL, EP., WHELAN, HT. HYPERBARIC MEDICINE PRACTICE. 3RD EDITION.

• HEALOGICS – WOUND CARE CENTERS.