Toplam Sayfa Görüntüleme Sayısı

24 Temmuz 2014 Perşembe

Hyperbaric Oxygen Therapy

Hyperbaric Oxygen Therapy

Abstract

Hyperbaric oxygen is a treatment in which a patient breathes 100% oxygen intermittently while inside a treatment chamber at a pressure higher than at sea level pressure (ie, >1 atm). In certain circumstances, it represents the primary treatment modality, whereas in others it is an adjunct to surgical or pharmacologic interventions. After reviewing all the scientific evidence available to date, the Undersea and Hyperbaric Medical Society, in its latest publication, Hyperbaric Oxygen Therapy Indications (12th ed.), recommends 13 indications for hyperbaric oxygen therapy. Several of these indications are related to our practice of wound care. The article discusses these indications in detail.
Keywords: Arterial insufficiency, Chronic osteomyelitis, Compartment syndrome, Crush injury, Diabetic wounds, Hyperbaric oxygen therapy, Limb salvage, Necrotizing fasciitis, Radiation injury, Wound care

Introduction

Hyperbaric oxygen is a treatment in which a patient breathes 100% oxygen intermittently while inside a treatment chamber at a pressure higher than at sea level pressure (ie, >1 atm abs). In certain circumstances, hyperbaric oxygen therapy (HBOT) is the primary treatment modality, whereas in others, it is an adjunct to surgical or pharmacologic interventions.1
Treatment can be carried out in either a monoplace or a multiplace chamber. In a monoplace chamber, a single patient is accommodated, the entire chamber is pressurized with 100% oxygen, and the patient breathes the ambient chamber oxygen directly. A multiplace chamber holds 2 or more people and is pressurized with compressed air while patients breathe 100% oxygen via masks, head hoods, or endotracheal tubes.
Topical oxygen therapy is not HBOT. The patient must receive the oxygen by inhalation within a pressurized chamber, and the Undersea and Hyperbaric Medical Society position paper indicates that pressurization should be at least 1.4 abs or higher for the therapy to be considered HBOT.2
After reviewing all the scientific evidence available to date, the Undersea and Hyperbaric Medical Society, in its latest publication, Hyperbaric Oxygen Therapy Indications (12th ed.), recommends the following 13 indications for HBOT.1
  • 1.
    Air or gas embolism
  • 2.
    Carbon monoxide poisoning and carbon monoxide poisoning complicated by 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
    • a.
      Central retinal artery occlusion
    • b.
      Enhancement of healing in selected problem wounds
  • 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
Most of these indications are approved by Medicare and other insurance, but it is advisable to check with local Medicare intermediaries and insurance companies for coverage determination.
The indications that we commonly see in our wound care practice are discussed in detail in the following sections of this article.

Clostridial Myositis and Myonecrosis (Gas Gangrene)

Clostridial myositis and myonecrosis, or gas gangrene, is an acute, rapidly progressive nonpyogenic, invasive clostridial infection of the muscles, characterized by profound toxemia, extensive edema, massive death of tissue, and a variable degree of gas production. This infection is most commonly caused by anaerobic, spore forming, gram-positive, encapsulated bacilli of the genus Clostridium. The most commonly isolated organism is Clostridium perfringens type A.3
The onset of gas gangrene may occur between 1 and 6 hours after injury or an operation. It begins with severe and sudden pain in the infected area, and the pain is out of proportion to the lesion. Usually, pain starts after the trauma or an operation. The skin initially appears shiny and tense but quickly becomes dusky and progresses to a bronze discoloration. Any delay in recognition of this condition can be fatal. Other clinical findings are hemorrhagic bulla, vesicles, swelling and edema of the infected area, and noncontractile dark red to black or greenish muscles that do not bleed when cut. Crepitus is usually present.3
X-ray shows featherlike figures between muscle fibers, an early and highly characteristic sign of clostridial myonecrosis.3
A serious concern in gas gangrene is the rapidly advancing phlegmon caused by continuous production of alpha toxin in the infected but still viable tissue. It is essential to stop alpha toxin production as soon as possible and to continue HBOT until the advancement of the disease process has clearly been arrested.2,3 Van Unnik found that it is necessary to achieve tissue Po2 of 250 mm Hg to stop toxin production, and this Po2 can be achieved only by starting HBOT as soon as possible.1,3
The recommended treatment profile consists of hyperbaric oxygen at 3.0 atm abs for 90 minutes, 3 times a day for the first 24 hours, followed by twice per day for the next 2 to 5 days. If patient remains toxic, the treatment profile needs to be extended.1,3

Crush Injuries and Skeletal Muscle Compartment Syndromes

Crush Injuries represent a spectrum of injury to body parts as a result of trauma. Typically the injury may involve skin, subcutaneous tissue, muscle, tendons, bone and joint. Complications arising from crush injuries can be osteomyelitis, nonunion of fractures, failed flap and amputations that occur in approximately 50% of the cases. HBOT can be used as an adjunct to get better outcomes.1,4
Compartment syndrome is another consequence of trauma. Edema, bleeding, or a combination within the confined fascial envelope increases the pressure within the skeletal muscle compartment. When tissue fluid pressure increases above the capillary pressure, signs of ischemia set in. In early stages, HBOT assists with slowing the progression and complication before fasciotomy is required.1,5,6,7
In crush injuries and compartment syndrome, HBOT helps in one of the following 3 ways: (1) supplements oxygen to poorly perfused areas in early postinjury period, (2) reduces edema, and (3) mitigates the reperfusion injury.1,5,6,7
Patients with crush injuries benefit from HBOT based on the seriousness of injury and the ability of the host to respond to the injury. However, the best time to start HBOT is with the initial management of the crush injuries, when complications are predictable, such as the Gustilo IIIB and C fractures and in lesser Gustilo grades in impaired and decompensated hosts.6,7
Compartment syndrome is divided into 3 stages: suspected, impending, and established. HBOT is not recommended in the suspected stage, when compartment syndrome is not actually present but there is a suspicion that a compartment syndrome may develop.7 In the established stage, the patient should be monitored with frequent neurocirculatory checks of the injured extremity.7
In the impending stage, the patient develops signs such as increasing pain, hyperesthesias, muscle weakness, discomfort with passive stretch, and tenseness in the compartment. The compartment pressure should be measured. If the compartment cannot be measured or if pressure is such that immediate fasciotomy is not needed, then HBOT should be started as soon as possible. However, the patient should demonstrate 3 or more clinical findings suggestive of compartment syndrome.1,5,6,7
In the established stage, symptoms, signs, and pressure measurement suggest compartment syndrome and immediate fasciotomy must be done. However, after fasciotomy, HBOT is used if the patient has significant residual problems, such as ischemic muscle, threatened flaps, residual neuropathy, massive swelling, or significant host impairment.1,7
Treatment criteria for HBOT in crush injuries varies depending on suspected pathophysiology. HBOT is given at 2 ATA in monoplace chambers and 2.4 ATA in multiplace chambers, with 3 treatments in 24 hours for critical ischemia; twice a day for threatened flaps, and once a day when one is dealing with infections or healing delay because of impaired host.1,7
HBOT for compartment syndrome is given at 2.0 to 2.4 ATA for 90 to 120 minutes, twice a day, for 7 to 10 days.1,7

Problem Wounds

Problem wounds represent a significant and growing challenge to our health care. The hypoxic nature of all wounds has been demonstrated, and the hypoxia, when pathologically increased, correlates with impaired wound healing and increased rates of wound infection.1,8 The rate at which all normal wounds heal has been shown to be oxygen dependent.8,9 Fibroblast replication, collagen deposition, angiogenesis, resistance to infection, and intracellular leukocyte bacterial killing are oxygen-sensitive responses essential to normal wound healing. Evidence suggests that intermittent oxygenation of hypoperfused wound beds, a process achievable only in selected patients by exposing them to HBOT, sets in motion a cascade of events that leads to wound healing.8,9
Although HBOT is used in a variety of problem wounds, the best evidence exists for treatment of Wagner grade 3 or worse diabetic foot ulcers.1
For a cost-effective application of HBOT, identifying wounds that would most likely benefit from HBOT is paramount. Although aggressive distal lower-extremity bypass grafting and lower-extremity angioplasty do increase limb salvage rates, the microcirculation component causes difficulty with salvage in spite of aggressive lower extremity revascularization.10,11
Transcutaneous oxygen tension measurements provide a direct, quantitative assessment of oxygen availability to the periwound skin and an indirect measurement of periwound microcirculatory blood flow. Hypoxia (ie, wound Po2 < 40 mm Hg) generally best defines wounds appropriate for HBOT. It is important to note that transcutaneous oxygen study is a better predictor of failure than success.10,11

Diabetic Foot Ulcer

While the evidence suggests that all hypoxic diabetic lower extremity wounds could benefit from HBOT, the majority of clinical trials on HBOT have included wounds on the basis of severity and level of tissue involvement. The Centers for Medicare and Medicaid Services has approved coverage for HBOT in patients with diabetic wounds of the lower extremities who met the following criteria:
  • 1.
    Patient has type 1 or 2 diabetes mellitus and has lower-extremity wound due to diabetes.
  • 2.
    Patient has wound classified as Wagner grade 3 or higher.
  • 3.
    Patient has failed an adequate course of standard wound therapy. (Standard wound therapy is defined as 30 days of standard treatment, including assessment and correction of vascular abnormalities, optimization of nutritional status and glucose control, debridement, moist wound dressings, off-loading, and treatment of infection.)
For HBOT to continue, reevaluation at 30-day intervals must show continued progress in healing.1 The usual treatment protocol for HBOT in diabetic wounds is HBOT given at 2.0 to 2.4 ATA for 90 minutes daily for 30 to 40 days.1,12,13
HBOT may be recommended in other wound indications in a specific situation, but it may not be reimbursed by some third-party payers.

Arterial Insufficiency Ulcer

The Wound Healing Society clinical practice guidelines for arterial insufficiency ulcer were published in 2006. Guideline 6B1a states, “In patients with non-reconstructable anatomy or whose ulcer is not healing despite revascularization, HBOT should be considered as adjuvant therapy.” Selection criteria include ulcers that are hypoxic (because of ischemia) and whose hypoxia is reversible by hyperbaric oxygenation. Guideline 6B1b states, “HBOT should be investigated in the treatment of ischemia-reperfusion injury after revascularization in patients with arterial ulcers.”1,14

Venous Stasis Ulcer

HBOT is not indicated in the primary management of venous stasis ulcers of the lower extremities. HBOT may be required to support skin grafting in patients with concomitant peripheral arterial occlusive disease and in diabetic patients whose hypoxia is not corrected by control of edema.1

Pressure Ulcer

HBOT is not indicated in routine decubitus ulcer management. It may be necessary for the support of skin grafts or flaps showing evidence of ischemic failure, for ulcer developing in previously radiated fields, in presence of refractory osteomyelitis, or in presence of progressive necrotizing infections.1

Necrotizing Soft Tissue Infections

Necrotizing fasciitis is an acute, potentially fatal infection of the superficial and deep fascia of the skin and soft tissues and progresses to ischemic dermal necrosis after involvement of the dermal blood vessels, which traverse through the fascial layers.1,15

Clinical Presentation

A patient with necrotizing fasciitis usually presents with pain out of proportion to the skin findings, swelling, fever, and chills. Mistakenly, the area of infection is assumed to be cellulitis and not a serious form of infection. However, with time, the infection will progress rapidly, causing areas of blisters and bullae formation. Eventually, skin starts appearing dusky, grayish, or frankly black. A surgeon confirms the diagnosis during debridement when the necrotic fascia are found.1,15

Microbiology

Common organisms are groups A, C, or G β-hemolytic streptococci; other commonly isolated organisms are Enterobacteriaceae, Enterococcus species, Bacteroides species, Peptococcus species, Candida species, and methicillin-resistant Staphylococcus aureus—community acquired. The occurrence of S aureus plus anaerobic streptococci is also known as Meleney's synergistic gangrene.1,15

Clinical Management

Numerous studies have continued to demonstrate the beneficial effect of HBOT in the management of necrotizing fasciitis. The protocol for treating necrotizing fasciitis with HBOT includes initiating therapy at 2.0 to 2.5 atm abs for 90 minutes of oxygen given twice a day for the first few days until there appears to be no further extension of necrosis in previously debrided areas and the infection is controlled. Patients will need standard wound care; debridement of necrotic tissue; drainage of fluid collections and abscesses; antibiotics directed at the expected range of organisms; intravenous gamma globulin, particularly if the necrotizing soft tissue infection is associated with group A hemolytic streptococcal infection and toxic shock syndrome; and goal-directed management of sepsis.1,15,16

Refractory Osteomyelitis

Osteomyelitis is an infection of bone or bone marrow, usually caused by pyogenic bacteria or mycobacteria. Refractory osteomyelitis is defined as a chronic osteomyelitis that persists or recurs either after definitive surgical debridement or after a period of 4 to 6 weeks of appropriate antibiotic therapy.1,17
The Cierny-Mader classification of osteomyelitis can be used as a guide to determine which patients will most likely benefit from adjunctive HBOT. Stage 1 disease in the Cierny-Mader classification is primarily managed with antibiotics alone. Stage 2 disease generally responds well to appropriate antibiotics and superficial debridement of the affected bone and soft tissues. Patients with stage 3 or 4 osteomyelitis, complicated by adverse local or systemic risk factors, are most likely to benefit from HBOT as an adjunct to continued antibiotics and repeat surgical debridement.1
HBOT is usually given on a daily basis, 5 to 7 times per week, and timed to begin just after the most recent surgical debridement. Initial treatment at 2.4 to 2.5 ATA may provide the best theoretical balance between clinical efficacy and oxygen toxicity risk. A total of 30 to 40 treatments are required to attain the desired clinical results. If osteomyelitis fails to resolve or recurs after a total of 6 to 8 weeks of continuous, culture-directed antibiotics and hyperbaric oxygen treatment (30-40 sessions), then nidus for reinfection, such as occult sequestra or fixation hardware refractory to sterilization, should be suspected.1,17

Delayed Radiation Injuries (Soft Tissue and Bony Necrosis)

Delayed radiation injuries are typically seen after a latent period of 6 months or more and may develop many years after the radiation exposure. Sometimes, delayed injuries are precipitated by an additional tissue insult such as surgery within the radiation field.1,18
Delayed radiation injury causes vascular changes characterized by obliterative endarteritis and stromal fibrosis. HBOT induces neovascularization in hypoxic tissues by stimulating angiogenesis and improving tissue oxygenation, reduces fibrosis, and mobilizes and stimulates an increase of stem cells within the irradiated tissues.1,18
The most widely applied and most extensively documented indication of HBOT in chronic radiation injury is in the treatment and prevention of radiation necrosis of the mandible.1,18 The likelihood of mandibular necrosis because of therapeutic radiation varies widely among several reports. Reports indicate 0% incidence below doses of 6,000 cGy, increasing to 1.8% at doses from 6,000 to 7,000 cGy and 9% at doses greater than 7,000 cGy.1,18 Usual HBOT protocol for treatment of osteoradionecrosis is given at 2.4 ATA for 30 daily treatments, followed if necessary by 10 additional daily treatments.1,18 For prevention of osteoradionecrosis in patients who require dental surgery and dental extraction in a previously radiated field, 20 hyperbaric oxygen treatments before and 10 treatments after tooth removal are recommended.1,18
HBOT is also useful for radiation-induced soft tissue radionecrosis, mainly laryngeal necrosis, soft tissue necrosis of the head and neck, chest wall necrosis, radiation cystitis, proctitis, enteritis, myelitis, and brain necrosis. HBOT protocol is 2.0 to 2.5 ATA for 90 to 120 minutes for 30 to 60 treatments.1,18

Compromised Grafts and Flaps

All flaps, by definition, have an inherent blood supply, whereas grafts are avascular tissues that rely on quality of the recipient bed for survival and revascularization. Therefore, diagnosis of a compromised graft begins with proper assessment of the recipient wound bed. Compromised grafts can be salvaged by prompt institution of HBOT.1,19
There are many etiologies for flap compromise, mainly random ischemia, venous congestion, and occlusion to arterial circulation.
Free flaps can be exposed in both ischemia-reperfusion injury and secondary ischemic insults, which can compromise the viability of the flap. In many cases, there is no correctable mechanical cause for decreased flap perfusion. HBOT can reduce the need for repeat flap procedures, decreasing overall patient morbidity.1,19
Usual HBOT protocol is 2.0 to 2.5 ATA for 90 to 120 minutes. Initial treatment should be twice a day. Once the graft and flap are more viable, the patient can get once-a-day treatment. HBOT should be started as soon as signs of flap compromise appear. Usually, 20 treatments are required for wound bed preparation, and another 20 treatments are required after a flap or graft has been placed into its recipient bed.1,19

Acute Thermal Burn Injury

Severe thermal injury is one of the most devastating physical and psychological injuries a person can suffer. The goal of burn treatment include survival of the patient, with rapid wound healing, minimal scarring and abnormal pigmentation, and cost-effectiveness.1,20
The burn wound is a complex and dynamic injury characterized by a central zone of coagulation surrounded by an area of stasis, bordered by an area of erythema. The zone of coagulation or complete capillary occlusion may progress during the first 48 hours after injury. Local microcirculation is compromised to the worst extent 12 to 24 hours postburn. Usually, ischemic necrosis and edema follow.1,20
HBOT is recommended in treatment of serious burns, burns that are greater than 20% of total body surface area or with involvement of the hands, face, feet, or perineum, that are deep partial- or full-thickness injuries.1,20
Adjunctive HBOT is helpful in decreasing healing time in major burn injuries, especially if the wounds are deep second-degree burns. It is also used to support a skin graft and flap.1,20 Ideally, HBO is initiated as soon as possible after injury, often during initial resuscitation. Treatments are attempted 3 times within the first 24 hours and twice daily thereafter on a regimen of 90 minutes at 2.0 to 2.4 ATA. A total of 30 to 40 treatments may be needed. In large burns of 40% or greater, treatment is rendered for 10 to 14 days, in close consultation with the burn surgeon.1,20
Current data show that HBOT, when used as an adjunct in a comprehensive program of burn care, can significantly reduce morbidity and mortality, reduce length of hospital stay, and lessen the need for surgery.1,20

Conclusion

HBOT has proved to be an useful adjunct in the treatment of multiple conditions in the wound care clinic. Judicious use of HBOT will greatly increase wound healing rates in patients with compromised split thickness skin grafts or flaps, refractory osteomyelitis, radiation injury, and progressive necrotizing fasciitis.

Footnotes

Conflict of interest: The author reports no conflicts of interest.

References

1. Gesell L.B., editor. Hyperbaric Oxygen Therapy Indications. 12th ed. Undersea and Hyperbaric Medical Society; Durham, NC: 2008.
2. Feldmeier J.J., Hopf H.W., Warriner R.A., III, Fife C.E., Gesell L.B., Bennett M. UHMS position statement: Topical oxygen for chronic wounds. Undersea Hyperb Med. 2005;32(3):157–168. [PubMed]
3. Heimbach R.D. Gas Gangrene. In: Kindwall E.P., Whelan H.T., editors. Hyperbaric Medicine Practice. 3rd ed. Best; Flagstaff, AZ: 2008. pp. 549–574.
4. Stevens D.L., Bryant A.K. The role of clostridial toxins in the pathogenesis of gas gangrene. Clin Inf Disease. 2002;35:S93–S100. [PubMed]
5. Gustilo R. WB Saunders; Philadelphia, PA: 1982. Management of Open Fractures and Their Complications.
6. Strauss M.B., Hargens A.R., Gershuni D.H., Hart G.B., Akeson W.H. Delayed use of hyperbaric oxygen for treatment of a model compartment syndrome. J Orthop Res. 1986;4(1):108–111. [PubMed]
7. Strauss M.B. Crush injury, compartment syndrome and other acute traumatic peripheral ischemias. In: Kindwall E.P., Whelan H.T., editors. Hyperbaric Medicine Practice. 3rd ed. Best; Flagstaff, AZ: 2008. pp. 753–778.
8. Mustoe T. Understanding chronic wounds: a unifying hypothesis on their pathogenesis and implications for therapy. Am J Surg. 2004;187(suppl 5):S65–S70. [PubMed]
9. Hopf H.W., Gibson J.J., Angeles A.P. Hyperoxia and angiogenesis. Wound Rep Regen. 2005;13(6):558–564. [PubMed]
10. Smart D.R., Bennett M.H., Mitchell S.J. Transcutaneous oximetry, problem wounds, and hyperbaric oxygen therapy. Diving & Hyperbaric Med. 2006;36(2):72–86.
11. Fife C.F., Buyukcakir C., Otto G.H. The predictive value of transcutaneous oxygen tension measurement in diabetic lower extremity ulcers treated with hyperbaric oxygen therapy: a retrospective analysis of 1144 patients. Wound Rep Reg. 2002;10:198–207. [PubMed]
12. Brem H., Sheehan P., Boulton A.J.M. Protocol for treatment of diabetic foot ulcers. Am J Surg. 2004;187(suppl May):1S–10S. [PubMed]
13. Zamboni W., Wong H., Stephenson L. Evaluation of hyperbaric oxygen for diabetic wounds: A Prospective Study. Undersea Hyperbaric Med. 1997;24(3):175–179. [PubMed]
14. Hopf H, West J. Arterial subcommittee: should hyperbaric oxygen therapy be utilized in the control arm of clinical research studies for arterial (ischemic) wounds? provisional guidelines for chronic wound care: arterial, diabetic, pressure and venous. Wound, Ostomy and Continence Nurses Society and Wound Healing Society, June 21, 1999.
15. Anaya D.A., Pachen Dellinger E. Necrotizing soft-tissue infections: diagnosis and management. Clin Infect Dis. 2007;44:705–710. [PubMed]
16. Jallali N., Withey S., Butler P.E. Hyperbaric oxygen as adjuvant therapy in the management of necrotizing fasciitis. Am J Surg. 2005;189(4):462–466. [PubMed]
17. Mader J.T., Adams K.R., Wallace W.R., Calhoun J.H. Hyperbaric oxygen as adjunctive therapy for osteomyelitis. Infect Dis Clin North Am. 1990;4(3):433–440. [PubMed]
18. Marx R.E. Radiation injury to tissue. In: Kindwall E.P., editor. Hyperbaric Medicine Practice. 2nd ed. Best; Flagstaff, AZ: 1999. pp. 665–723.
19. Zamboni W.A. Applications of hyperbaric oxygen therapy in plastic surgery. In: Oriani G., Marroni A., Wattel F., editors. Handbook on Hyperbaric Medicine. 1st ed. Springer; New York, NY: 1996. pp. 443–507.
20. Cianci P., Lueders H., Lee H. Adjunctive hyperbaric oxygen reduces the need for surgery in 40%-80% burns. J Hyperbar Med. 1988;3:97.
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601859/

Hyperbaric oxygen and wound healing

Hyperbaric oxygen and wound healing

Abstract

Hyperbaric oxygen therapy (HBOT) is the use of 100% oxygen at pressures greater than atmospheric pressure. Today several approved applications and indications exist for HBOT. HBOT has been successfully used as adjunctive therapy for wound healing. Non-healing wounds such as diabetic and vascular insufficiency ulcers have been one major area of study for hyperbaric physicians where use of HBOT as an adjunct has been approved for use by way of various studies and trials. HBOT is also indicated for infected wounds like clostridial myonecrosis, necrotising soft tissue infections, Fournier's gangrene, as also for traumatic wounds, crush injury, compartment syndrome, compromised skin grafts and flaps and thermal burns. Another major area of application of HBOT is radiation-induced wounds, specifically osteoradionecrosis of mandible, radiation cystitis and radiation proctitis. With the increase in availability of chambers across the country, and with increasing number of studies proving the benefits of adjunctive use for various kinds of wounds and other indications, HBOT should be considered in these situations as an essential part of the overall management strategy for the treating surgeon.
KEY WORDS: Air embolism, compartment syndrome, crush syndrome, decompression sickness, diabetes mellitus, diabetic foot, gas gangrene, hyperbaric medicine, hyperbaric oxygen therapy, hyperbaric, hyperbaric oxygenation, necrotising fasciitis, osteomyelitis, osteoradionecrosis, radiation injuries, radiation necrosis, reperfusion injury, soft tissue infections, surgical flaps, transcutaneous oximetry

INTRODUCTION

Wound healing is a subject of great interest and involvement for the surgeon. While much of the physiology of wound healing is understood, gaps still exist in our understanding of the phenomenon. The surgeon attempts to modify the wound milieu by various means at his disposal. One such method is hyperbaric oxygen therapy (HBOT).
HBOT is the use of 100% oxygen at pressures greater than atmospheric pressure. The patient breathes 100% oxygen intermittently while the pressure of the treatment chamber is increased to greater than 1 atmosphere absolute (ATA).[1] HBOT has had very exciting and interesting beginnings. In 1620, Drebbel developed a one-atmosphere diving bell.[2] Thereafter, a British clergyman named Henshaw built and ran the first well-known chamber called the domicilium that was used to treat a multitude of diseases. The idea of treating patients under increased pressure was continued by the French surgeon Fontaine, who built a pressurised, mobile operating room in 1879. Dr. Orville Cunningham, a professor of anaesthesia, ran what was known as the “Steel Ball Hospital.” The structure, erected in 1928, was six stories high and 64 feet in diameter and could reach 3 atmospheres pressure. The hospital was closed in 1930 because of the lack of scientific evidence indicating that such treatment alleviated disease and was broken down during World War II for scrap.[3,4] The modern age of hyperbaric medicine began in 1937, when Behnke and Shaw used a hyperbaric chamber to treat decompression sickness (DCS), but it was not until 1955 that HBOT was used for conditions other than DCS. That year, Churchill-Davidson began to use oxygen therapy in a hyperbaric chamber to treat radiotherapy-induced damage in cancer patients. In 1956, Boerema of Holland even performed the first reported heart surgery in a hyperbaric chamber.[2,4]
Since then, the number of indications for which HBOT has been used has been steadily increasing so much so that one article mentioned 132 documented past and present indications for which it has been used.[1] Undersea and Hyperbaric Medicine Society (UHMS) has recognised various indications as “Approved” indications [Table 1].[5] These indications had also been approved by the British Hyperbaric Association.[6] The 2004 European consensus conference in addition recommended HBOT for some additional conditions based on sufficient evidence in the form of expert consensus opinion [Table 2].[7]
Table 1
UHMS approved indications for HBOT[5]
Table 2
Additional indications recommended by 2004 European Consensus Conference[7]
Apart from the approved indications, a number of areas are being explored to determine if HBOT might be of some clinical benefit.[8] These areas include senility, stroke, multiple sclerosis, sports injuries, high altitude illness, myocardial infarction, brain injuries, migraine, glaucoma, head injuries, management of chronic fatigue in HIV-positive patients[9] and enhancement of survival in free flaps.[10]

ADMINISTRATION OF HBOT

HBOT is administered inside chambers that are pressurised using air or oxygen to pressures more than atmospheric. Broadly, there are two types of chambers, multiplace which can hold more than one patient and monoplace chambers designed to cater for a single patient. Multiplace chambers use masks or hoods to administer oxygen to the patient and are more suitable for management of critical patients. Monoplace chambers were once made of metal, but are now made of transparent acrylic and are pressurised directly using oxygen, and therefore the patient does not need to wear a mask or hood. For hyperbaric chambers, monitoring and intensive care equipment are available where equipments are placed outside the chamber and probes fixed to the patient via biomedical connectors fixed to the bulkhead of the chamber.[3] Only equipment certified for use inside a hyperbaric chamber may be used. In case of lack of clarity on certification, the clinician must refer the equipment manuals or contact the manufacturer for certification of use.
Most therapy is given at 2 or 3 ATA and the average duration of therapy is 60–90 min. Number of therapies may vary from 3 to 5 for acute conditions to 50–60 for radiation illnesses.[1]

MECHANISM OF ACTION

HBOT has two primary mechanisms of action, hyperoxygenation and a decrease in bubble size. Hyperoxygenation is an application of Henry's law and results from an increase in dissolved oxygen in plasma as a result of increased partial pressure of arterial oxygen. A pressure of 3 ATA results in 6 ml of O2 being dissolved per 100 ml of plasma, thus rendering as much O2 delivery as by haemoglobin bound O2. Hyperoxygenation is valuable in management of crush injury, compartment syndrome, flap salvage and acute blood loss anaemia. Decrease in bubble size is an application of Boyle's law according to which the volume of a bubble decreases directly in proportion to increasing pressure and is the primary mechanism at work in management of decompression sickness and arterial gas embolism.[3,4,1113]
Secondary mechanisms of action include vasoconstriction, angiogenesis, fibroblast proliferation, leukocyte oxidative killing, toxin inhibition and antibiotic synergy. Hyperoxia in normal tissues causes vasoconstriction which reduces post-traumatic tissue oedema, contributing to the treatment of crush injuries, compartment syndromes and burns. This vasoconstriction, however, does not cause hypoxia as this is more than compensated by increased plasma oxygen content and microvascular blood flow.
Oxygen is vital for hydroxylation of lysine and proline residues during collagen synthesis and for cross linking and maturation of collagen which is required for strong wound healing. Lack of oxygen is corrected during HBOT, leading to adequate amounts of mature collagen formation.
Hypoxia is a vital stimulant for angiogenesis, but development of adequate capillary network requires adequate amounts of tissue oxygen concentration. HBOT increases the oxygen gradient between the centre and periphery of the wound, thus creating a strong angiogenic stimulus. This along with fibroblastic proliferation leads to increased neovascularisation.
HBOT increases the generation of oxygen free radicals, which oxidise proteins and membrane lipids, damage DNA and inhibit bacterial metabolic functions. Superoxide dismutase, catalase, glutathione and glutathione reductase keep the formation of these radicals in check until the oxygen load overwhelms the enzymes, leading to the detrimental effects on cell membranes, proteins and enzymes. HBOT is particularly effective against anaerobes which lack superoxide dismutase and facilitates the oxygen-dependent peroxidase system by which leukocytes kill bacteria.
Hyperoxia during HBOT further inhibits clostridial toxin production and improves potency of antibiotics like Fluoroquinolones, Amphotericin B and Aminoglycosides, all of which use oxygen for transport across cell membranes.

APPLICATIONS IN PLASTIC SURGERY

The indications of HBOT of interest to the plastic surgeon are discussed below.

Non-healing wounds: Diabetic, vascular insufficiency ulcers

Non-healing wounds are those which fail to heal within a reasonable time frame despite adequate management. Although multifactorial in aetiology, these wounds are typically hypoxic which is where HBOT becomes very effective. The rationale for treatment of chronic non-healing wounds with HBOT uses the known secondary mechanisms of action. HBOT leads to improved angiogenesis through a multifactorial mechanism. First, fibroblast proliferation and collagen synthesis are oxygen dependent, and collagen is the foundational matrix for angiogenesis. In addition, HBOT likely stimulates growth factors, particularly vascular endothelial growth factor (VEGF), involving angiogenesis and other mediators of the wound healing process. Hyperbaric oxygen also has been shown to have direct and indirect antimicrobial activity; in particular, it increases intracellular leukocyte killing. Decreased oedema due to systemic vasoconstriction allows better diffusion of oxygen and nutrients through tissues while also relieving pressure on the surrounding vessels and structures.[3,11]
Non-healing wounds where HBOT has been successfully used include diabetic foot ulcers, venous and arterial insufficiency ulcers. Diabetic lower extremity ulcers have been the focus of most wound research in hyperbaric medicine, since the aetiology of these wounds is multifactorial, and HBOT can address many of these factors. Several randomised controlled clinical trials have proven the beneficial effects of HBOT for the treatment of diabetic lower extremity wounds, apart from many prospective, non-controlled clinical and retrospective studies.[1,3,14]
HBOT in diabetic wounds is used in conjunction with other wound management techniques including wound debridement, dressings, pressure-relieving strategies, appropriate glycaemic control, and nutrition and antibiotic management.
Patient selection and follow-up is usually done objectively with transcutaneous oximetry (TcPO2) [Figure 1].
Figure 1
Flow chart for patient selection and predictor of outcomes in patients managed with HBOT based on transcutaneous oximetry measurements[15,16]
Patient selection for HBOT is usually based on measurement of oxygen tension around the wound using TcPO2. TcPO2 can be successfully used to predict patient outcome in wound management with HBOT. It has been proven to be a better predictor of healing outcome compared to Ankle Brachial Index (ABI) and Toe Blood Pressure (TBP).[15] Also, in-chamber TcPO2 >200 mmHg with patient breathing 100% O2 inside the hyperbaric chamber is the single best discriminator between success and failure with HBOT.[16]
A flow chart for patient selection and suitability for HBOT using TcPO2 is shown in Figure 1.[16,17]
In case of nonavailability of TcPO2, Modified Wagner's grading for wounds can also be used for patient selection. Grades IIIb and above are generally regarded as ideal candidates for HBOT.[17]
Figure 2 shows sequential photographs of a 53-year-old male diabetic suffering from spontaneous gangrene of the thigh who was managed successfully with HBOT at a tertiary care hospital of the Armed Forces.
Figure 2
A combination picture showing sequential progress of spontaneous gangrene in a 53-year-old male diabetic managed with HBOT

Infected wounds: Clostridial myonecrosis, necrotising soft tissue infections, Fournier's gangrene

HBOT has direct effect in inhibiting the production of clostridial alpha toxin and the high concentration of oxygen induces greater oxidative free radical mediated microbicidal killing by polymorphonuclear lymphocytes. These mechanisms help in faster and better management of necrotising soft tissue infections and gas gangrene. Multiple studies have proven the beneficial effect of, and justified the use of adjunctive HBOT, in addition to aggressive surgical debridement and aggressive antibiotic therapy which remain the cornerstones of treatment. Studies have also demonstrated significantly reduced mortality rates in patients of necrotising fasciitis and Fournier's gangrene managed with adjunctive HBOT compared to patients managed without HBOT.[4]
HBOT in these cases is given aggressively, twice a day initially, and is best initiated as quickly as possible.[1,3]

Traumatic wounds: Crush injury, compartment syndrome

Hyperbaric oxygen ameliorates the effects of acute traumatic ischaemia through four mechanisms: hyperoxygenation, vasoconstriction, and influence on reperfusion and host factors.[18] HBOT also decreases neutrophil activation, preventing margination, rolling and accumulation of WBCs, thereby reducing the production of free radicals by neutrophils and preventing reperfusion injury.[3] HBOT is also seen to reduce sludging of RBCs.[1]
Besides adequate shock management, direct surgical intervention with debridement and repair of soft tissues and of any damaged vessels and stabilisation of bony elements are of paramount importance. Adjuvant HBOT should be administered as soon as possible; when it is given early it can prevent large expanses of ischaemic necrosis, minimise the frequency and extent of amputations, reduce oedema, control infection, support healing and prevent reperfusion injury.[18]
Gustilo classification of open fractures is commonly used for objective assessment in crush injuries to determine whether HBOT is indicated or not. For the uncompromised host, HBOT is recommended for all Gustilo Grade III B and III C fractures. In the compromised host, the indication for using adjunctive HBOT should start at Grade II.[18]
HBOT should be started as soon as is feasible, ideally within 4–6 h from the time of injury. After emergent surgical intervention, the patient should undergo HBOT at 2–2.5 ATA for 60–90 min. For the next 2–3 days, perform HBOT 3 times daily, then twice daily for 2–3 days, and then daily for the next 2–3 days.[3]

Compromised skin grafts and flaps

Most skin grafts and flaps in normal hosts heal well. In patients with compromised circulation, this may not be the case. The leading pathophysiological factor of compromised grafts and flaps is hypoxia. HBOT benefits patients by reducing the oxygen deficit. The mechanism of improvement of survival of skin grafts may be twofold, by effects on the bed and by effects on the graft. As discussed earlier, wound beds are improved by the hyperoxia, angiogenesis, leukocyte function enhancement and antimicrobial actions of HBOT.[3,11,19] The effects on the graft are principally the improvement of oxygenation. In the first 48 h of grafting, the graft survives by “plasmatic imbibition.” As discussed earlier, oxygen is the most critical needs of tissues. Improved oxygen availability contributes to better graft survival and engraftment. In the usual circumstances, this should not be necessary. However, in the compromised graft/bed, it may be invaluable. The benefit has been established in several animal and clinical studies. HBOT is indicated when the TcPO2 in the wound is less than 40 mmHg and compromised wounds may reveal values as low as 15 mmHg.[19] The benefit of HBOT is expected to be maximal in cases where a relatively large bulk of tissue is transferred as graft, i.e. full-thickness skin grafts and particularly composite grafts which in the process of “take” regularly show a cyanotic period before successful engraftment.
In compromised flaps also, HBOT is found to be of value. Again, the benefits may accrue partly from improvement of the bed and by effects on the flap. An acutely elevated flap is known to be hypoxic and ischaemic. With passage of time, there is an improvement and reorientation in the circulation within the surviving flap. Mechanisms of action on the flap include hyperoxia and anti-oedema effect which improves microcirculation. Further, as reperfusion occurs, HBOT is seen to reduce reperfusion injury and decreases the “no flow” phenomenon. This last action may be due to the effects of HBOT on neutrophils, endothelium and free radicals.[19] A unique mechanism of action of HBOT for preserving compromised flaps is the possibility of closing arteriovenous shunts, decreasing non-nutritive blood flow. Additionally, the same mechanisms of action that improve wound healing, namely, improved fibroblast and collagen synthesis and angiogenesis, also are likely to reduce flap dehiscence.[3]
In clinical practice, improvement in the surviving length of a compromised flap is seen with the use of HBOT.
HBOT treatments are performed at a pressure of 2.0–2.4 ATA for duration of 90 min twice daily for 2–3 days and then, as soon clinical stabilisation occurs, once per day to a total of 20–30 treatments. In case of total venous or arterial occlusion, specifically in free tissue transfer, treatments are given thrice daily on the first day, twice daily for the next 2 days, followed by once daily thereafter along with appropriate surgical therapy.[19]
The action of HBOT on the flap can be quantified by TcPO2 measurements. If intra-chamber (at 2.4 ATA on 100% O2) TcPO2 remains below 50 mmHg, flap survival is unlikely despite the use of HBOT.[19]

Radiation-induced wounds

Radiation injury alters the normal tissue physiology and anatomy. Radiation-induced wounds are typically hypocellular, hypovascular, and hypoxic due to an occlusive endarteritis caused by radiation injury. Hyperbaric oxygen promotes angiogenesis and hyperoxygenation to the irradiated tissues. Increasing the oxygen content to the surrounding tissues markedly increases the overall oxygen gradient between these tissues and the central hypoxic area. The increased oxygen gradient is the essential catalytic factor for angiogenesis.[11]
Typically, radiation-induced wounds are chronic and non-healing and show poor skin graft take. HBOT has been a very successful adjunct in the management of late complications of radiotherapy.[20] Typically, in mandibular reconstruction, in an irradiated field, HBOT has been found to markedly improve outcomes after composite reconstruction. HBOT has been particularly beneficial in the management of mandibular osteoradionecrosis. Similarly, complications of radiotherapy in the pelvic region (cystitis, proctitis) are also benefited by adjunctive HBOT.[3,4]
Multiple hyperbaric treatments, sometimes as many as 50–60,[1] are usually required to significantly increase the capillary density in the affected tissues and promote healing. Prophylactic hyperbaric oxygen is also recommended for procedures (e.g. tooth extraction) on irradiated mandibles.[11]

Thermal burns

Although burns have been mentioned as one of the approved indications for HBOT by UHMS, there is lack of universal consensus on the issue.[21] The mechanisms of action at play in improving the outcome in a burnt patient may involve the following. Hyperoxia produces pre-capillary vasoconstriction. This results in reduced plasma exudation while preserving and enhancing tissue oxygenation. The resultant reduction in oedema and fluid loss cause a marked reduction in the amount of fluids required for resuscitation. Hart,[22] in a prospective study on burn patients, found that HBOT treated patients required 2.2 ml/kg/% total body surface area (TBSA) of fluids as opposed to 3.4 ml/kg/% TBSA in the control group.
Burn wounds typically have a central zone of coagulation surrounded by a zone of stasis, in turn surrounded by a zone of hyperaemia. HBOT was noted to reduce the capillary stasis in the zone of stasis and reduce the increase in size of the zone of coagulation as occurs in burns. Thus, HBOT assists in tissue preservation. This mechanism might be of particular value in the case of burns in aesthetically or functionally important zones (face, hands, perineum) or with delicate vascularisation (cartilaginous - ears, nose). Further, HBOT may exert beneficial effects by way of its anti-sludging effect in the microcirculation and prevention of injury by oxygen free radicals.[21]
Many cases of burns will have associated smoke inhalation with concomitant carbon monoxide poisoning which is a universally accepted leading indication for the use of HBOT. HBOT will thus be invaluable in these cases.
Patients who are likely to benefit most from HBOT are those with a 20–80% TBSA mixed second/third degree burns. In these patients, the first HBOT session should be given within 6 h of the burn injury, followed by two sessions per day, at a pressure of 2.0 ATA, for the first 4–5 days only. Volume of fluids required to be administered is likely to be less than calculated, and hence should be closely monitored so as to prevent pulmonary overload.[21]
Treatment must be in a multiplace chamber equipped for intensive care treatments, preferably with optimal bacteriological isolation and provision for mechanical ventilation and continuous (invasive) monitoring of haemodynamic parameters as may be required.
HBOT in the later stages of management of burns may be useful by its antibacterial action (thus reducing sepsis) and by improved take of skin grafts.

CONTRAINDICATIONS

The absolute contraindication for HBOT is the presence of an untreated pneumothorax as compression and decompression during HBOT could lead to development of tension pneumothorax and gas emboli. Concurrent administration of some medication is also seen as an absolute contraindication. Bleomycin could cause interstitial pneumonitis; Disulfiram blocks superoxide dismutase, and thus reduces body's protection against oxygen toxicity; Cisplatin and Sulfamylon have a mechanism of action opposite to that of HBOT in wound healing, and thus could nullify any benefit from HBOT, and Doxorubicin could cause cardiotoxicity.[3,11]
Relative contraindications include claustrophobia, asthma, chronic obstructive pulmonary disease (COPD), pregnancy, congenital spherocytosis, upper respiratory tract infection or any other Eustachian tube dysfunction, fever, pacemaker in situ and seizures/epilepsy.

COMPLICATIONS

When used in standard protocols, HBOT is safe.[1]
The most common complication during HBOT is barotrauma (injury caused by pressure as a result of an inability to equalise pressure from an air-containing space and the surrounding environment) usually of the middle ear. For an unconscious patient, myringotomy may be done to prevent middle ear barotrauma. Other organs affected by barotrauma are external and inner ear, air sinuses, GI tract and tooth cavities.
Other complications include pulmonary barotrauma which could arise as a result of cavitary or fibrotic lesions in the lung parenchyma, and development of acute CNS oxygen toxicity (known as Paul Bert effect and caused by acute exposure to high partial pressures of oxygen) leading to lowering of seizure threshold and precipitation of seizures inside the chamber. Prolonged exposure to lower pressures of oxygen could cause pulmonary oxygen toxicity (known as Loraine Smith effect) leading to reversible pulmonary restrictive changes. At our centre, as part of a protocol, patients are given a break of about a week from hyperbaric oxygen after 2 weeks of daily sessions in order to prevent the development of pulmonary oxygen toxicity.[3,4,11]
Development of reversible myopia and clouding of pre-existing cataracts are other complications of HBOT.

HBOT: RESULTS OF TREATMENT

Non-traumatic wounds form a major clientele for any HBOT centre. Data from an Armed Forces HBOT centre in a tertiary care hospital for the year 2008 and part of 2009 (January–September) showed that of all the patients who were administered HBOT in these years, non-traumatic wounds formed 40% and 36% of the total HBOT workload, respectively.[23] In this group of patients, significant healing of wounds was seen in 87%. Another study from the same centre, which discussed the healing rates of non-traumatic wounds, found that 84.7% of the cases managed during the period were diabetics with only one patient not having a lower extremity ulcer.[13] Satisfactory healing was seen in 88.37% of cases in this study.
Doctor et al.[14] did a prospective controlled trial to study the effect of HBOT in chronic diabetic foot lesions. Thirty diabetics with chronic foot lesions were randomised to study and control groups and were assessed for average hospital stay, control of infection and wound healing. In the study group managed with HBOT, positive cultures decreased significantly compared to the control group (most pronounced for Escherichia coli) and the need for major amputation was significantly less. The average hospital stay was not affected. They concluded that HBOT could be safely used and would be beneficial as an adjuvant therapy in chronic diabetic foot lesions.

CONCLUSION

HBOT was started as a treatment modality for management of decompression sickness and, with the passage of time, its scope has gradually increased to include numerous indications. Indications of particular interest to the plastic surgeon include ischaemic wounds, diabetic ulcers, traumatic wounds, necrotising infections, failing grafts and flaps, radiation wounds, and thermal burns, and the use of HBOT must be considered by the managing surgeon.
HBOT administration was once the sole purview of the Armed Forces hospitals, that too, in only two centres across the country, namely, Institute of Aerospace Medicine, Bangalore, and Institute of Naval Medicine, Mumbai [Figures [Figures335]. Today, HBOT is available at 10 hospitals in the country. These chambers are located in Mumbai (four hospitals), New Delhi, Ahmedabad (two each), Pune and Trichur (one hospital each). Further, it is believed that there are 10 more hospitals in the country where installation of hyperbaric chambers is being planned.
Figure 3
A multiplace hyperbaric chamber installed at INHS Asvini
Figure 5
Control panel of the same hyperbaric chamber
Figure 4
A combination photograph showing auxiliary units of a hyperbaric chamber
HBOT is witnessing a phase of phenomenal growth in the country, something which took place much earlier in other countries. It is time that we recognise the benefits of this treatment modality so that our patients are benefited by the advantages that HBOT has to offer both in terms of speedier recovery as well as cost benefits.

Footnotes

Source of Support: Nil
Conflict of Interest: None declared

REFERENCES

1. Sahni T, Hukku S, Jain M, Prasad A, Prasad R, Singh K. Recent advances in hyperbaric oxygen therapy. Medicine update. Assoc Physicians India. 2004;14:632–9.
2. Neubauer RA, Maxfield WS. The polemics of hyperbaric medicine. J P and S. 2005;10:15–7.
3. Latham E, Hare MA, Neumeister M. Schraga BD, Windle ML, Mosenifar Z, editors. Hyperbaric oxygen therapy. eMedicine. Medscape. [Last accessed on 2009 Oct 02, Last updated on 2008 Nov 7]. Available from: http://emedicine.medscape.com/article/1464149-overview .
4. Sharkey S. Current indications for hyperbaric oxygen therapy. Journal of the Australian Defence Health Service (ADF Health) 2000;1:64–72.
5. Indications for hyperbaric oxygen therapy. Definition of Hyperbaric Oxygen Therapy. UHMS. [Last accessed on 2012 Jan 10]. Available from: http://membership.uhms.org/?page=Indications .
6. Camporesi EC, editor. Current diseases approved for treatment, hyperbaric oxygen therapy: A Committee Report. UHMS. [Last cited in 1996]. Available from: http://hyperbaric.org.uk/conditionsTreatment.htm .
7. European committee for hyperbaric medicine. Lille, France: 2004. Proceedings of the 7th European consensus conference on hyperbaric medicine.
8. Sahni T, Singh P, John MJ. Hyperbaric oxygen therapy: Current trends and applications. J Assoc Physicians India. 2003;51:280–4. [PubMed]
9. Bhutani S. HBOT reduces fatigue in HIV positive patients. Jour Marine Medical Society. 2011;13:57–9.
10. Vishwanath G. Hyperbaric oxygen therapy in free flap surgery: Is it meaningful? Medical journal armed forces India (MJAFI) 2011;67:253–6.
11. Michael N. Cram AE, Talavera F, Newsome RE, Slenkovich NG, Torre JT, editors. Hyperbaric oxygen therapy. eMedicine. [Last accessed on 2005 May 20]. Available from: http://emedicine.com/plastic/topic526.htm .
12. Leach RM, Rees PJ, Wilmshurst P. ABC of oxygen, hyperbaric oxygen therapy. BMJ. 1998;317:1140–3. [PMC free article] [PubMed]
13. Bhutani S, Verma R. Hyperbaric oxygen therapy in non-healing wounds. Jour Marine Medical Society. 2010;12:89–92.
14. Doctor N, Pandya S, Supe A. Hyperbaric oxygen therapy in diabetic foot. J Postgrad Med. 1992;38:112–4. [PubMed]
15. Löndahl M, Katzman P, Hammarlund C, Nilsson A, Landin-Olsson M. Relationship between ulcer healing after hyperbaric oxygen therapy and transcutaneous oximetry, toe blood pressure and ankle-brachial index in patients with diabetes and chronic foot ulcers. Diabetologia. 2011;54:65–8. [PubMed]
16. Smart DR, Bennett MH, Mitchell SJ. Transcutaneous oximetry, problem wounds and hyperbaric oxygen therapy. Diving Hyperb Med. 2006;36:72–86.
17. Matos L, Nunez A. Enhancement of healing in selected problem wounds. In: Kindwall EP, Wheelan HT, editors. Hyperbaric Medicine Practice. 2nd ed. Florida: Best Publishing; 1999. pp. 813–49.
18. Kemmer A. Crush injury and other traumatic ischemia. In: Mathieu D, editor. Handbook on hyperbaric medicine. Netherlands: Springer; 2006. pp. 311–2.
19. Mesimeris TA. Compromised skin graft and flap. In: Mathieu D, editor. Handbook on hyperbaric medicine. Netherlands: Springer; 2006. pp. 329–61.
20. Pasquier D, Schmutz J, Lartigau E. Radio-induced lesion in normal tissues. In: Mathieu D, editor. Handbook on hyperbaric medicine. Netherlands: Springer; 2006. pp. 363–99.
21. Germonpre P. Burns. In: Mathieu D, editor. Handbook on Hyperbaric Medicine. Netherlands: Springer; 2006. pp. 479–94.
22. Hart GB, O’Reilly RR, Broussard ND. Treatment of burns with hyperbaric oxygen. Surg Gynecol Obstet. 1974;139:693–6. [PubMed]
23. Bhutani S. Poster presentation at: XXIV Annual Conference of the Marine Medical Society. Mumbai: Marine Medical Society; 2009. Hyperbaric oxygen therapy; pp. 24–5.
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495382/