Clinical and Health Affairs
Hyperbaric Oxygen for Treatment of Problem Wounds
By Cheryl Adkinson, M.D.
■ Hyperbaric oxygen treatment has seen a resurgence of interest in recent years, with more academic medical centers building facilities and more physicians becoming board-certified in undersea and hyperbaric medicine. The reason for the growing interest is better understanding of the role of hypoxia in wound healing and an appreciation for the role of HBOT in reversing tissue hypoxia and enhancing the healing process. This has resulted in a number of new evidence-based indications for HBOT. This article describes the role of HBOT in wound healing and how it specifically applies to treatment of delayed radiation injury, one of the conditions for which it is commonly used.
Although Dutch physician Ita Boerema first described adjunctive use of hyperbaric oxygen for clostridial myonecrosis (gas gangrene) in 1940,1 it wasn’t until the 1960s that hyperbaric oxygen therapy (HBOT), in which 100% oxygen is inhaled while the entire body is at increased atmospheric pressure, came into use in civilian medicine in the United States.
Inspired by reports of successful treatment of gas gangrene and its potential in facilitating open-heart surgery and organ transplantation, several academic institutions constructed large hyperbaric research facilities in the mid-’60s. Those chambers were used extensively for about a decade. However, as other means of accomplishing heart surgery and organ transplantation were developed, academic interest in hyperbaric medicine waned, although some commercial entities offered HBOT for off-label maladies including wrinkles, hair loss, and impotence. Thus, during the 1970s and 1980s, legitimate use of HBOT was limited to treatment of gas gangrene, decompression sickness, cerebral air embolism, and carbon monoxide poisoning.
Over the last two decades, however, there has been a resurgence of interest in hyperbaric oxygen treatment. The number of hyperbaric facilities in the United States grew from 215 in 1991 to 514 in 2000 to 950 in 2010. The number of patient treatments in established facilities increased as well, from 1,362 in 1990 to 3,131 in 2010 at Hennepin County Medical Center, for example, and from 2,000 in 1990 to 10,000 in 2008 at Virginia Mason Medical Center in Seattle.2 During this same period, hyperbaric medicine became a subspecialty recognized by the American Board of Medical Specialties. There are now 446 U.S. physicians board-certified in undersea and hyperbaric medicine.
The greatest impetus for growth in hyperbaric medicine practice has been better understanding of the role of hypoxia in nonhealing wounds3 and an appreciation for the role of HBOT in reversing tissue hypoxia and enhancing wound healing. This has resulted in a number of new evidence-based indications for HBOT, all of which share the therapeutic basis of correcting tissue hypoxia (Table 1). The two medical conditions that are currently contributing most to the growing interest in hyperbaric medicine are chronic diabetic foot ulcers, which are associated with life- and limb-threatening infections, tissue necrosis, osteomyelitis, amputations, and nonhealing amputation sites; and delayed radiation injury, which is associated with bone and soft-tissue necrosis and failure of skin flaps and grafts. This article discusses how HBOT promotes healing, with a particular focus on delayed radiation injury.
Factors Contributing to Poor Wound Healing
A problem wound is one that fails to progress normally through the typical stages of healing. It demonstrates poor granulation, persistent exudates, retarded contraction, and/or failure of neo-epithelialization. Skin flaps and grafts fail to integrate with the underlying tissue, leading to retraction and death of the flap or graft and to re-exposure of the original wound in its initial or a worsened state. In some cases, the overt cause of a problem wound is a surgical procedure in tissue that is intact but compromised.
Multiple factors can contribute to the failure of a wound to heal. Low tissue oxygenation, caused either by decreased systemic oxygenation or by poor tissue perfusion, is foremost among these factors. Others include inflammation; infection; nutritional deficiencies; repetitive trauma; poor glucose and lipid control; hematologic, rheumatologic, and autoimmune disorders; use of certain medications; and social and economic concerns such as alcohol and tobacco use, poverty, and homelessness (Table 2).4 Therefore, treating any wound that is not healing properly must involve identification of all contributing factors and a focused attempt to eliminate or ameliorate each one. Tobacco use bears special mention because it is common and avoidable. Tobacco contributes to the development of wounds, delays in healing, wound dehiscence, and infection. Nicotine causes vasoconstriction, resulting in local tissue hypoxia.4
Vasoconstriction in the microcirculation has been demonstrated within five to 10 minutes of smoking one cigarette, and microvascular flow is reduced by 30% to 38% after two cigarettes.5,6 Nicotine substitutes have the same effect. Smoking also appears to be correlated with long-term endothelial vasomotor alterations, endothelial dysfunction, accelerated atherosclerosis, platelet activation, and decrements in collagen synthesis,7-10 all of which contribute to poor wound healing in current and former smokers.
The Role of Oxygen in Wound Healing
Hypoxia plays an important role in initiating the healing process. Local tissue hypoxia generates specific proteins that maintain oxygen homeostasis and regulate hypoxia-inducible genes. These proteins are called hypoxia-inducing factors (HIF), and the genes they regulate include human erythropoietin (EPO), vascular endothelial growth factor (VEGF), heme oxygenase I (OH I), lactate dehydrogenase A (LDHA), inducible nitric oxide synthase (iNOS), and glucose transporter I. These hypoxia-inducible genes help to resolve hypoxia by increasing the number of erythrocytes in the blood, enhancing development and relaxation of blood vessels, and adapting cellular metabolism to low oxygen conditions, thereby improving the oxygen-carrying capacity of the blood, tissue perfusion, and local cellular adaptation to low-oxygen tensions.4 Although hypoxia is required to initiate the healing process, adequate oxygen is necessary to support the cell proliferation stage of wound healing.11,12 Neutrophils remove necrotic tissue, bacteria, and debris from the wound through oxidative killing, which is oxygen-dependent.13 Neutrophils also secrete growth factors and chemotactic factors for macrophages. The macrophages are instrumental in regulating the wound-healing process and are the primary source for vascular endothelial growth factor, which plays a major role in the development of a vascular network within the wound.14,15 The proliferation of leukocytes, fibroblasts, and keratinocytes requires adequate tissue oxygen content. And the rate of fibroblast production of collagen is dependent on the level of oxygen.16< Therefore, after the initial injury, wounds that do not have adequate oxygen do not heal.
How Hyperbaric Oxygen Therapy Works
(Photos and descriptions)
The primary therapeutic mechanism of hyperbaric oxygen is improving oxygen delivery to tissue by dissolving oxygen in plasma. Under normal conditions at sea level, a healthy person has a hemoglobin saturation of 97% to 100% and a negligible amount of oxygen dissolved in plasma (0.3 vol %, which equals 0.3 cc of oxygen for every 100 cc of blood). Because hemoglobin is already nearly saturated, the only way to increase the oxygen-carrying capacity of blood is to dissolve more oxygen in the plasma. The same healthy person breathing 100% oxygen at sea level will have a hemoglobin saturation of 100% and dissolved oxygen in plasma of 2 vol %. Because the solubility of a gas in a liquid increases with pressure, another 2 vol % oxygen is added to plasma for every additional atmosphere of pressure. Breathing pure oxygen at two times atmospheric pressure will result in an arterial pO2 of about 1,400 mmHg and 4 vol % oxygen dissolved in plasma.17 At three times normal atmospheric pressure, arterial pO2 is 2,100 mmHg and 6 vol % oxygen is dissolved in the plasma, which is sufficient to meet the requirements of the heart and brain in the absence of circulating hemoglobin, thus accounting for survival of patients with severe acute blood loss anemia treated with HBOT.1
The dramatic increase in the arterial oxygen content of the blood going to tissues during HBOT creates a steep diffusion gradient favoring oxygen movement to tissue and increasing the diffusion distance of oxygen. At three times normal atmospheric pressure, for example, the diffusion distance from the precapillary arteriole into the extravascular compartment is increased from 64 microns to 240 microns.18 This is thought to enable a smaller number of capillaries to deliver oxygen to a larger volume of tissue.
HBOT and Wound Healing
Hyperbaric oxygen therapy promotes wound healing in a number of ways (Table 3) including intermittent correction of tissue hypoxia and direct enhancement of fibroblast proliferation, collagen synthesis, neovascularization, and epithelialization.14,19,20 It also reduces local tissue edema by causing vasoconstriction of both arterial and venous vessels. Although blood “in-flow” is reduced, with very high arterial oxygen content, the net effect of HBOT is an increase in tissue oxygen.13,16,21 Hyperbaric oxygen therapy also improves the host immune response. It is toxic to anaerobes and promotes leukocyte bactericidal action against both Gram- positive and Gram-negative aerobes.22-24 In addition, HBOT enhances the transport of aminoglycoside antibiotics across the bacterial cell wall, enhancing the efficacy of these drugs, which is inhibited in vivo by local tissue hypoxia.25
Hyperbaric oxygen therapy raises the low-tissue oxygen tensions in infected bone to normal or above-normal levels26 and stimulates osteoblast and osteoclast function, which is impaired under hypoxic conditions. It also up-regulates the gene expression for the platelet-derived growth factor (PDGF) beta receptor, which may be one of the mechanisms by which HBOT enhances angiogenesis.27 Of interest with respect to acute ischemia in crush injury and compartment syndrome, closed head trauma, and replantation surgery, HBOT mitigates leukocyte-mediated post-ischemic reperfusion injury in muscle and brain tissue by preventing leukocyte adhesion to the venule wall, thereby limiting the production of oxygen free radicals.28-30
HBOT for Delayed Radiation Injury
(Case Study - photos and discriptions)
Hyperbaric oxygen therapy has been used successfully to treat the complications of delayed radiation injury for 30 years. Delayed radiation injury is usually seen six months or more after radiation and is characterized by endarteritis, hypocellularity, and severe secondary fibrosis. The current thinking is that the obliterative endarteritis, the prolonged depletion of cell lines (fibroblasts, squamous cells) and stem cells, and the release of fibrogenic cytokines by the radiation all play a role in the permanent and progressive damage to these tissues. Wound healing in irradiated tissue is inhibited both by the hypoxia resulting from endarteritis and by the absence of cells essential for wound repair.31
Hyperbaric oxygen therapy stimulates angiogenesis in irradiated tissue, resulting in increased vascularity.32 Increased oxygen tensions in the irradiated tissue accompany this increased vascularity as patients progress through a series of hyperbaric treatments. This improvement in resting tissue oxygen levels is robust over time.33 In the animal model, even the vascular density of irradiated bone has been shown to increase with HBOT.34 Increased cellular density also has been demonstrated in heavily irradiated tissue in humans.32 Two studies have shown that HBOT can mobilize stem cells by increasing nitric oxide,35,36 although this has not yet been shown to have a direct impact on irradiated tissue. The beneficial effect of HBOT on irradiated tissue is likely to involve all three mechanisms: stimulating angiogenesis, reducing fibrosis and increasing cellular density, and mobilizing stem cells.
Although spontaneous necrosis of soft tissue or bone in the irradiated field may occur, more often, complications of delayed radiation injury happen because of surgical procedures in the irradiated field.31 These surgical procedures fall into one of several categories: 1) surgical salvage for cancer recurrence in the irradiated field (eg, laryngectomy for recurrent laryngeal cancer), 2) surgery in the irradiated tissue for a condition unrelated to the initial malignancy (eg, CABG after radiation for breast cancer), or 3) surgery to address radiation-induced injury (dental extractions for severe radiation caries; flap coverage after debridement of radiation tissue necrosis).
Based on the results of current research, a case may be made for preoperative HBOT to improve the outcome of any major surgical procedure that is to occur in a field that was heavily irradiated more than four months previously. Preoperative HBOT is a well-established practice in the case of extraction of nonrestorable teeth from within a heavily irradiated field. Pre- and postoperative HBOT have been shown to reduce the incidence of subsequent mandibular osteoradionecrosis from 29.9% to 5.4%.37Significant improvement in osseous integration and reduction of subsequent osteoradionecrosis has been demonstrated when dental implants within an irradiated field are supported by pre- and postimplant HBOT.38 The successful eradication of mandibular osteoradionecrosis has been demonstrated with presurgical HBOT, then debridement of all necrotic bone, followed by postsurgical HBOT, whereas, historically, either surgery alone or HBOT alone have failed to halt this progressively destructive process.33 This combined approach has been shown to be less expensive than surgery or HBOT alone.39 Improved outcomes have been reported for bladder surgery following HBOT.40
Serious wound complications are common after head and neck surgeries within a previously irradiated field.31 In a series of patients for whom surgery was planned to repair radiation necrosis wounds or to resect recurrent cancer, a marked reduction was reported in the incidence of wound infection, wound dehiscence, and delayed healing when HBOT was used before and after surgery, compared with controls. However, patients requiring urgent salvage surgery for recurrent cancer in an irradiated field may not have the option of pretreatment. Hyperbaric oxygen therapy still has a role in reducing wound complications in these patients. When surgical resection is performed for laryngeal or pharyngeal cancers in previously irradiated fields, starting HBOT when it is evident that the wounds are not healing results in much-improved outcomes compared with historical controls.41 An even greater reduction in complications, as compared with patients who do not undergo HBOT, is associated with starting HBOT immediately after surgery, without waiting for evidence of wound complications.42 More research is needed to identify the patients at greatest risk for and the procedures most associated with serious postoperative wound complications. Cost analyses are not available for head and neck salvage procedures. Given the cost of a major flap procedure that fails (initial surgical costs, prolonged hospitalization, repeat debridements, and a second reconstructive procedure), for example, it is likely to be less expensive to undertake a coordinated plan of surgery and HBOT.
Conclusion
The field of hyperbaric medicine has grown over the past two decades primarily because of its efficacy for treating problem wounds. It has proved to be especially helpful for diabetic patients with chronic lower extremity wounds and for cancer patients with healing problems caused by delayed radiation injury. Additional research will improve our understanding of these and other problem wounds and the role of HBOT in improving outcomes. MM
Cheryl Adkinson is medical director of hyperbaric medicine at Hennepin County Medical Center and an associate professor of emergency medicine at the University of Minnesota.
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