In a non-irradiated wound, there is usually an area of injury closely surrounded by relatively normal tissue. The oxygen tension at the center of the wound is typically extremely low, and the adjacent tissue possesses normal oxygen tensions. This naturally steep oxygen gradient from injured to normal tissue over a short distance attracts macrophages and stimulates macrophage derived angiogenesis factor and macrophage derived growth factor.^56,104 These growth factors promote capillary budding and collagen synthesis,⁵⁶ thus promoting revascularization of the injured tissue.

In irradiated bone and soft tissue, radionecrosis develops because a diffuse injury pattern inhibits revascularization. Radiation is delivered at greater dosages and, thus, creates greater cellular damage at the center of the radiation port than at the periphery. The dose and injury diminish at incremental distances from the center of the port towards the periphery, producing a graded, diffuse injury pattern. The incrementally diminishing injury pattern compromises oxygenation of the tissue in a gradually declining pattern. The result is a shallow oxygen gradient between injured and normal tissue, a pattern similar to that in brain radionecrosis. The shallow oxygen gradient inhibits the physiochemical response, and macrophages are not stimulated to induce angiogenesis. Studies in bone and soft tissue have shown that hyperbaric oxygen therapy can artificially create a steep oxygen gradient from a shallow one to trigger the biochemical response required for angiogenesis.^89,90 Hyperbaric oxygen therapy increases the oxygen gradient by providing inhaled one hundred percent oxygen at pressure, raising the arterial oxygen partial pressure about ten to thirteen times above normal levels.⁴¹ Hyperbaric oxygen therapy has been shown to induce angiogenesis, promote healing and reverse injury in irradiated soft tissue and bone.^{1, 4, 14, 19, 21, 22, 23, 24, 31, 32, 33, 55, 59, 69, 70, 71, 74, 76, 78, 84, 86, 88, 94, 96, 99, 112}

Both the National Institutes of Health and the National Cancer Institute (NCI) have endorsed the use of hyperbaric oxygen therapy for the amelioration of osteoradionecrosis.^84,86 The Consensus Development Panel of the National Institutes Health of has issued a consensus statement on oral complications of cancer therapies. It states that "the keystone of treatment of osteoradionecrosis is the provision of adequate tissue oxygenation in damaged bone.

Figure 2. The hypothesized mechanism of action of hyperbaric oxygen therapy in brain radionecrosis.
ENLARGE

This is best done by using hyperbaric oxygen therapy." "Early stages of osteoradionecrosis may be cured by hyperbaric oxygen therapy alone."⁸⁶ Our belief is that a similar mechanism occurs in brain radionecrosis and that hyperbaric oxygen therapy will induce neovascularization and reverse injury in brain tissue.

In addition to promoting neovascularization, hyperbaric oxygen therapy has been shown to:

     • decrease cerebral edema
     • decrease elevated intracerebral pressure

in both animal models and clinical studies of traumatic cerebral edema.^{12, 16, 17, 35, 43, 48, 52, 53, 80, 81, 82, 85, 107, 108} Hyperbaric oxygen lowers intracerebral pressure (ICP) by decreasing both vasogenic edema and cytotoxic edema. Reduction of cerebral blood flow and volume, which in turn decreases edema and ICP, is obtained through regulatory vasoconstriction. This vasoconstriction occurs secondary to the hyperoxygenated state created through hyperbaric oxygen therapy. Because the patient is hyperoxygenated, decreased cerebral blood flow is not detrimental and cerebral oxygenation is maintained. In addition to maintaining already oxygenated tissue, hyperbaric oxygen therapy is able to reverse cerebral hypoxia. Mitigation of cerebral hypoxia reduces cytotoxic induced cerebral edema and halts the cycle of hypoxia/edema.⁵¹ Both of these mechanisms, individually and combined, reduce cerebral edema which perpetuates the injury leading to progressive brain injury and necrosis.