The injuries caused by carbon monoxide (CO) traditionally have been viewed as due to a hypoxic stress mediated by an elevated carboxyhemoglobin (COHb) level. While hypoxic stress is clearly an element of poisoning, some injuries appear to be mediated by systemic oxidative stress. Perivascular and neuronal injuries arise by mechanisms other than hypoxia.(1,2) Neuropathology is due to a complex cascade of biochemical events involving several pathophysiologic processes,(3-10) some independent of pure hypoxic stress(11-13). Furthermore, the COHb level does not correlate with the development of neurological or cognitive sequelae.(14-18)

The two organ systems most susceptible to injury from CO are the cardiovascular and central nervous systems. Human and animal data indicate that major cardiac injury at the time of poisoning is due primarily to CO-induced hypoxic stress.(19-21) In addition, the risk for cardiovascular-related death in patients with initial CO-induced cardiac injury appears to be increased over the 10 years following injury.(22) Many neurological problems can follow CO poisoning and include motor weakness, peripheral neuropathies, hearing loss, and Parkinsonian-like syndrome. Cognitive sequelae following CO poisoning are common. Also, the incidence of anxiety and depression is high following acute CO poisoning and may not be influenced by hyperbaric oxygen therapy (HBO2).(23)

Administration of supplemental oxygen is the cornerstone of treatment of CO poisoning, although there are no clinical trials demonstrating improved outcomes using oxygen therapy administered at atmospheric pressure. Nevertheless, supplemental oxygen inhalation will hasten dissociation of CO from hemoglobin and provide enhanced tissue oxygenation. HBO2 hastens COHb dissociation compared to breathing pure oxygen at sea-level pressure.(24-27) Additionally, HBO2, but not ambient pressure oxygen treatment, has several actions, which have been demonstrated in animal models to be beneficial in ameliorating central nervous system (CNS) injuries. These include an improvement in mitochondrial oxidative processes,(28,29) inhibition of lipid peroxidation,(30) and impairment of leukocyte adhesion to injured microvasculature.(31) Animals poisoned with CO and treated with HBO2 have been found to have more rapid improvement in cardiovascular status,(24) lower mortality,(32) and lower incidence of neurological sequelae.(33,34)

Since 1960, the clinical use of HBO2 for CO poisoning has occurred with increasing frequency. Among patients treated with HBO2, both mortality and neurocognitive morbidity are improved beyond that expected with ambient pressure supplemental oxygen therapy.(38-43) The optimal benefit from HBO2 occurs in those treated with the least delay after exposure.(39) In selected patients, repeated treatments may yield a better outcome than a single treatment.(43)

Carbon monoxide and cyanide poisoning frequently occur simultaneously in victims of smoke inhalation.(70-76) In combination, these two agents exhibit synergistic toxicity.(77,78) HBO2 should be strongly considered in such cases. In addition to its effect on CO, HBO2 may have a direct effect in reducing the toxicity of cyanide(79-83) and in augmenting the benefit of antidote treatment.(84 86) Clinical reports involving the use of HBO2 in pure cyanide poisoning are infrequent; however, some reports suggest a benefit.(87-89) Since the condition carries a high mortality risk, HBO2 treatment is justified if standard therapy is unsuccessful. The traditional antidote for cyanide poisoning involves formation of methemoglobin through the infusion of sodium nitrite.(90,91) This treatment has the potential to impair the oxygen carrying capacity of hemoglobin. In the smoke inhalation victim, with concomitant COHb and possible pulmonary injury, there is an obvious added risk associated with methemoglobin formation. The HBO2 mediated increase in plasma-dissolved oxygen content offers a direct benefit. However, one must be cautious in this setting because the methemoglobin level may be directly lowered by hyperoxia (at least at 4 atm abs), possibly reducing the efficacy of antidotal therapy.(92)

Antidotal therapies other than nitrite methemoglobin formation exist, although their use is still investigational. Hydroxocobalamin and dicobalt EDTA directly bind cyanide, obviating the need for methemoglobin formation,(93,96) however, since these agents possess their own toxicities, their use is currently limited. Until direct antidotes become available, HBO2 is recommended as an adjunct to the treatment of combined CO poisoning complicated by cyanide poisoning.

For clostridial myositis and myonecrosis (gas gangrene) or spreading clostridial cellulitis with systemic toxicity (or a presumptive diagnosis of either) the preferred treatment is a combination of hyperbaric oxygen (HBO2), surgery, and antibiotics.

Clostridial myositis and myonecrosis or gas gangrene is an acute, rapidly progressive, non-pyogenic, invasive clostridial infection of the muscles, characterized by profound toxemia, extensive edema, massive death of tissue, and a variable degree of gas production.(1) Gas gangrene is either an endogenous infection, caused by contamination from a clostridial focus in the body, or an exogenous infection, mostly in patients with compound and/or complicated fractures with extensive soft tissue injuries after street accidents.

The infection is caused by anaerobic, spore‑forming, Gram‑ positive encapsulated bacilli of the genus clostridium, discovered by William H. Welch in 1891.(2) More than 150 species of clostridium have been recognized but the most commonly isolated is C. perfringens type A (95%) either alone or in combination with other pathogenic clostridia, C. novyi (8%), C. septicum (4%), and C. histolyticum, C. fallax, and C. sordelli (1% or less of the infections).(3,4)

A further subdivision can be made in clostridia that are toxo-genic, i.e., C. perfringens, C. septicum, C. novyi, and clostridia that are believed to be only proteolytic, i.e., C. histolyticum, C. bifermentans, C. sporogenes, and C. fallax, which augment an infection by their proteolytic capabilities but do not cause the classical gas gangrene syndrome. C. tertium, C. sphenoides, and C. sordelli can be considered as contaminants. It is not known if and what these microorganisms add to the disease process. The essential role of alpha-toxin in the pathogenesis of gas gangrene was recently confirmed by Williamson and Titball,(5) who developed a genetically engineered vaccine against alpha-toxin. Immunization with the C-Domain of α-toxin proved to be of value in animal experiments.(6)

Clostridium perfringens is not a strict anaerobe; it may grow freely in O2 tensions of up to 30 mmHg and in a restricted manner in O2 tensions up to 70 mmHg.(7)

The complete genome sequence of C.Perfringens has been published recently by Shimizu et al.(8)

The key to understanding the pathophysiology of gas gangrene is to approach it as a clinical concept, rather than a definitive bacteriologic or pathologic entity.

For the induction of gas gangrene, two conditions have to be fulfilled:

The presence of clostridial spores and An area of lowered oxidation‑reduction potential caused by circulatory failure in a local area or by extensive soft tissue damage and necrotic muscle tissue. This condition results in an area with a low O2 tension where clostridial spores can develop into the vegetative form.

More than 20 different clostridial exotoxins have been identified, nine of which are implicated in the local and systemic changes seen in gas gangrene; alpha‑toxin, theta‑toxin, kappa‑ toxin, mu‑toxin, nu‑toxin, fibrinolysin, neuraminidase, "circulating factor," and "bursting factor."(9-11)

The most prevalent is the O2‑stable lecithinase‑C, alpha‑ toxin, which is hemolytic and tissue‑necrotizing. It destroys platelets and polymorphnuclear leukocytes and causes widespread capillary damage and is often lethal.(12)

The other toxins are ancillary to the alpha‑toxin, which gives rise to hemoglobinuria, hemolysis, jaundice, anemia, tissue necrosis, renal failure, and serious systemic effects such as cardiotoxicity and brain dysfunction. The other exotoxins are synergistic and enhance the rapid spread of infection by destroying, liquefying, and dissecting healthy tissue. The clostridial organisms surround themselves with toxins. Local host defense mechanisms are abolished when the toxin production is sufficiently high. This results in fulminating tissue destruction and further clostridial growth. Alpha‑toxin can be fixed to susceptible skin cells in 20-30 min, is detoxified within 2 hours after its elaboration, and causes active immunity with production of a specific antitoxin.(10,13) The infection, however, is so progressive with continuous production of alpha‑toxin that the patient dies before any immunity can develop.

Stevens et al(14) investigated the role of theta-toxin in the pathogenesis of clostridial gas gangrene. They found evidence for the suggestion that theta-toxin in high concentrations is a potent cytolysin and promotes direct vascular injury at the site of infection. At lower concentrations, theta-toxin activates PMNs and endothelial cells, and in so doing promotes vascular injury distally by activating adherence mechanisms by PMN-dependent adherence molecules such as the integrin CD11/CD18.

The rapid tissue necrosis associated with C. perfringens infection is related to progressive vascular compromise orchestrated by dysregulated host cell responses induced by theta-toxin.(14) In earlier papers, Stevens et al(15,1) already described the lethal effects and cardiovascular effects of purified alpha- and theta-toxins from C.perfringens.

An extensive and updated review about the role of clostridial toxins in the pathogenesis of gas gangrene was given by Stevens and Bryant.(16)

Awad et al,(17) showed genetic evidence for the essential role of alpha-toxin in gas gangrene.

Eaton et al(18) have further described the crystal structure in combination with the working mechanisms of alpha toxin. In conjunction with previous findings, almost the whole working mechanism with the structure of their toxin is known now.

Stevens et al,(19) also showed evidence that alpha- and theta-toxins differentially modulate the immune response and induce acute tissue necrosis in clostridial gas gangrene. Much more has become known in recent years about the action and also the interaction between the various clostridial toxins in the onset and progression of gas gangrene. A very informative review on a cellular and molecular model of the pathogenesis of clostridial myonecrosis, including the above mentioned data is given by Stevens(1) and Titbal.(12)

The action of HBO2 on clostridia (and other anaerobes) is based on the formation of O2 free radicals in the relative absence of free radical degrading enzymes, such as superoxide dismutases, catalases, and peroxidases. Van Unnik(20) showed that an O2 tension of 250 mmHg is necessary to stop alpha‑ toxin production. Although it does not kill all clostridia, it is bacteriostatic both in vivo and in vitro.(20-24) Tissue O2 measurements made by Schoemaker,(25) Kivisaari and Niinikoski,(26) and Sheffield(27) have shown that treatment with HBO2 at 3.0 atm abs is required to achieve tissue partial pressures above 300 mmHg. Free-circulating toxins and/or tissue‑ bound toxins are not affected by high O2 levels but they are rapidly detoxified by normal host factors.(9,21,28,29)

If further toxin elaboration is prevented by the addition of hyperbaric oxygen, a very sick patient can rapidly be made non-toxic.

The diagnosis of clostridial myonecrosis is based primarily on clinical data, supported by the demonstration of Gram‑ positive rods from the fluids of the involved tissues as well as a virtual absence of leukocytes. A leukocytosis indicates a mixed infection.

Roggentin et al.(30) developed an immunoassay for rapid and specific detection of C. perfingens, C. septicum, and C. sordelli by determining their sialidase activity (neuraminidase) in serum and tissue homogenates. Sialidases produced by these three clostridia were bound to polyclonal antibodies raised against the respective enzymes and immobilized onto microtiter plates. Applied to nine samples from patients, there was a high correlation between the results of the immunoassay and the bacteriological analysis of the infection.(30)

Scheven(31) described identification of C.perfringens in mixed-infected clinical materials by means of a modified reversed CAMP-test.

The onset of gas gangrene may occur between 1 and 6 hours after injury or an operation and begins with severe and sudden pain in the infected area before the clinical signs appear. This seemingly disproportionate pain in a clinically still normal area must make the clinician highly suspicious for a developing gas gangrene, especially after trauma or an operation. The body temperature is initially normal but than rises very quickly. The skin overlying the wound in the early phases appears shiny and tense and then becomes dusky and progresses to a bronze discoloration. The infection can advance at a rate of 6 inches per hour. Any delay in recognition or treatment may be fatal. Hemorrhagic bullae or vesicles may also be noted. A thin, sero-sanguinolent exudate with a sickly, sweet odor is present. Swelling and edema of the infected area is pronounced. The muscles appear dark red to black or greenish. They are noncontractile, and do not bleed when cut.

The tissue gas seen on radiographs appears as feather‑like figures between muscle fibers and is an early and highly characteristic sign of clostridial myonecrosis. Crepitus is usually present as well.

The acute problem in gas gangrene is not normal tissue or already necrotic tissue, but the rapidly advancing phlegmon in between, which is caused by the continuous production of alpha toxin in infected but still viable tissue. It is essential to stop alpha‑toxin production as soon as possible and to continue therapy until the advance of the disease process has been clearly arrested. Since van Unnik showed that a tissue PO2 of 250 mmHg is necessary to stop toxin production completely, the only way to achieve this is to start hyperbaric oxygen therapy as soon as possible.(20)

A minimum of three to four HBO2 treatments is necessary for this response. Treatment starts on the basis of the clinical picture and the positive Gram‑stained smear of the wound fluid (without leukocytes). HBO2 treatment stops alpha‑toxin production and inhibits bacterial growth thus enabling the body to utilize its own host defense mechanisms.(20-24) Although a three‑pronged approach consisting of HBO2, surgery, and antibiotics is essential in treating gas gangrene, initial surgery can be restricted to opening of the wound. An initial fasciotomy may be undertaken, but lengthy and extensive procedures in these very ill patients can usually be postponed, depending on how rapidly HBO2 therapy can be initiated. Debridement of necrotic tissue can be performed between HBO2 treatments and should be delayed until clear demarcation between dead and viable tissues can be seen.

The first clinical results in gas gangrene were remarkable, but were difficult to reproduce in the animal model.(22,23,46)

Despite wide variations in O2 tolerance between small and large laboratory animals and human beings, HBO2 therapy has been used to treat experimental clostridial infections in animals. The greatest reduction in mortality in dogs was achieved by a combination of HBO2, surgery, and antibiotics.(24) In general, studies of several investigators(22,23,32,33,34,46) have shown that HBO2 substantially reduced mortality and morbidity in animals following clostridial infections, when used in combination with surgery and antibiotics.

Major retrospective clinical studies indicate that the lowest morbidity and mortality are achieved with initial conservative surgery and rapid initiation of HBO2 therapy. Results decline progressively when HBO2 therapy is delayed. Early aggressive surgery and delayed HBO2 treatment lead to a significantly higher mortality and morbidity than when HBO2 is administered promptly.(35,36,37) Ertmann and Havemann indicate, on the basis of their experience in a series of 136 patients, treated over a twenty year period, the necessity for a combined treatment approach. However, they place surgery earlier in the protocol, sometimes after the first hyperbaric session already. All patients treated without hyperbaric oxygen or only once or twice, died.(38)

The work by Brummelkamp et al.(39,40) updated by Bakker(41,1) totaling 409 cases of clostridial gas gangrene showed a mortality directly related to the clostridial infection of 11.7%. All 48 patients who died did so within 26 h after the start of HBO2 therapy. HBO2 therapy also greatly reduced the amputation rate: only 18% required amputation post-hyperbaric therapy vs. 50-55% following primary surgery.(4,35,36)

Hart et al.(42) reported a 17% amputation rate with combined therapeutic management. Reduced mortality rates were also demonstrated by Hart et al.,(42) Hitchcock et al.,(10) Holland et al.,(43) Van Zijl,(44) and Heimbach.(45) Heimbach(11) showed a 5.1% mortality rate among 58 patients whose HBO2 therapy began within the first 24 hours; these results reinforce earlier clinical trials.

Mortality in the series of Hirn(46) was 28%. He concluded that mortality and morbidity could be reduced if the disease is recognized early and appropriate therapy applied promptly. He recommends adequate and operative debridement, antibiotics, HBO2, and surgical intensive care.

In experimental monomicrobial gas gangrene, the combination therapy of surgery and HBO2 started 45 min after the inoculation of bacteria, reduced mortality to 13% compared with 38% with surgery alone. The combination therapy appeared to be especially effective in wound healing and in prevention of morbidity compared with surgical debridement alone. The effectiveness of the combination therapy was strongly time dependent.

In the multimicrobial gas gangrene model, the additon of HBO2 to surgery tended to reduce mortality, but the difference between the groups was not statistically significant. However, the combined therapy with surgery and HBO2 was highly effective in reducing morbidity and mortality and improving wound healing compared with surgical debridement alone.(46)

The advantages of early HBO2 treatment are that: It is life‑saving because less heroic surgery needs to be performed in gravely ill patients and the cessation of alpha‑toxin production is rapid. It is limb and tissue‑saving because no major amputations or excisions are done prematurely (except opening of wounds). It clarifies the demarcation, so that within 24-30 hours there is a clear distinction between dead and still‑living tissue. In this way, both the number and the extent of amputations are reduced. In 1984 Peirce already concluded that the modern treatment of gas gangrene involves the simultaneous use of antibiotics, surgical debridement and hyperbaric oxygen.(47) He also believed, that even at that time, it would be unethical to carry out a randomized clinical study to compare these three modalities. This opinion was based on the results published until 1984.(41,47)

Subsequent experience continues to support the approach he recommended. With the same therapy these results have been consistent over the years, and the outcome has been further improved with advanced intensive care medicine.

Introduction and Definitions: Crush injuries represent a spectrum of injury to body parts as result of trauma. Presentations vary from minor contusions to limb threatening damage. Typically, the injury involves multiple tissues from skin and subcutaneous to muscle and tendons to bone and joints. In their most severe presentations, predictable complications including osteomyelitis, non-union of fractures, failed flaps and amputations occur in approximately 50 percent of the cases with "standard of practice” surgical and medical interventions.(1-3)

The skeletal muscle- compartment syndrome (SMCS) is another consequence of trauma, but in this situation the target tissues are muscles and nerve. Edema and/or bleeding within the confines of the fascial envelope increase the pressure within the skeletal muscle-compartment. When the tissue fluid pressure within the compartment exceeds the capillary perfusion pressure to the muscles and nerves in the compartment, these tissues are rendered ischemic and manifest the signs and symptoms of a SMCS. The SMCS, especially in its insipient stages before a fasciotomy is required, is a therapeutic challenge since no means to arrest its progression other than hyperbaric oxygen (HBO2) exist.

Unfortunately, HBO2 is woefully neglected as an adjunct for managing crush injury and SMCS. Strong arguments for its use based on evidenced-based information and how HBO2 mitigates the pathology of these conditions exist.

Pathophysiology: Trauma plus tissue hypoxia are the common denominators of crush injuries and SMCS. This leads to two consequences; first, a continuum of injury from normal to irreversibly damaged, and second, a self-perpetuating (i.e. vicious circle) progression of edema contributing to tissue ischemia and vice versa. Consequences of trauma include visible damage to tissue, injury at the cellular level and biochemical alterations. If the trauma and consequent energy transfer to the tissues is great enough, the tissues will immediately die. The only options in these circumstances are debridement if the site of involvement is small or major limb amputation if large.

At the cellular level the self-perpetuating aspects of these injuries manifest themselves. Trauma to blood vessels, especially at the microcirculation level, leads to transudation of fluid (i.e. edema formation), interstitial bleeding, sluggish flow, stasis, slugging, rouleau formation, and obstruction. The consequences are ischemia and hypoxia to the tissues perfused by the damaged vasculature. When this occurs, cells are no longer able to maintain their metabolic functions such as retaining their intracellular water. This further contributes to edema and third spacing of fluid. If the edema occurs in a closed space the increased pressure will collapse the microcirculation, eliminate oxygen transfer across the capillary endothelium and further contribute to the hypoxic insult.

Events at the biochemical level, the ultimate determinants of outcome, are manifested in two ways. First, oxygen is required for all cellular metabolic functions. If oxygen tensions are insufficient, wound healing and angiogenesis responses as elaborated through the fibroblast and bacterial killing by the neutrophil are thwarted.(4-6) Oxygen tensions in the tissue fluids greater than 30 mmHg are required for these responses to occur7. The second biochemical event is that of the reperfusion injury.(8) Once perfusion is temporarily interrupted, occurring in varying degrees with crush injuries and compartment syndromes, the endothelium becomes sensitized to the hypoxic insult. This results in activation of adhesion molecules leading to the attachment of neutrophils to the endothelium. The consequence is a cascade of biochemical events arising from the neutrophil releasing its reactive oxygen species. These oxygen radicals damage tissue beyond repair and cause severe vasoconstriction, defining the reperfusion injury and the no reflow phenomenon associated with it.

Mechanisms of HBO2: The immediate justifications for using HBO2 in crush injuries and compartment syndromes are twofold: First, HBO2 supplements oxygen availability to hypoxic tissues during the early post-injury period when perfusion is most likely to be inadequate. Second, HBO2 increases tissue oxygen tensions to sufficient levels for the host responses mentioned above to function. Hyperbaric oxygen exposures at two atmospheres absolute (ATA) increase the blood oxygen content (the combination of hemoglobin and plasma carried oxygen) by 125 percent. The oxygen tensions in plasma as well as tissue fluids is increased 10-fold (1000 %).(9-11) Sufficient oxygen can be physically dissolved in plasma under HBO2 conditions to keep tissues alive without hemoglobin-borne oxygen.(11) Increased tissue oxygen tensions result in a three-fold "driving force” (mass effect) for oxygen to diffuse through tissue fluids.(12,13) This helps to compensate for the hypoxia resulting from the increased oxygen diffusion distance from the capillary to the cell through the surrounding edema.

Edema reduction is a secondary effect of tissue hyperoxygenation. Hyperbaric oxygen induces vasoconstriction which reduces blood flow by 20 percent.(10,14) Since inflow is decreased by 20 percent through vasoconstriction while outflow is maintained, the net effect is edema reduction of 20 percent.(14-18) Edema reduction occurs because of decreased filtration of fluid from the capillary to the extracellular space as a consequence of vasoconstriction while resorption of fluid at the capillary level is maintained. Hyperoxygenation of the plasma maintains oxygen delivery to tissues in the presence of HBO2-induced vasoconstriction.(10,19,20) Another consequence of decreasing the interstitial fluid pressure through edema reduction is improved blood flow through the microcirculation. The reason for this is that once the interstitial fluid pressure is reduced below the capillary perfusion pressure, the collapsed microcirculation can again open-up and allow perfusion to resume. By reducing edema while supplementing tissue oxygenation, HBO2 interrupts the self-perpetuating, edema-ischemia "vicious circle” cycle to prevent progression of the injury.

Mitigation of the reperfusion injury is another effect of HBO2 for crush injuries and compartment syndromes.(21-23) It interrupts the interactions between toxic oxygen radicals and cell membrane lipids by perturbing lipid peroxidation of the cell membrane and inhibiting the sequestration of neutrophils on post-capillary venules.(24-26) The biochemical mechanism that accounts for this latter effect is that HBO2 interferes with the adherence of neutrophils elaborated through the Beta2 integrin (Cluster-Designation-11) on the sensitized capillary endothelium.(22) The result is interruption of the superoxide anion interaction with nitric oxide that produces the highly reactive peroxynitrite radical.(27) Another benefit of HBO2 for reperfusion injury is the help in providing an oxygenated environment for the generation of oxygen radical scavengers (such as superoxide dismutase, catalase, peroxidase and glutathione) that detoxify reactive oxygen species.(28,29)

Decompression sickness (DCS, "bends”) is due to the formation of inert gas bubbles in tissues and/or blood due to supersaturation, where either the mechanical stresses caused by bubbles or their secondary cellular effects cause organ dysfunction.(1-5) DCS can be caused by a reduction in ambient pressure during ascent from a dive, rapid altitude excursion, in space or a hyperbaric/hypobaric chamber. In diving, compressed gas breathing is usually necessary, although rarely DCS has occurred after either repetitive or deep breath hold dives.(6,7) Bubble formation occurs when decompression occurs sufficiently fast that tissue inert gas partial pressure exceeds ambient pressure, causing supersaturation and bubble formation. The resulting clinical manifestations include joint pains (limb bends), cutaneous eruptions or rashes (skin bends), neurological dysfunction (peripheral or central nervous system bends), cardiorespiratory symptoms and pulmonary edema (chokes), shock and death.(8) Several mechanisms have been hypothesized by which bubbles may exert their deleterious effects. These include direct mechanical disruption of tissue, occlusion of blood flow, platelet deposition and activation of the coagulation cascade,(9) endothelial dysfunction(10.11) and capillary leakage,(12-16) complement activation(17,18) and leukocyte-endothelial interaction.(19)

The diagnosis of DCS is made on the basis of signs and/or symptoms after a dive or altitude exposure.(8) Manifestations most commonly include paresthesias, hypesthesia, joint pain, skin rash and malaise. More serious signs and symptoms include motor weakness, ataxia, dyspnea, urethral and anal sphincter dysfunction, shock and death.(8,20,21) Severe DCS may be accompanied by hemoconcentration and hypotension.(12-14,16) Severe symptoms usually occur within 1-3 hours of decompression; the vast majority of all symptoms manifest within 24 hours, unless there is an additional decompression (e.g. altitude exposure).

Chest radiography prior to HBO2 treatment in selected cases may be useful to exclude pneumothorax (which may require tube thoracostomy placement before recompression). If the clinical presentation is ambiguous, neural imaging is occasionally useful to exclude causes unrelated to diving for which treatment other than HBO2 would be appropriate (e.g. herniated disc). However, imaging studies are rarely helpful for the evaluation or management of DCS.(22.23) MRI is not sufficiently sensitive to detect anatomic correlates of neurological DCI. Bubbles causing limb pain cannot be detected radiographically. Neither imaging nor neurophysiological studies should be relied upon to confirm the diagnosis of DCS or be used in deciding whether a patient with suspected DCS needs HBO2. Improvement of decompression sickness symptoms as a result of compression was first noted in the nineteenth century.(24) Recompression with air was first reported as a specific treatment for that purpose in 1896.(25) Oxygen breathing was observed to improve the signs of decompression sickness in animals.(26) The use of oxygen with pressure to accelerate gas diffusion and bubble resolution in humans was first suggested in 1897(27) and eventually tested in human DCS and recommended for the treatment of divers in the 1930’s.(28) The rationale for treatment with hyperbaric oxygen (HBO2) includes immediate reduction in bubble volume, increasing the diffusion gradient for inert gas from the bubble into the surrounding tissue, oxygenation of ischemic tissue and reduction of CNS edema. It is also likely that HBO2 has other beneficial pharmacological effects, such as a reduction in neutrophil adhesion to the capillary endothelium.(29,30) The efficacy of administration of oxygen at increased ambient pressure (hyperbaric oxygen, HBO2) is widely accepted, and HBO2 is the mainstay of treatment for this disease.(31-34)

Background

Central retinal artery occlusion is a relatively rare emergent condition of the eye resulting in sudden painless vision loss. This vision loss is usually dramatic and permanent and the prognosis is poor. Patients particularly at risk include those with giant cell arteritis, atherosclerosis, and thromboembolic disease, a wide variety of treatment modalities have been tried over the last one hundred years with little to no success, with the exception of hyperbaric oxygen therapy.

Rationale For Hyperbaric Oxygen Therapy (HBO) In The Management Of Central Retinal Artery Occlusion (CRAO)

The arterial blood supply to the eye is provided by the ophthalmic artery, one of the branches of cavernous portion of the internal carotid artery. Some of the branches of the ophthalmic artery (lacrimal, supraorbital, ethmoidals, medial palpebral, frontal, dorsal nasal) supply orbital structures, while others (central artery of the retina, short and long posterior ciliaries, anterior ciliaries) supply the tissues of the globe.(1) The central retinal artery enters the globe within the substance of the optic nerve and serves the inner layers of the retina through its many branches. The long posterior ciliary arteries provide blood to the choroid and the outer layers of the retina. There are approximately twenty short posterior ciliary arteries and usually two long posterior ciliary arteries. The posterior ciliary vessels originate from the ophthalmic artery and supply the entire uveal tract, cilioretinal arteries, the sclera, the margin of the cornea, and the adjacent conjunctiva. The anterior ciliary arteries also arise from the ophthalmic artery, supply the extraocular muscles, and anastamose with the posterior ciliary vessels to form the major arterial circle of the iris, which supplies the iris and ciliary body.

The visual signs and symptoms of vascular occlusive diseases of the retina are dependent on both the particular vessel occluded, the degree of occlusion, the location of the occlusion, and the presence or absence of a cilioretinal artery. In approximately 15%-30% of individuals, a cilioretinal artery is present. This artery is part of the ciliary (not retinal) arterial supply but supplies the area of the retina around the macula (central vision area.) If a cilioretinal artery is present, central vision may be preserved in central retinal artery occlusion (CRAO). The outcome of these disorders also depends on the vessel occluded and the degree of occlusion, but also on the time interval until therapy is initiated and the presence of alternate sources of oxygen to the ocular tissues.

In CRAO, the inner retinal layers (ganglion cell layer and inner nuclear layer), which are normally served by the retinal circulation, may obtain enough oxygen via diffusion from the choroidal circulation to function normally if the individual is exposed to elevated partial pressures of oxygen. Animal models have shown the choroidal supply of oxygen to the inner layers of the retina may be sufficient to maintain ganglion cell viability even when the retinal vessels have been completely obliterated.(2) Normally, the choroidal circulation supplies the majority of the oxygen to the retina. Under normoxic conditions, approximately 60% of the retina’s oxygen comes from the choroidal circulation. Under hyperoxic conditions, the choroid is capable of supplying 100% of the oxygen needed by the retina.(3)

In considering the effect of treating CRAO with supplemental oxygen, four key factors determine success: 1) therapy must be initiated before the retinal tissue is irreparably damaged; 2) the degree of occlusion of the blocked vessel may vary - this may account for why some patients respond to oxygen at lower partial pressures than others; 3) some patients may not respond to oxygen therapy, even if it is initiated promptly, if the level of occlusion is at the ophthalmic artery because in this event, the blood supply to the posterior ciliary vessels is blocked as well and there is no alternate choroidal blood supply to provide oxygenation of the inner layers of the retina; and 4) an adequate partial pressure of oxygen must be maintained to keep the retina viable until circulation is restored.

The etiology of the arterial occlusion (thrombosis, embolus, arteritis, vasospasm) has also been described as affecting outcome.(4,5) Careful classification of the factors involved in an individual case of CRAO is crucial to understanding the natural outcome and results of therapy. In the largest published series of CRAO patients, Hayreh describes the natural progression of this condition without hyperbaric oxygen therapy. He found that patients with transient CRAO (resolution of symptoms in minutes to hours) and those with cilioretinal arteries had much better outcomes than those who did not. In those patients without cilioretinal arteries, 80% had a final outcome of counting fingers or less and only 1.5% of them obtained a final vision of 20/40 or better.(5)

Recanalization occurs in retinal vessels after CRAO.(6,7) In relatively few cases, however, does this angiographic reperfusion lead to an improvement of vision.(7) The retina has the highest rate of oxygen consumption of any organ in the body at 13ml/100g/min.(8,9) Therefore, it is very sensitive to ischemia. In order to be effective, the administration of supplemental oxygen must be continued until such time as flow through the retinal artery has resumed to a level sufficient to maintain inner retinal viability under normoxic conditions.

Hypoxia And Wound Healing Failure

Problem wounds represent a significant and growing challenge to our healthcare system. Venous leg ulcers represent the most common lower extremity wound seen in ambulatory wound care centers with recurrences frequent and outcomes often less than satisfactory. Pressure ulcers are common in patients in long term institutional care settings adding significant increases in cost, disability, and liability. Foot ulcers in patients with diabetes contribute to over half of lower extremity amputations. In response to this challenge specialized programs have emerged designed to identify and manage these patients using standardized protocols and a variety of new technologies to improve outcomes. Hyperbaric oxygen treatment (HBO2T) has been increasingly utilized in an adjunctive role in many of these patients coinciding with optimized patient and local wound care.

Although the underlying physiology and basic science support the contention that HBO2T is likely to be useful in a variety of problem wounds, the best evidence exists for treatment of ischemic, infected (Wagner Grade III or worse) diabetic foot ulcers. This review will therefore focus on these areas, along with suggesting appropriate areas for further research. As more studies are completed in other types of wounds, for example in ischemic, non-diabetic foot ulcers, the recommendations in this review will be updated.

Normal wound healing proceeds through an orderly sequence of steps involving control of contamination and infection, resolution of inflammation, regeneration of the connective tissue matrix, angiogenesis, and resurfacing. Several of these steps are critically dependent upon adequate perfusion and oxygen availability. The end result of this process is sustained restoration of anatomical continuity and functional integrity. Problem or chronic wounds are wounds that have failed to proceed through this orderly sequence of events and have failed to establish a sustained anatomic and functional result.(2) This failure of wound healing is usually the result of one or more local wound or systemic host factors inhibiting the normal tissue response to injury. These factors include persistent infection, malperfusion and hypoxia, cellular failure, and unrelieved pressure or recurrent trauma.(3)

The hypoxic nature of all wounds has been demonstrated,(4) and the hypoxia, when pathologically increased, correlates with impaired wound healing(5) and increased rates of wound infection.(6) Local oxygen tensions in the vicinity of the wound are approximately half the values observed in normal, non-wounded tissue.(7,8,9) The rate at which normal wounds heal has been shown to be oxygen dependent. Fibroblast replication, collagen deposition,(10) angiogenesis,(11,12,13,14) resistance to infection,(15,16,17) and intracellular leukocyte bacterial killing(18,19) are oxygen sensitive responses essential to normal wound healing. However, if the periwound tissue is normally perfused, steep oxygen gradients from the periphery to the hypoxic wound center support a normal wound healing response.(20,21)

Peripheral arterial occlusive disease (PAOD) is common and progressive. It often results in critical limb ischemia, non-healing ulcers, and amputation. PAOD is a common co-morbidity that frequently complicates the management of both venous leg ulcers and diabetic foot ulcers.(95)

Measurement Of Wound Hypoxia

Transcutaneous oxygen tension (PtcO2) measurements provide a direct, quantitative assessment of oxygen availability to the periwound skin and an indirect measurement of periwound microcirculatory blood flow. The application of PtcO2 measurement in the assessment of peripheral vascular disease has been well described by Scheffler(22) and its application to wound healing problems by Sheffield.(23) This technology allows objective determination of the presence and degree of local, periwound hypoxia serving as a screening tool to identify patients at risk for failure of primary wound or amputation flap healing. It can also be used during assessment of patients with lower extremity wounds as a screening tool for occult peripheral arterial occlusive disease.

PtcO2 measurements are made by applying a Clark polarographic electrode on the prepared surface of the skin. A constant voltage is applied to the cathode that reduces oxygen molecules that have diffused from the superficial dermal capillary plexus through the epidermis, stratum corneum, and electrode membrane generating a current that can be measured and converted to a value representing the partial pressure of oxygen in mmHg. The electrode heats the surface of the skin to 43 to 45o C to increase cutaneous blood flow, skin permeability, and oxygen diffusion. The electrode is typically about 0.3mm from the capillary network in normal skin.(24) PtcO2 is non-linear with respect to blood flow, exhibiting a hyperbolic response to changes in blood flow that is more pronounced as flow rates decrease. PtcO2 is a more accurate reflection of changes in perfusion than is measurement of ankle brachial index.(25)

Although several tests intended to identify significant wound hypoxia and / or ischemia have been used, including ankle brachial index, skin perfusion pressure, and laser Doppler flow, transcutaneous oximetry (PtcO2 or TCOM) is generally accepted as most useful(26) for predicting failure to heal a wound without intervention, failure to heal a planned amputation, and failure to respond to HBO2T, as well as evaluating the success of revascularization.

There is some variability in PtcO2 values obtained based upon the type of electrode and temperature used, in general, values below 25-40 mmHg have been associated with poor healing of wound and amputation flaps with the lower the value the greater the degree of healing impairment. Multiple studies(27,28,29,30,31,32,33,34,35) have demonstrated that PtcO2 values are a better predictor of flap healing success or failure following amputation or revascularization procedures than arterial Doppler studies or clinical assessment, particularly in patients with diabetic foot ulcers.(36,37) The addition of provocative testing with lower extremity elevation or dependency(38,39) or following occlusion induced ischemia and recovery(40) or with 100% oxygen breathing(41) may increase the sensitivity of the test as a screening tool for detecting occult lower extremity arterial insufficiency.

The laboratory evidence for hypoxia playing a major role in wound healing failure is not in dispute. Clinical studies identifying the risks of wound or amputation flap healing failure define periwound hypoxia as a primary determinant of future healing failure. Pecoraro(42) reported that when periwound PtcO2 values were below 20 mmHg they were associated with a 39 fold increased risk of primary healing failure. In clinical practice, hyperbaric medicine physicians routinely measure transcutaneous PO2 and use the information obtained to make patient selection and treatment decisions. Unfortunately, however, the clinical trials and case series described below have not used measured periwound hypoxia as a specific patient selection criterion.

Identifying wounds most likely to benefit is paramount for cost effective application of HBO2T. Patients with wounds that fall within a category defined as potentially appropriate for adjunctive HBO2T should be evaluated for likelihood of benefit. Hypoxia (i.e. wound PO2 < 40 mmHg) generally best defines wounds appropriate for HBO2T—or rather, lack of hypoxia (i.e. wound PO2> 40-50 mmHg) defines wounds potentially not appropriate for HBO2T. Breathing 100% oxygen at 1 ATA or under hyperbaric conditions can improve the accuracy of PtcO2 measurement in predicting successful healing with adjunctive hyperbaric oxygen treatment. The following conclusions were drawn from a study of 1144 diabetic foot ulcer patients who underwent adjunctive hyperbaric oxygen treatment in support of wound healing or limb salvage.(43) PtcO2 measured on air at sea level defines the degree of periwound hypoxia but has almost no value in predicting benefit with subsequent hyperbaric oxygen treatment. These measurements are more useful in predicting who will fail to heal without hyperbaric oxygen treatment. PtcO2 values below 35 mmHg obtained while breathing 100% oxygen at sea level are associated with a 41% failure rate of subsequent hyperbaric oxygen treatment while values obtained greater than 35 mmHg were associated with a 69% likelihood of a beneficial response. PtcO2 values measured during hyperbaric oxygen treatment exceeding a cutoff value of 200 mmHg were 74% reliable in predicting wound healing improvement or limb salvage as the result of a therapeutic course of hyperbaric oxygen. This positive predictive value is consistent with those reported by others in both arterial insufficiency and diabetic lower extremity wounds.(44,45,46) Lack of an increase in PtcO2 to >100 mmHg appears to be an appropriate cut-off for predicting failure to heal, at least in ischemic diabetic foot ulcers. This requirement for achieving supraphysiologic wound oxygen concentration lends support to the argument that restoration of wound normoxia is not the primary mechanism of action of HBO2T in healing hypoxic wounds. The failure rate for 100 mmHg is not 100%, however, so that it is not unreasonable to give a trial of HBO2T (10-15 treatments) to such patients for whom the alternative is amputation.

It is notable that PtcO2 is a better predictor of failure than success. While aggressive distal lower extremity bypass grafting and lower extremity angioplasty have contributed to increased wound healing and limb salvage rates, technical grafting success does not necessarily equate with limb salvage. Hyperbaric oxygen treatment offers an intriguing opportunity to maximize oxygen delivery and ultimately to increase wound blood flow via neovascularization in the setting of minimal or insufficiently corrected blood flow.

This underlines the central role of oxygen in wound healing. That is, there is a level of oxygen below which a wound does not have the capacity to heal. Wounds with a PO2 higher than that level, however, are not guaranteed to heal, because there are a variety of non-oxygen related impediments to healing that may prevent the normal progression of repair in the presence of adequate tissue oxygen.

Unfortunately there is a lack of prospective clinical trial data linking periwound hypoxia as a selection criterion for hyperbaric oxygen and demonstrating the contribution of hyperbaric oxygen treatment to improved outcome in these circumstances. Independent evidenced-based reviews of hyperbaric oxygen treatment in problem wounds(47,48) have been unable to define a "hypoxic wound” as a specific wound category. Instead these reviews have endorsed treatment of specific wound types such as diabetic foot ulcers, acute traumatic ischemic injuries, radiation tissue injury, and compromised grafts and flaps, among others.

Physiology Of Hyperbaric Oxygenation Of Wounds

Regardless of the primary etiology of problem wounds, a basic pathway to non-healing is the interplay between tissue hypoperfusion, resulting hypoxia, and infection. A large body of evidence exists which demonstrates that intermittent oxygenation of hypo-perfused wound beds, a process only achievable in selected patients by exposing them to hyperbaric oxygen treatment, mitigates many of these impediments and sets into motion a cascade of events that leads to wound healing.(49) Hyperbaric oxygenation is achieved when a patient breathes 100% oxygen at an elevated atmospheric pressure. Physiologically, this produces a directly proportional increase in the plasma volume fraction of transported oxygen that is readily available for cellular metabolism. Availability of substrate for oxygen dependent enzymatic reactions critical to repair and resistance to infection is even more important than normalization of metabolic rate. Furthermore, oxidants appear to be among the most important signals that control the healing process, and this may be another mechanism for the benefits of HBO2T in hypoxic wounds. Arterial PO2 elevations to 1500 mmHg or greater are achieved with 2 to 2.5 atm abs with soft tissue and muscle PO2 levels elevated correspondingly. Oxygen diffusion varies in a direct linear relationship to the increased partial pressure of oxygen present in the circulating plasma caused by hyperbaric oxygen therapy. This significant level of hyperoxygenation allows for the reversal of localized tissue hypoxia, which may be secondary to ischemia or to other local factors within the compromised tissue (eg, edema and inflammation).

In the hypoxic wound, hyperbaric oxygen therapy acutely corrects the pathophysiology related to oxygen deficiency and impaired wound healing. A key factor in hyperbaric oxygen therapy’s enhancement of the hypoxic wound environment is its ability to establish adequate oxygen availability within the vascularized connective tissue compartment that surrounds the wound. Proper oxygenation of the vascularized connective tissue compartment is crucial to the efficient initiation of the wound repair process and becomes an important rate-limiting factor for the cellular functions associated with several aspects of wound healing.

Neutrophils, fibroblasts, macrophages, and osteoclasts are all dependent upon an environment in which oxygen is not deficient in order to carry out their specific inflammatory or repair functions. Improved leukocyte function of bacterial killing(50,51,52) and antibiotic potentiation,(53,54) have been demonstrated. Suppression of synthesis of many bacterial toxins(55) occurs when tissue PO2 values are sufficiently elevated during treatment. Blunting of systemic inflammatory responses(56) and prevention of leukocyte activation and adhesion following ischemic reperfusion(57,58,59) are effects that may persist even after completion of hyperbaric oxygen treatment.

Stimulation of tissue growth supporting wound healing has also been demonstrated by a variety of mechanisms: 1) Vascular endothelial growth factor (VEGF) release is stimulated(60) and platelet derived growth factor (PDGF) receptor appearance(61,62,63) is also induced. 2) Boykin(64) has recently demonstrated persistent increases in nitric oxide in wound fluid in diabetic ulcers associated with increased granulation tissue formation and wound closure when patients are exposed to 20 hyperbaric oxygen treatments at 2.O ATA for 90 minutes 3) Thom(65) has shown that stem/progenitor cell release from bone marrow through a nitric oxide dependent mechanism occurs in patients receiving hyperbaric oxygen treatment for soft tissue and osteoradionecrosis. The population of CD34 cells in peripheral circulation doubled in response to single HBO treatment (2 ATA, 120 mins). Over course of 20 treatments circulating CD34 cells increased 8 fold, total WBC count unchanged

The net result of serial hyperbaric oxygen exposures is improved local host immune response, clearance of infection, enhanced tissue growth and angiogenesis leading to progressive improvement in local tissue oxygenation and healing of hypoxic wounds.

Patients who have marked loss of red blood cell mass by hemorrhage, hemolysis, or aplasia run the risk of lacking adequate oxygen carrying capacity by blood. The more quickly the severe anemia develops, the less tolerant the patient may be of the insult.

Hemoglobin (Hgb), a powerful carrier for oxygen, carries 1.38 ml of oxygen per gram. The amount of oxygen that will dissolve in one milliliter of plasma is 0.003 ml per mmHg of the partial pressure of oxygen (O2) in inhaled gas. CaO2 and CvO2 respectively represent the arterial or venous content of oxygen in blood. The formula for determination of arterial oxygen content is given as follows:(1)

CaO2 = (grams Hgb x 1.38 ml O2 x % O2 Hgb) + (0.003 + O2 x mm pO2)

Oxygen delivery (DO2) is calculated by multiplying arterial O2 content by cardiac index

(CI) and is given by the following formula:(2)

CI = cardiac output (CO) ÷ m2 body surface area (BSA)

DO2 = CI x CaO2

Oxygen consumption (VO2) is calculated by the Fick equation given by the following formula:(3)

VO2 = CO (CaO2 – CvO2)

On the average, the body extracts 5 to 6 ml of O2 for every 100 ml of blood that sweeps through the microvasculature of most organ systems. Physiologic normal levels of Hgb readily supply tissue oxygen extraction rates of 5 to 6 volume percent. As Hgb drops to 6 g/dL, oxygen delivery, to offset these baseline oxygen extraction rates, becomes problematic and is clearly inadequate at Hgb levels below 3.6 g/dL.

Accumulative oxygen debt is defined as the time integral of the VO2 measured during and after shock insult minus the baseline VO2 required during the same time interval. Clinical research in evaluation of patients with severe hemorrhage, demonstrates no chance of survival if the accumulative oxygen debt exceeds 33 L/m2. Multiorgan failure (MOF) occurs if the accumulative oxygen debt exceeds 22 L/m2. All patients who have an accumulative oxygen debt of 9 L/m2 survive without residual disability.(4)

Clinical Setting

Inability to transfuse red blood cells (RBCs) in severe anemia occurs when the patient refuses blood upon religious grounds or if the patient cannot be crossmatched to receive blood. Transfusion-transmitted infection (TTI), while statistically now less likely with nucleic acid testing (NAT) [approaches 1 per 2,000,000 units transfused for both human immunodeficiency (HIV) and hepatitis C (HCV)], still prompts patients to exercise their right to refuse transfusion.(5)

Untoward inflammatory and immunomodulatory effects of large RBC transfusions may also be a reason to seek alternatives.(6,7) Blood substitutes, by way of use of perfluorocarbons or cell wall free polymerized Hgb are still undergoing randomized clinical trials. While both approaches demonstrate advantages as well as disadvantages, neither have yet had final FDA approval for routine clinical uses.(8)

Pulsed HBO2 therapy provides a way to clinically rectify accumulating oxygen debt in severe anemia when transfusion is not possible. The patient initially can be placed at treatment pressures of 2.0 to 3.0 ATA or 0.2 to 0.3 Mpa (million pascals) of oxygen with air breaks for up to three or four hours with surface interval titrated to avert symptoms associated with reoccurring oxygen debt. Occurrence of end organ dysfunction (altered mental status, ischemic EKG change, sprue-like diarrhea from ischemic bowel, hypotension, diminished urinary output, etc) also may be used as guidance, but are less desirable as their advent represents more progressed end points of illness or injury. By adjunctive use of hematinics, the surface intervals between HBO2 treatments can be lengthened gradually until the patient's baseline Hgb builds to allow for proper O2 delivery.(11)

Role Of Hyperbaric Oxygen Therapy

The two most prodigious oxygen using, mammalian organ systems are the heart and the brain. Oxygen extraction rates of these systems based on patient activity are 6 ml of O2 per 100 ml of circulated blood in the brain and 10-20 ml of O2 per 100 ml of circulated blood in the heart.(12)

As early as 1959, Boerema demonstrated that swine which were exchanged transfused with 6% dextran/dextrose/Ringers' lactate solutions to produce Hgb levels of 0.4 to 0.6 g/dL could survive in the short-term if they underwent assisted O2 ventilation in a hyperbaric chamber at 0.3 MPa.(13) HBO2 therapy has repeatedly allowed survival in what would have otherwise clearly been unsurvivable clinical circumstance without blood transfusion.

HBO2 therapy provides a way in severe anemia to successfully correct accumulating oxygen debt in untransfusible patients.(14) Evidence Based Evaluation of Hyperbaric Oxygen Therapy by the Undersea & Hyperbaric Medical Society's Hyperbaric Oxygen Committee Standard Approval Criteria

In medical resuscitative intervention, evidence based criteria is widely accepted to guide clinical therapeutic intervention.(15) Normobaric oxygen (NBO2) is considered a class I indication while HBO2 may be a class II.b. indication. Controlled animal studies support this assumption as referenced in the following table:

Evidence-Based Evaluation (29 studies found for review)

AHA Level	Class	Evidence Source
		NCI-PDQ	*BMJ **
6a (16–37) (decisive control groups)	II.b. (acceptable and useful) (16–27) (29–30), (34–37)	NA	NA
	Indeterminate(28, 31, 32, 33)
6b (38–43) (not decisive control group)	II.b. (acceptable and useful)(38,39,40)
	Indeterminate(41, 42, 43, 44)

* National Cancer Institute Patient Data Query evidence-based criteria (NCI-PDQ)(45)

** British Medical Journal evidence-based criteria (BMJ)(46)

Rather consistently this body of literature confirms over and over again better survival in animal models of both hemorrhage to a predetermined mean arterial pressure (Wiggers model)(47) or fixed volume hemorrhage.(48) Both increased short-term and long-term survival for HBO2 groups over normobaric air (NBA) or NBO2 groups.

Published human case reports and case series allow similar evidence-based acceptance. Published case reports or case series are referenced below for tabulated uniform approval:

AHA Level	Class	NCI-PDQ	BMJ
		5 (case series and case reports)		3.iii. (case series or presentation neither consecutive or population based)(11,49-53,55,56)	Most likely beneficial(11, 49-53, 55, 56)
II.b. (acceptable and useful) (53)			-
Indeterminate (11, 49–52, 55, 56)			-
6	II.b. (54)	NA	NA

(A more detailed repots of the above tabulated findings has been published in a focused journal review article on the use of HBO2 in acute blood loss anemia)(57)

In summary, both by the support of animal work and human clinical experience evidence-based analysis firmly supports the use of HBO2 as a treatment option in severe anemia using AHA, NCI-PDQ, and BMJ evidence-based criteria.

The term "intracranial abscess” (ICA) includes the following disorders: cerebral abscess, subdural empyema and epidural empyema. These disorders share many diagnostic and therapeutic similarities and, frequently, very similar etiologies.

The overall mortality described in six case series of ICA from different countries during the years 1981-1986 ranged from 10 to 36%, with a summed death rate of 22% (142 deaths in 636 patients).(1-6) Fifteen subsequent studies during the years 1987-1993 suggest that the mortality may have decreased slightly, with a combined death rate of 18% (115 in 634 patients).(7-21) Summing these 21 studies, the average mortality from ICA was 20%. This was confirmed in the neurosurgical literature in the late 1990's.(22)

Factors possibly responsible for a decrease in mortality include: (a) earlier and more accurate diagnosis through expanded use of computed tomography (CT), (b) advances in minimally invasive surgery, e.g. CT-guided fine needle aspiration, and (c) improved understanding of the bacteriology of ICA, leading to more appropriate antibiotic therapy.

Because of improving mortality, there is a general trend toward a more conservative therapeutic approach in the management of ICA patients. This is reflected in the current international literature. However, patients with certain conditions and complications continue to pose major therapeutic problems. These include patients with: (a) multiple abscesses, (b) abscess in a deep or dominant location, (c) immune compromise, and (d) no response or further deterioration in spite of standard surgical and antibiotic treatment.

Under these circumstances, adjunctive hyperbaric oxygen (HBO2) therapy may confer additional therapeutic benefit. A number of mechanisms can be postulated by which HBO2 could provide benefit in ICA. First, high partial pressures of oxygen may inhibit the flora found in ICA, the predominance of which are anaerobic.(1-4,23-40) Second, HBO2 can cause a reduction in perifocal brain swelling.(41-47) Third, HBO2 has the potential to enhance host defense mechanisms.(48,49) Finally, HBO2 has been reported to be of benefit in cases of concomitant skull osteomyelitis.(40,50)

Patient Selection Criteria

Adjunct HBO2 should be considered under the following conditions:

1. Multiple abscesses
2. Abscesses in a deep or dominant location
3. Compromised host
4. In situations where surgery is contraindicated or where the patient is a poor surgical risk
5. No response or further deterioration despite standard surgical treatment (e.g., 1–2 needle aspirations) and antibiotic therapy

Clinical Management

Hyperbaric oxygen treatment is administered at a pressure of 2.0 to 2.5 atmospheres absolute, with oxygen administration from 60 to 90 minutes per treatment. HBO2 treatment may be one or two sessions per day depending on the condition of the individual patient. In the initial phase, twice daily treatment may be considered. The optimal number of HBO2 treatments for ICA is unknown. In the largest series of ICA patients treated with HBO2, the average number of HBO2 sessions was 13 in the absence of osteomyelitis. Duration of the HBO2 course must be individualized, based upon the patient's clinical response as well as radiological findings.

Hyperbaric oxygen therapy is a recognized accepted adjunct to surgical debridements, antibiotic therapy and maximal goal-directed critical care therapy for infections of soft tissues resulting in necrosis. A number of clinical scenarios, specific lesions and syndromes have been described over the years, based on the affected tissues and location of infection, the etiologic organism or combination of organisms involved in the infection, and particular host immunologic and vascular risk factors. In all of these clinical situations, there appears to be the common denominator of the development of hypoxia resulting in necrosis.

Hypoxia is known to impair phagocytosis by polymorphonuclear leukocytes.(1) After an infective process is initiated, metabolic products of aerobic and anaerobic metabolism tend to lower the oxidation-reduction potential (Eh), leading to a drop in pH, which creates a milieu for growth of strict and facultative anaerobic organisms. When the blood supply to the skin is affected by involvement within a phlegmon, with edema and necrosis in the deep fascial layers in which they reside, the decreased perfusion pressure and ischemia predispose to rapid progression and advancement of the infectious process within the skin and subcutaneous tissues, exacerbated by the dysfunctioning polymorphonuclear leukocytes. Local hypoxia occurs, with up-regulation of endothelial adherence molecules, resulting in leukocyte adhesion and endothelial cytotoxicity. Leukocytes may become sequestered in vessels, impairing local immunity, and incomplete substrate oxidation results in hydrogen and methane accumulation in the tissues. Tissue necrosis occurs, with purulent discharge and gas production. Quantities of gas within tissues are frequently seen in gas gangrene, crepitant anaerobic necrotizing cellulitis, and necrotizing fasciitis.

Hyperbaric oxygen therapy can reduce the amount of hypoxic leukocyte dysfunction occurring within an area of hypoxia and infection,(1,2,3) and provide oxygenation to otherwise ischemic areas, thus limiting the spread and progression of infection. The diffusion of oxygen dissolved in plasma in the circulation, where it is initially carried in large vessels, proceeds to areas of poorly perfused tissue, from regions of very high O2saturation down a gradient to lower oxygen levels in tissue. Integrin inhibition decreases leukocyte adherence, reducing systemic toxicity.(5)

In cases where the antibiotic being used requires oxygen for transport across cell walls, hyperbaric oxygen therapy can act to enhance antibiotic penetration into target bacteria. Enhancement of the post-antibiotic effect by hyperbaric oxygen has been demonstrated for aminoglycosides and Pseudomonas.(6)

Clinical classification of the necrotizing infections of soft tissues is easiest early in the course of infection, when anatomic levels of involvement of skin, superficial or deep fascia, and muscle involvement can be assessed either during exploration, on punch biopsy, or by radiologic investigation. However, as infection progresses, distinction between some of the clinical entities may become blurred as full thickness necrosis extends into muscle late, after having extended through skin, fat, fascia, and into muscle via direct extension of infection. At presentation, it may be difficult to differentiate these necrotizing soft tissue infections one from another, or from Clostridial myositis and myonecrosis, until either Gram stain or cultures are available. Considering their historical differences and evolution, it remains useful to examine the separate categories of infection separately in order to anticipate pathways of extension of infection, anticipate complications, and identify when adjunct hyperbaric oxygen therapy should be considered.

Clinical Entities: Necrotizing Fasciitis

Introduction: Necrotizing fasciitis is an acute, potentially fatal infection of the superficial and deep fascia of the skin and soft tissues, which progresses to ischemic dermal necrosis after involvement of the dermal blood vessels which traverse the fascial layers. The popular media refer to this entity as infection with "Flesh-eating bacteria.”

Etiology

Necrotizing fasciitis was initially described and named "hemolytic streptococcal gangrene” by Meleney in 1924.(7) He described an illness characterized by gangrene of subcutaneous tissues, followed by rapid necrosis of the overlying skin from involvement of the blood vessels supplying the skin, which are found in the affected fascial layers. All his patients grew hemolytic streptococci on cultures, and the patients were all seriously ill. Surgical extirpation appeared to be the therapeutic approach. Reference to this entity as necrotizing fasciitis appears around the time of the report by Wilson.(8)

The characteristic level of infection is at the deep fascia. Because infection with necrosis is noted to spread along fascial planes deep to the skin, it is not an uncommon event for there to be minimal skin signs early on. Pain out of proportion to findings could be an early tip off to the presence of deep fascial infection. Since blood vessels supplying overlying skin travel thru fascia, it is the involvement of these vessels by infection that leads to rapid progression to dermal necrosis. Microbiologically, groups A, C, or G beta-hemolytic streptococci can be isolated from tissue specimens in 50 to 90% of case series, with one or two more organisms often also accompanying the streptococci in up to half the cases. The occurrence ofStaphylococcus aureus plus anaerobic streptococci is also known as Meleney's synergistic gangrene. Commonly isolated organisms include Enterobacteriaceae, Enterococci, Bacteroides species, Peptococcus species. Candida species have also been reported.(9) Necrotizing fasciitis is also reported to be caused by community-acquired strains of methicillin-resistant Staphylococcus aureus (CA-MRSA) alone.(10) In many cases, infection is polymicrobial, with Enterobacteriaceae and anaerobes frequently isolated.

Risk Factors

The most common risk factors associated with necrotizing fasciitis are traumatic breaks in the skin, most commonly lacerations, insect bites, burns, deep abrasions, puncture wounds, or following surgery, particularly those involving bowel perforations. Diabetes appears to be a strong risk factor, as are obesity, alcoholism, smoking, and intravenous drug abuse. Reports of necrotizing fasciitis as a result of infection of otherwise typical lesions of chickenpox have been published.(11) An association with the use of non-steroidal anti-inflammatory agents has also been suggested.(12,13) NSAIDs are cyclo-oxygenase inhibitors and may have an adverse effect on neutrophil killing and cell-mediated immunity. NSAIDs are reported to inhibit monocyte superoxide production.(14)

Most common sites of occurrence of necrotizing fasciitis are the lower extremities, while an increased incidence in the upper extremities is seen in the parenteral drug abuse population. However, any location of the body can be affected, including the abdominal wall of neonates, in association with omphalitis.(15) Involvement of the scrotum and perineum in the male is known as Fournier's Gangrene, which is essentially necrotizing fasciitis of the superficial perineal fascia, also known as Colles' fascia; which can spread infection to the penis and scrotum via Buck's fascia or Dartos' fascia; or Scarpa's fascia, which connects to, and can spread infection to, the abdominal wall. Perianal or perirectal infection may also spread into these areas, and undrained or inadequately drained perirectal abscesses are often cited as a source of Fournier's Gangrene. Perineal necrotizing fasciitis can also occur in the female. Diabetes mellitus remains a strong risk factor in this particular form of necrotizing fasciitis as well. Fournier's Gangrene is more likely to have multiple mixed organisms cultured, particularly Enterobacteriaceae, Group D streptococci, and anaerobic organisms, such as Bacteroides fragilis.

Clinical Presentation

The patient with necrotizing fasciitis will typically present with an acute combination of pain and swelling, which may or may not be accompanied by fever and chills. There may already be a focus of cellulitis apparent, but in some instances early on, there may be very few skin changes. In some patients, there may be pain out of proportion to the skin findings, which may not be unexpected considering that the initial level of infection is the fascia, not necessarily the skin. In others, manifestations of a large phlegmon may be quite obvious, although at times the area of infection may have been assumed to be cellulitis and not a more serious form of infection. Pain may proceed to numbness, as a result of compression of nerves which also pass through the fascia. With time however, the infection will rapidly proceed to cause areas of blistering and bullae formation. Hints of darkening of the skin may appear as perfusion decreases, until obvious areas of dermal ischemia appear, making the skin appear dusky, grayish or frankly black. Upon exploration of the process, a clinical diagnosis can be confirmed at the time of biopsy or debridement, when the fascia is grossly observed by the surgeon to be necrotic, and will give way easily to a probing finger or surgical clamp, giving the sensation of "thunking” of the skin against the underlying muscle layers, instead of remaining tight and crisply defined. It has been suggested that limbs of patients with necrotizing fasciitis, as opposed to those with cellulitis only, may be observed to have markedly reduced tissue oxygen saturations as measured by near -infra-red spectroscopy throughout the involved site, with oxygen saturations in the 52% ±18% range, compared to control measurements of 86% ±11% in uninvolved sites.(16)

In the neonate, necrotizing fasciitis of the abdominal wall can be seen as a complication of omphalitis in 10 to 16% of cases,(17) and appears to carry over a 50% mortality rate even when treated with aggressive debridement of involved skin, subcutaneous tissue and fascia.(18)

A number of diagnostic observations have been made to enable confirmation of the diagnosis of necrotizing fasciitis. Frozen section soft-tissue biopsy early in the evolution of a suspect lesion may provide definitive diagnosis.(19) CT scan findings are also revealing. Asymmetrical fascial thickening that was at least twice the contralateral side and associated with fat stranding was seen in 80% of 20 patients with necrotizing fasciitis. Gas tracking along fascial planes was seen in 55%, characteristically did not involve muscle and was not associated with abscess formation.(20) The authors note that the areas of black, gangrenous skin were far smaller than the widespread infection in the underlying fascial planes. Also of note was that 7 of the 20 patients had associated deep space abscesses requiring immediate surgical drainage, which demonstrates the need for CT studies to assess extent of disease, particularly in patients who do not appear to be responding to therapy.

Magnetic resonance imaging (MRI) also demonstrates the extent of affected tissue well, is able to differentiate fluid and gas through differential signal intensities, and is useful in differentiating cellulitis from necrotizing fasciitis, after injection of gadolinium contrast. But in a study of 15 patients, MRI overestimated the extent of deep fascial involvement in one patient who only had cellulitis, following IM injections which showed up on MRI as thickening of both superficial and deep fascia of the deltoid muscle.(21)

Cultures of deep tissue at the time of debridement for aerobes, anaerobes and fungi, are imperative as up to 75% of patients in some series' have demonstrated polymicrobial etiologies. Fungal cultures are particularly important in the immunocompromised, diabetic and cancer populations and in patients who have not responded to standard anti-bacterial antibiotics.

Amputation rates of 26%(22) up to 50%(23) are reported in cases of necrotizing fasciitis of the extremities, without hyperbaric therapy. Mortality in reported series range from 16.9% up to 66% without the use of hyperbaric oxygen. Mortality is often associated with delayed diagnosis, underlying immunocompromise, and underlying heart disease, degree of leukocytosis, septic shock and severe underlying metabolic abnormalities.

Gozal et al(27) treated necrotizing fasciitis patients with combined antibiotics, radical surgery and hyperbaric oxygen, and reduced the historic mortality rate from 38% to 12.5%. Of 29 patients reported retrospectively by Riseman et al,(28) 12 were treated by surgical debridement and antibiotics only, and 17 received hyperbaric oxygen treatments in addition. Both groups had similar parameters of age, race, sex, wound bacteriology and antimicrobial therapy. Body surface area was also similar. However, perineal involvement (53% vs. 12 %) and septic shock (29% vs. 8%) were more common in the hyperbaric group, yet the overall mortality was significantly lower at 23%, versus 66% in the non-hyperbaric oxygen treated group. Additionally, only 1.2 debridements per patient in the hyperbaric treatment group were performed, vs. 3.3 debridements per patient in the surgery plus antibiotics-only group.

Differential Diagnosis

Clearly a goal when making the diagnosis of necrotizing fasciitis is to make it as early as possible so as to be able to start appropriate treatments and avoid rapid spreading and the onset of sepsis. Time is tissue. The main differential diagnoses includes standard cellulitis, which may be a precursor of necrotizing fasciitis in some cases; and erysipelas, with its erythematous well-delineated border. Additional entities which should be considered include Clostridial myositis and myonecrosis; non-Clostridial myositis and myonecrosis; toxic shock syndrome, which may accompany necrotizing fasciitis; Zygomycotic gangrenous cellulitis; mixed aerobic/anaerobic necrotizing cellulitis; toxic epidermal necrolysis (TEN), also known as Lyell's Disease, usually due to exposure to particular medications; and Staphylococcal Scalded Skin Syndrome, also known as Ritter's Disease, due to exfoliative toxins produced by Staphylococci, with the latter two entities being most common in neonates and children under 5 years of age. In the neonate with omphalitis, violaceous discoloration of the skin appears to be a strong marker for the emergence of necrotizing fasciitis. Aeromonas infections also occur following open wounds acquired in sea water. Cutaneous anthrax may present with a blackened central area and surrounding edema.

Clinical Management

Numerous studies have continued to demonstrate the beneficial effect of hyperbaric oxygen therapy in the management of necrotizing fasciitis. Wilkinson and Doolette(29) reported a 5- year retrospective cohort Australian study of 44 patients with necrotizing soft tissue infection, between 1994 and 1999, looking at the primary outcome of survival to hospital discharge, and secondary outcomes of limb salvage and long-term survival after hospital discharge. Logistic regression analysis determined the strongest association with survival was the intervention of hyperbaric therapy (p=.02). Hyperbaric oxygen therapy increased survival with an odds ratio of 8.9 (95% confidence interval, 1.3-58.0) and a number of 3 needed to treat to benefit. Hyperbaric oxygen therapy also reduced the incidence of amputation (p=.05) and improved long-term outcome (p=.002). In the series by Escobar et al, there were no further amputations beyond those already done prior to transfer, once hyperbaric oxygen therapy was initiated in their series of 42 patients.(30) The negative study by Brown at al(31) which purports to be a multi-center retrospective review of treatment at 3 facilities over 12 years, of 54 patients, had numerous discrepancies in the demographics of their two groups. Half of the hyperbaric-oxygen-treated group of 30 patients, all from one institution, were noted to have Clostridial infections, while the non-hyperbaric treated group had only 4 of 24 patients (17%) with Clostridial infection. 6 of the 30 in the hyperbaric group are noted to have the diagnosis of Clostridial myositis and myonecrosis, whereas only one of the non-hyperbaric oxygen treated patients were so diagnosed. Hence this clearly shows the same diseases were not being compared in this study. Additionally, as is pointed out in a subsequent letter to the editor,(32) 80% of the patients received 4 or fewer treatments, the remaining 20% received between 5 and 7 treatments, and the timing of these treatments is not specified. If the guideline of treating three times in the first 24 hours were followed, and then twice per day until the patient is stable and shows no relapse of toxicity between treatments, the gas gangrene patients in this study were treated for less than a day and a half, which is a shorter period of time than most other studies, and the others were treated for around 2 days. In the Wilkinson study, patients received a median of 8 treatments, which is more than that received by the patient with the greatest number of treatments in Brown et al. The authors state that the mortality difference between the two groups (9/30, or 30% of the hyperbaric group, versus 10/24, or 42% in the non-hyperbaric group) was not statistically significant. Thus the Brown et al study should not be used as an argument that the use of hyperbaric oxygen for truncal necrotizing fasciitis is "controversial,” because these mortality statistics are not comparable, with a different mix of diagnoses in the two, compounded by the fact that the numbers themselves are small, resulting in a study that had insufficient power to demonstrate a statistically significant result.. Furthermore the study does not add to the literature of necrotizing fasciitis involving the limbs and other non-truncal sites.

Hyperbaric oxygenation was observed to reduce systemic toxicity, prevent extension of the necrotizing process, and increased demarcation, improving overall outcomes. 2 of the 3 patients who died were moribund upon arrival to their facility. Management included diverting colostomies for those patients with a perirectal or perineal source, and orchiectomy, although sometimes reported in all series, is not routinely done since the blood supply to the testes is from the spermatic vessels which do not perfuse the scrotum and penis. Suprapubic cystostomy was indicated and performed when the source of the infection was genitourinary.

Due to the difficulty in making direct comparisons of clinical series', a Fournier's Gangrene Severity Index Score was developed(36) in order to assess a number of variables rather than the presence of the disease itself. The score uses degrees of deviation from normal of physiologic variables to generate a score that correlates with patient mortality. It is clear that the amount of disease, related by some to body surface area of involvement, may be a significant variable. The Duke University analysis of 50 consecutive patients seen at their institution over a 15 year period had a 20% overall mortality.(37) Three statistically significant predictors of outcome were identified when examined using univariate analysis: extent of infection, depth of the necrotizing infection, and treatment with hyperbaric oxygen. However the same data using multivariate regression analysis identified only the extent of the infection as the only statistically significant independent predictor of outcome in the presence of other co-variables. Patients with disease involving a body surface area of 3.0% or less all survived. The numbers of patients with disease extent greater than 3%, where hyperbaric oxygen would thus be expected to play a role, became smaller, and with small numbers of patients, the power of the study to demonstrate a significant response was not present. Using multivariate analysis, the p value for statistical significance for hyperbaric oxygen treatments was equal to .06. With such strong case series evidence of reductions in morbidity and mortality for necrotizing fasciitis and the subset of Fournier's Gangrene, it is difficult to envision ever seeing a controlled, double-blinded study of hyperbaric oxygen therapy.

Critical Synopsis

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 after appropriate interventions have been performed or where acute osteomyelitis has not responded to accepted management techniques.(1)

To date, no randomized clinical trials examining the effects of HBO2 therapy on refractory osteomyelitis exist. However, the substantial majority of available animal data, human case series and non-randomized prospective trials suggest that the addition of Hyperbaric Oxygen (HBO2) therapy to routine surgical and antibiotic management in previously refractory osteomyelitis is safe and improves the ultimate rate of infection resolution.

In most cases, the best clinical results are obtained when HBO2 therapy is administered in conjunction with culture-directed antibiotics and scheduled to begin soon after thorough surgical debridement. HBO2 therapy is ordinarily delivered on a daily basis for 90–120 minutes using 2.0-3.0 atmospheres of absolute pressure (ATA). Recommendation of a specific treatment pressure is not supported by data. Where clinical improvement is seen, the present regimen of antibiotic and HBO2 therapy should be continued for approximately four to six weeks.

Typically, 20-40 postoperative HBO2 sessions will be required to achieve sustained therapeutic benefit. In cases where extensive surgical debridement or removal of fixation hardware may be relatively contraindicated (e.g. cranial, spinal, sternal or pediatric osteomyelitis), a trial of limited debridement, culture-directed antibiotics and HBO2 therapy prior to more radical surgical intervention provides a reasonable chance for osteomyelitis cure. Again, a course of four to six weeks of combined HBO2 and antibiotic therapy should be sufficient to achieve the desired clinical results. In contrast, if prompt clinical response is not noted or osteomyelitis recurs after this initial treatment period, then continuation of the existing antibiotic and HBO2 treatment regimen is unlikely to be effective. Instead, clinical management strategies should be reassessed and additional surgical debridement and/or modification of antibiotic therapy implemented without delay. Subsequently, re-institution of HBO2 therapy will help maximize the overall chances for treatment success.

Rationale

Initial evidence for a beneficial therapeutic effect of HBO2 in managing osteomyelitis stemmed from reports collected during the 1960's.(2-5) In vitro and in vivo studies have subsequently uncovered specific mechanisms of action. Common to each of these mechanisms is the restoration of normal to elevated oxygen tensions in the infected bone. Mader and Niinikoski demonstrated that the decreased oxygen tensions typically associated with bony infections can be returned to normal or above normal levels while breathing 100% oxygen in a hyperbaric chamber.(6,7) Achieving such elevations has important consequences for the hypoxic milieu of osteomyelitic tissues.(8)

Neutrophils require tissue oxygen tensions of 30-40 mmHg to destroy bacteria by oxidative killing mechanisms.(9,10) Leukocyte mediated killing of aerobic Gram-negative and Gram-positive organisms, including Staphylococcus aureus, is restored when the low oxygen tensions intrinsic to osteomyelitic bone are increased to physiologic or supra-physiologic levels. Mader et. al. confirmed this finding in an animal model of S. aureus osteomyelitis, demonstrating that phagocytic killing markedly decreased at a PO2 of 23 mmHg, improved at 45 and109 mmHg, but was most effective at 150 mmHg.(7) In this study, animals exposed to air achieved a mean PO2 of 21 mmHg and 45 mmHg in infected and uninfected bone, respectively. When the same animals were exposed to 100% oxygen at 2 ATA, mean PO2 levels of 104 and 321 mmHg in infected and non-infected bone were respectively achieved. Subsequent animal studies by Esterhai confirmed these infection and PO2 dependent results, measuring mean oxygen tensions in infected bone of 16±3.8 mmHg in sea level air, 17.5±2.7 mmHg in sea level oxygen, 198.4±19.7 mmHg in 2 ATA oxygen and 234.1±116.3 mmHg at 3 ATA oxygen, respectively; with the corresponding values for non-infected bone being 31±4.6 mmHg in sea level air, 98.8±22.0 mmHg in sea level oxygen, 191.5±47.9 mmHg in 2 ATA oxygen and 309.3±29.6 mmHg at 3 ATA oxygen.(11) Additionally, HBO2 therapy has been noted to exert a direct suppressive effect on anaerobic infections.(3,8) This effect can be clinically important, as anaerobes make up approximately 15% of the isolates in chronic, non-hematogenous osteomyelitis.

In addition to enhanced leukocyte activity, HBO2 helps to augment the transport of certain antibiotics across bacterial cell walls. Aminoglycoside transport across the bacterial cell wall is both oxygen-dependent and impaired in a hypoxic environment. More specifically, active transport of antibiotics (e.g. gentamicin, tobramycin, amikacin) across bacterial cell walls does not occur if tissue oxygen tensions are below 20 to 30 mmHg.(12) Therefore, HBO2 exposures can enhance the transport and augment the efficacy of antibiotic action.(12-14) This synergistic effect has also been shown for the cephalosporin class of antibiotics, where the combination of cefazolin and HBO2 therapy produced a 100-fold greater reduction in bacterial counts than either antibiotics or HBO2 therapy alone.(15,16) Comparable effects are also seen with HBO2 in mitigating localized soft tissue infections. Sugihara et. al. demonstrated a 46% reduction in infection resolution time from a mean of 13 to only 6 days when HBO2 therapy was added to antibiotics in the management of soft tissue infections.(17) As infected soft tissues often act as conduits for initiating and sustaining cortical bone infections, HBO2 therapy's parallel benefit in ameliorating soft tissue infections may be critical to its overall efficacy in refractory osteomyelitis.(18)

There is evidence that HBO2 enhances osteogenesis.(19-23) Animal data suggests that bone mineralization and healing can be accelerated by intermittent exposure to HBO2.(24,25) Remodeling of bone by osteoclasts is an oxygen-dependent function. Consequently, inadequate oxygen tensions inhibit microscopic debridement of dead, infected bone by osteoclasts. As previously noted, HBO2 can restore physiologic or provide supra-physiologic oxygen tension in hypoxic bone environments, thus osteoclast function in infected bone can be improved. HBO2 therapy's stimulatory effect on osteoclasts has been confirmed in animal models.(26,27) Furthermore, as demarcation between healthy and necrotic bone is not always clear at the time of surgery, osteoclast enhancement may improve the overall quality of bony debridement and reduce the chances that local infections will recur.(28)

Risk Factors

The pathophysiology of chronic osteomyelitis is characterized by both acute and chronic sources of ischemia. HBO2 therapy has been shown to be effective in acutely reducing tissue edema, lowering intra-compartmental pressures and ameliorating the detrimental effects of inflammatory reactions.(29-32) Over the longer term, HBO2 can be used to promote new collagen formation and capillary angiogenesis in both hypoxic bone and surrounding tissues.(33-36) This neovascularization works to counter the less easily reversible consequences of osteomyelitis, such as surgical trauma, tissue scarring and nutrient blood vessel occlusion. By creating a sustained increase in the arterial perfusion of previously hypoxic bone and soft tissues, HBO2 can reduce the susceptibility of these tissues to recurrent infection and necrosis.

Introduction

Hyperbaric oxygen is among the most studied and frequently reported applications in the treatment of delayed radiation injuries. This application of hyperbaric oxygen to the treatment and prevention of delayed radiation injury will be the topic of this chapter. The management of delayed radiation injury, especially when bone necrosis is present, requires mult-disciplinary management. The nature of delayed radiation injury, the mechanisms whereby hyperbaric oxygen is effective, clinical results, the effects of hyperbaric oxygen on cancer growth and future areas for research will be discussed.

The Nature Of Radiation Injury

Radiation injuries should be further sub-classified as acute, sub-acute or delayed complications.(1) Acute injuries are due to direct and near immediate cellular toxicity caused by free radical-mediated damage to cellular DNA. Many cells suffer a mitotic or reproductive death, i.e. enough damage has been rendered to the DNA that successful subsequent mitosis is prevented. Acute injuries are usually self-limited, and are treated symptomatically. However, they can be very debilitating during their duration. Sub-acute injuries are typically identifiable in only a few organ systems, e.g. radiation pneumonitis following the treatment of lung cancer with an onset typically 2 to 3 months after completion of irradiation. Subacute injuries have been shown to occur in the lung with a clinical syndrome mimicking bronchitis. They have also been shown to occur in the spinal cord where temporary demyelinization causes the so-called Lhermitte's syndrome where patient's experience electric-like shocks down their legs with spinal extension. These, too, are generally self-limited but occasionally evolve to become delayed injuries. Some sub-acute injuries may persist for several months. Delayed radiation complications are typically seen after a latent period of six months or more and may develop many years after the radiation exposure. Sometimes, acute injuries are so severe that they never resolve and evolve to become chronic injuries indistinguishable from delayed radiation injuries.(2)These are termed "consequential effects” and are not characterized by a symptom-free latent period. Often, delayed injuries are precipitated by an additional tissue insult such as surgery within the radiation field.

A role for hyperbaric oxygen in acute and sub-acute radiation injuries has not been well-studied or established, although there is some interest in pursuing this application.(3)

The Etiology Of Delayed Radiation Injury

The exact causes and biochemical processes leading to delayed radiation injury are complex and only partially understood at this time. In virtually all organ systems which demonstrate radiation damage, we observe vascular changes characterized by obliterative endarteritis. Because hyperbaric oxygen has been shown to enhance angiogenesis in hypoxic tissues, the hyperbaric oxygen community has previously postulated that the enhancement of angiogenesis was the primary if not the sole therapeutic effect of hyperbaric oxygen in radiated tissues. Some radiation biologists are now convinced that in some organ systems vascular changes play at most a minor role in the evolution of delayed radiation injury.(4)

A more complex model of radiation damage continues to evolve in the radiation oncology community. In the past, radiation oncologists had made a distinction between the causes of acute and delayed injuries. The belief was that they were not directly related. Indeed, it is not uncommon to find a patient with serious acute reactions who will not suffer significant chronic complications or someone with severe chronic complications who had experienced no worse than average acute reactions to the radiation. Radiation scientists now appreciate that the process of radiation injury begins at the time of radiation treatment and involves the elaboration and release of many bioactive substances including very prominently fibrogenetic cytokines.(5)A primary mechanism whereby therapeutic radiation inflicts damage on normal tissues has been termed the fibro-atrophic effect.(4) This model emphasizes the consequences of the observed depletion of parenchymal and stem cells and de-emphasizes the impact of vascular damage. It also highlights the exuberant fibrosis usually found in severely damaged irradiated tissues.(4-6,8) In this model vascular damage and stenosis continue to be recognized as a consistent finding in tissues exhibiting radiation damage including frank necrosis; however, endarteritis as a causative factor for delayed radiation injuries is de-emphasized.

A recent review of the delayed fibro-atrophic effects of radiation has been accomplished by Fleckenstein et al.(5) This paper identifies TGF-beta as the most frequently studied cytokine associated with radiation injury. Additional cytokines associated with radiation injury include IL-1, IL-2, IL- 4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNF-alpha and GMCSF.

Many studies of cytokines and radiation injuries have been accomplished in animal models of radiation-induced pneumonitis.(9) At the present, we are not able to make practical clinical application of these observed associations. No single marker is likely to provide us with a reliable estimate of future radiation damage.(10) Similarly, no practical strategies have as yet been developed to prevent or reduce the production of these cytokines or reduce their impact in a prophylactic fashion. We know that there is a very wide range of tolerance to radiation and that some patients are much more sensitive to radiation injury. If reliable predictors of delayed radiation injury were available, adjustments to the radiation dosing scheme could be made for the radio-sensitive patient. Some patients might be advised to seek alternative therapies instead of radiation. Moreover, prophylactic interventions such as hyperbaric oxygen or other yet to be developed pharmacologic interventions could be applied during the latent period but before the manifestation of the chronic injury. The hope and expectation would be that, by identifying a group at risk and intervening in this group before manifestation of the injury, delayed radiation injury could be prevented or at least reduced in its severity. Obviously this postulate will have to be subjected to clinical trials.

The Effects Of Hyperbaric Oxygen On Irradiated Tissues

Because a consistent cause and manifestation of radiation injury is vascular obliteration and stromal fibrosis, the known impact of hyperbaric oxygen in stimulating angiogenesis is an obvious and important mechanism whereby hyperbaric oxygen is effective in radiation injury. HBO2 induces neovascularization in hypoxic tissues. Marx(11) has demonstrated the enhanced vascularity and cellularity in heavily irradiated tissues after hyperbaric oxygen therapy by comparing histologic specimens from patients pre- and post- hyperbaric oxygen. Marx6 has also demonstrated the serial improvement in transcutaneous oxygen measurements of patients receiving hyperbaric oxygen as an indirect measure of vascular improvement. Marx et al(12) in an animal model have shown increased vascular density in rabbit mandibles after exposure to hyperbaric oxygen.

Feldmeier and his colleagues(7,8) in a murine model of radiation damage to the small bowel have shown that prophylactic hyperbaric oxygen can reduce the degree and mechanical effects of fibrosis by being applied prior to the manifestation of radiation injury. Assays of the murine bowel for collagen content and compliance included a mechanical stretch assay as well as quantitative histologic assays of fibrosis in the tunica media of the animal bowel utilizing Mason's trichrome staining.

This author has personally observed significant reduction in the woody fibrosis of soft tissues seen frequently in head and neck cancer patients after radiation with a course of hyperbaric oxygen intended to treat mandibular necrosis. To my knowledge, this effect has not yet been systematically studied.

The impact of hyperbaric oxygen in terms of its beneficial effects is likely to involve all three of the above mechanisms in irradiated tissues: 1) Hyperbaric oxygen stimulates angiogenesis and secondarily improves tissue oxygenation; 2) Hyperbaric oxygen reduces fibrosis; and 3 Hyperbaric oxygen is likely to mobilize and stimulate an increase of stem cells within irradiated tissues. The third mechanism is at this point putative and remains to be proven in radiation damaged tissues.

Hyperbaric oxygen has been applied as a therapy for delayed radiation injury for more than 30 years. Informal surveys have shown that at most hyperbaric centers in the U.S., nearly one half of patients receiving hyperbaric oxygen are being treated for radiation injury. Hyperbaric oxygen also has a frequent application in the prevention of mandibular osteoradionecrosis when dental extractions are required from heavily irradiated mandibles. The following sections will address the application of hyperbaric oxygen to radiation complications on an anatomic basis beginning with mandibular osteoradionecrosis.

Hyperbaric Oxygen As Treatment For Mandibular Radiation Necrosis (ORN)

The most widely applied and most extensively documented indication for hyperbaric oxygen in chronic radiation injury is its application in the treatment and prevention of radiation necrosis of the mandible. Multiple publications describing the use of hyperbaric oxygen in the treatment of mandibular necrosis have appeared in the medical literature since the 1970's.

The likelihood of mandibular necrosis as a result of therapeutic radiation varies widely among several reports. Bedwinek(15) has reported a 0% incidence below doses of 6,000 cGy increasing to 1.8% at doses from 6,000 to 7,000 cGy and to 9% at doses greater than 7,000 cGy. In his comprehensive review of radiation tolerance, Emami(16) estimates a 5% incidence when a small portion of the mandible (less than 1/3) is irradiated to 65 Gy or higher and a 5% incidence at 60 Gy or higher when a larger volume of the mandible is irradiated. It has been reported that 85% or more of cases resulting in exposed mandibular bone will resolve spontaneously with conservative management.(17) Unfortunately the remaining cases generally become chronic and may become progressive, often further complicated by associated soft tissue necrosis.

Much of the early work in this area considered radiation induced mandibular necrosis to be a subset of mandibular osteomyelitis.(11) Also, hyperbaric oxygen was delivered frequently as the sole treatment for mandibular necrosis without appropriate surgical management after failure of more conservative therapy. Although many cases would show temporary improvement, almost all cases of moderate to severe ORN would recur if hyperbaric oxygen was administered without appropriate surgical intervention.(18)

Dr. Robert Marx, D.D.S.(18,19) elucidated many basic principles in the etiology and management of mandibular ORN which have led to a rational approach to its management. He has provided several key principles in the understanding of the pathophysiology of mandibular necrosis. He has demonstrated that infection is not the primary etiology of mandibular necrosis by obtaining deep cultures of affected bone and showing the absence of bacteria. We now understand that osteoradionecrosis is the result of an avascular, aseptic necrosis. Marx(6) has also shown that for hyperbaric oxygen to be consistently successful, it must be combined with surgery in an optimal fashion. Marx has developed a staging system for classifying mandibular necrosis. This staging system is applied to determine the severity of mandibular necrosis. In addition it permits a plan of therapeutic intervention, which is a logical outgrowth of the stage/severity of necrosis.

Stage I ORN: This stage includes those patients with exposed bone who have none of the serious manifestations found in Stage III and described below. Generally, before hyperbaric oxygen, these patients have had chronically exposed bone or they have rapidly progressive ORN. These patients begin treatment with 30 HBO2 sessions followed by only minor bony debridement. If these patients' response is adequate, an additional 10 daily treatments are given, and the patients are followed to complete clinical resolution.

Stage II ORN: If patients are not progressing appropriately at 30 daily treatments or if a more major debridement is needed, they are advanced to Stage II and they receive a more radical surgical debridement in the operating room followed by 10 post-operative treatments. Surgery for Stage II patients must maintain mandibular continuity. If mandibular resection is required, patients are advanced to Stage III.

Stage III ORN: In addition to those failing treatment in Stage I or II, patients who present initially with grave prognostic signs such as pathologic fracture, orocutaneous fistulae or evidence of lytic involvement extending to the inferior mandibular border are treated in Stage III from the outset. When a patient is assessed to be at Stage III, mandibular segmental resection is a planned part of the treatment. In Stage III, patients are entered into a reconstructive protocol after mandibular resection. Marx has established the principle that all necrotic bone must be surgically eradicated here and in Stages I and II. Stage III patients receive 30 daily hyperbaric treatments prior to mandibular resection followed by 10 post-resection treatments. Typically after a period of several weeks, the patients complete a reconstruction which may involve various surgical techniques including free flaps or myocutaneous flaps. In its original design, the reconstruction made use of freeze-dried cadaveric bone trays from a split rib or iliac crest combined with autologous corticocancellous bone grafting. In his original work at Wilford Hall USAF Medical Center, Marx had reconstruction patients complete a full additional course of hyperbaric treatments in support of the reconstruction. Marx has subsequently found that the vascular improvements accomplished during the initial 40 hyperbaric exposures are maintained over time and patients can undergo reconstruction without a second full course of HBO2. Patients do receive 10 hyperbaric treatments after the reconstructive surgery to support initial tissue metabolic demands.

Marx(6) has reported his results in 268 patients treated according to the above protocol. In his hands with this technique, successful resolution has been achieved in 100% of patients. Unfortunately the majority of patients (68%) required treatment as Stage III patients necessitating mandibular resection and reconstruction. Dr. Marx requires that patients achieve reasonable cosmetic restoration as well as the success in supporting a denture before he counts them a success. These two issues, cosmesis and restoration of dentition for mastication, are necessary components in improving quality of life in this group of patients.

Feldmeier and Hampson(20) published a review of Hyperbaric Oxygen in the treatment of radiation injury in 2002. A total of 14 papers reporting the results in the treatment of mandibular necrosis were included. All but one of these were case series. A single study by Tobey et al(21) was a positive randomized controlled trial. It was a small study with only 12 patients enrolled; however, it was double blinded and reported to be a positive trial by the authors. Details of randomization and outcome determinants were not clearly stated. Patients received either 100% oxygen at 1.2 ATA or 2.0 ATA. The paper states that those treated at 2.0 ATA "experienced significant improvement” compared to the control group.

In this review, only one report of the remaining 13 publications, the publication by Maier et al,(22) failed to report a positive outcome in applying hyperbaric oxygen to the treatment of mandibular ORN. Maier and colleagues added hyperbaric oxygen to their management only after the definitive surgery was done. They failed to heed Marx's guidance that the optimal management of mandibular ORN requires that the majority of HBO2 be given prior to surgical debridement, resection or reconstruction in order to improve the quality of tissues prior to surgical wounding.

Since the review by Feldmeier and Hampson(20) several additional papers have been added to the literature. A multi-institutional randomized controlled trial by Annane et al(23) reported negative results in their study applying hyperbaric oxygen to Marx Stage I ORN. These results have created a stir in the hyperbaric oxygen community, and have prompted criticism of its methods from several sources. Patients were randomized to receive either 90 minutes of 100% O2 at 2.4 ATA or a breathing gas mix equivalent to air at sea level for 30 daily treatments. The study design has received criticism from several circles. The most serious flaw in the study design was its failure to adhere to Marx's guidance and to integrate hyperbaric oxygen into a multi-disciplinary approach to ORN treatment. The study's apparent intent was to investigate whether the application of hyperbaric oxygen could obviate the need for surgery in early mandibular ORN. It is not surprising that the study had negative results because more than 2 decades earlier Marx had shown an absolute necessity of surgically eradicating all necrotic bone. The need to debride all necrotic bone to achieve resolution was also confirmed by Feldmeier et al in their review of chest wall necrosis including some cases with ORN of the ribs and sternum.(24)

Additional criticisms of this study by Annane(23) have been made. Moon et al(25) have shown that nearly 2/3's of the hyperbaric group received fewer than 22 hyperbaric treatment. Laden(26) points out that the patients assigned to the control group had a risk for developing decompression sickness with the gas mix they breathed (9% oxygen and 91% nitrogen) at 2.4 ATA. This gas mix was designed to provide an inspired oxygen partial pressure equivalent to air at sea level.

In another recent report, Gal and associates(27) have published their results in treating a series of 30 patients with Marx Stage III mandibular ORN with debridement and reconstruction employing microvascular anastomosis. Twenty-one of these patients had previously been treated with hyperbaric oxygen without resolution, although it is not clear that any of these patients received a full course of treatment. At least some had had some debridement prior to coming to Gal. Once in the author's hands, they all had appropriate debridement and reconstruction with free flaps. Those patients who had not seen hyperbaric oxygen previously had a complication rate of 22% while the group who had received at least some hyperbaric oxygen had a much higher rate of complications of 52%. Of course this was not a randomized trial, and even the authors suggest that the hyperbaric group may have represented a group with refractory mandibular ORN. Obviously, those principles previously established by Marx, i.e. an emphasis on pre-surgical hyperbaric oxygen, debridement of all necrotic bone followed by reconstruction with post-operative hyperbaric oxygen were not followed. The authors of this paper also discuss that Marx Stage III ORN patients represent a heterogeneous group with a broad range of injuries, severity of injuries, and a subsequent broad range of outcomes.

Teng and Futran(28) have recently published their opinion that hyperbaric oxygen has no role in treating ORN. Their article presents no new clinical data and is a review article. The authors base their conclusions on the Annane study and the advancement of the fibro-atrophic model of radiation injury as now being dominant in the opinion of most experts of radiation pathology. Mendenhall,(29) a radiation oncologist from the University of Florida, in an editorial accompanying the Annane paper in the Journal of Clinical Oncology points out that the Annane paper was underpowered and therefore subject to question. He goes on, however, to state his belief that hyperbaric oxygen is not indicated for mandibular ORN although he remarks that it is hard to understand why the HBO2 group in the Annane study did worse than control.

Suffice it to say that these recent papers addressing the efficacy of hyperbaric oxygen in the treatment of ORN have expressed negative opinions. Only one was a randomized controlled trial, and it is subject to the criticisms in design discussed above. If we look at the total body of literature reporting the impact of hyperbaric oxygen on mandibular ORN, we find the following: In the publications reviewed in the Feldmeier/Hampson review,(20) 371 cases of mandibular ORN are reported with a positive outcome in 310 or 83.6%. Unfortunately, some of the papers report improvement rather than resolution as their outcome determinate. Of course a better determination of outcome would be resolution. In Marx's(6) reports, resolution is reported in 100%. Marx also indicates that success in Stage III patients requires not only re-establishment of mandibular continuity but also rehabilitation with a denture for cosmesis and mastication. By contrast if we look at the recent "negative” trials, only 22 patients are included in the Gal report(30) and 31 patients randomized to hyperbaric oxygen in the Annane(26) trial for a total of 53 patients. Practitioners of hyperbaric oxygen who treat mandibular ORN must do so in a multi-disciplinary manner and insure that treatment includes an oral surgeon who can accomplish the needed extirpation of necrotic bone.

Rationale

Hyperbaric oxygen therapy (HBO2T) is neither necessary nor recommended for the support of normal, uncompromised grafts or flaps. However, in tissue compromised by irradiation or in other cases where there is decreased perfusion or hypoxia, HBO2T has been shown to be extremely useful in flap salvage. Hyperbaric oxygen can help maximize the viability of the compromised tissue thereby reducing the need for regrafting or repeat flap procedures. The criteria for selecting the proper patients that are likely to benefit from adjunctive hyperbaric oxygen for graft or flap compromise is crucial for a successful outcome. Identification of the underlying cause for graft or flap compromise can assist in determining the proper clinical management and use of hyperbaric oxygen therapy. A number of studies have shown the efficacy of HBO2T on enhancement of flap and graft survival in a variety of experimental and clinical situations.

Rationale

Severe thermal injury is one of the most devastating physical and psychological injuries a person can suffer. Over 2 million burn injuries are brought to medical attention in the United States per year. Of these, there are 14,000 deaths and approximately 20,000 sustain injuries requiring admission to a specialized burn unit.(1) About 75,000 patients require hospitalization each year, and 25,000 of those remain hospitalized for more than 2 months.(2) The most common mechanisms of burn injury are flame and scalding, and the upper extremity, head and neck are the most common body areas involved.(3)

Goals of burn treatment include survival of the patient with rapid wound healing, minimal scarring and abnormal pigmentation, and cost-effectiveness. The optimal outcome is restoration, as nearly as possible, to the pre-burn quality of health and psychological wellbeing.(4)

The burn wound is a complex and dynamic injury characterized by a central zone of coagulation, surrounded by an area of stasis, and bordered by an area of erythema. The zone of coagulation or complete capillary occlusion may progress by a factor of 10 during the first 48 hours after injury; local microcirculation is compromised to the worst extent 12-24 hours post-burn. Burns are in this dynamic state of change for up to 72 hours after injury.(1) Ischemic necrosis quickly follows. Hematologic changes, including platelet microthrombi and hemoconcentration, occur in the postcapillary venules. Edema formation is rapid in the area of the injury; factors include increased capillary permeability, decreased plasma oncotic pressure, increased interstitial oncotic pressure, changes in interstitial space compliance, and lymphatic damage.(5)Edema is most prominent in directly involved burned tissues, but also develops in distant, uninjured tissue, including muscle, intestine and lung.

Changes occur in the distant microvasculature including red cell aggregation, white cell adhesion to venular walls, and platelet thromboemboli.(6) Inflammatory mediators are elaborated locally in part from activated platelets, macrophages, and leukocytes, contribute to local and systemic hyperpermeability of the microcirculation and appear histologically as gaps in the venular and capillary endothelium.(7) This progressive process may extend damage dramatically during the early days after injury.(8) The ongoing tissue damage in thermal injury is due to multiple factors including the failure of the surrounding tissue to supply borderline cells with oxygen and nutrients necessary to sustain viability,(9) capillary or microvascular occlusion in deeper burns leading to decreased perfusion of the burned tissue, and destruction of lymphatics resulting in impaired absorption. The impediment of circulation below the injury leads to desiccation of the wound, as fluid cannot be supplied via the thrombosed or obstructed capillaries. Topical agents and dressings may reduce, but cannot prevent, desiccation of the burn wound and the inexorable progression to deeper layers. Altered permeability is not caused by heat injury alone. Oxidants and other mediators (prostaglandins, kinins and histamine) also contribute to vascular permeability. Neutrophils are a major source of oxidants and injury in the ischemia-reperfusion mechanism. This complex process may be favorably effected by several interventions.

A decrease in edema formation has a marked positive proactive impact, especially on the early hemodynamic instability, as well as the later wound conversion from partial to full thickness injury,(2)defining a role for the use of adjunctive hyperbaric oxygen therapy as a modulator of inflammation.

Infection

Infection remains the leading overall cause of death from burns. Susceptibility to infection is greatly increased due to the loss of the integumentary barrier to bacterial invasion, the ideal substrate present in the burn wound, and the compromised or obstructed microvasculature that prevents humoral and cellular elements from reaching the injured tissue. Additionally, the immune system is seriously affected, demonstrating decreased levels of immunoglobulins and serious perturbations of polymorphonuclear leukocyte (PMNL) function including a reduction in chemotaxis, phagocytosis and diminished killing ability,(10) resulting in increased morbidity and mortality. Patients with specific polymorphisms in the tumor necrosis factor and bacterial recognition genes have a higher incidence of sepsis than the burn injury alone would predict.(11)

Regeneration cannot take place until equilibrium is reached; hence, healing is retarded. Prolongation of the healing process may lead to excessive scarring. Hypertrophic scars are seen in only 4% of cases requiring 10 days to heal, but up to 40% of cases requiring longer than 21 days to heal.(12) Therapy of burns, therefore, must be directed toward minimizing edema, preserving marginally viable tissue, protecting the microvasculature, enhancing host defenses, and promoting wound closure.

Adjunctive HBO2 therapy can benefit each of these problems directly, and shows promise in the treatment of inhalation injury.

Steven M. Piper, D.O., FAAEM Tracy Leigh LeGros, M.D., Ph.D., UHM, FACEP, FAAEM Heather Murphy-Lavoie, M.D., UHM, FACEP, FAAEM

Introduction

The Louisiana State University Undersea and Hyperbaric Medicine Fellowship brought two "new indication” proposals to the UHMS HBO Committee at the Annual Scientific Assembly in Fort Worth (June 2011). These indications were avascular necrosis (AVN) and idiopathic sudden sensorineural hearing loss (ISSHL). Both the "pro” and "con” arguments were heard for these proposed indications. Following deliberations, ISSHL was positively proposed as a new indication. This recommendation was ratified by the board in October 2011.

Background

Changes occur in the distant microvasculature including red cell aggregation, white cell adhesion to venular walls, and platelet thromboemboli.(6) Inflammatory mediators are elaborated locally in part from activated platelets, macrophages, and leukocytes, contribute to local and systemic hyperpermeability of the microcirculation and appear histologically as gaps in the venular and capillary endothelium.(7) This progressive process may extend damage dramatically during the early days after injury.(8) The ongoing tissue damage in thermal injury is due to multiple factors including the failure of the surrounding tissue to supply borderline cells with oxygen and nutrients necessary to sustain viability,(9) capillary or microvascular occlusion in deeper burns leading to decreased perfusion of the burned tissue, and destruction of lymphatics resulting in impaired absorption. The impediment of circulation below the injury leads to desiccation of the wound, as fluid cannot be supplied via the thrombosed or obstructed capillaries. Topical agents and dressings may reduce, but cannot prevent, desiccation of the burn wound and the inexorable progression to deeper layers. Altered permeability is not caused by heat injury alone. Oxidants and other mediators (prostaglandins, kinins and histamine) also contribute to vascular permeability. Neutrophils are a major source of oxidants and injury in the ischemia-reperfusion mechanism. This complex process may be favorably effected by several interventions.

Idiopathic sudden sensorineural hearing loss is classically defined as a hearing loss of at least 30 dB occurring within three days over at least three contiguous frequencies. The most common clinical presentation involves an individual experiencing a sudden unilateral hearing loss, tinnitus, a sensation of aural fullness and vertigo. The incidence is estimated at 5 to 20 cases per 100,000 annually in the United States. However, the incidence may be higher, as many cases are likely unreported. Additionally, it has been estimated that as many as 65% of cases may resolve spontaneously.

Rationale for HBO2

The etiologies and pathologies of ISSHL remain unclear. Several pathophysiological mechanisms have been described including: vascular occlusion, viral infections, labyrinthine membrane breaks, immune associated disease, abnormal cochlear stress response, trauma, abnormal tissue growth, toxins, ototoxic drugs and cochlear membrane damage.

The rationale for the use of hyperbaric oxygen to treat ISSHL is supported by an understanding of the high metabolism and paucity of vascularity to the cochlea. The cochlea and the structures within it require a high oxygen supply. The direct vascular supply, particularly to the organ of Corti, is minimal. Tissue oxygenation to the structures within the cochlea occurs via oxygen diffusion from cochlear capillary networks into the perilymph and the cortilymph. The perilymph is the primary oxygen source for these intracochlear structures. Unfortunately, perilymph oxygen tension is decreased significantly in patients with ISSHL. To achieve a consistent rise of perilymph oxygen content, the arterial-perilymphatic oxygen concentration difference must be extremely high. This can be restored with hyperbaric oxygen therapy. Evidence-based medicine While there is a large body of literature comparing therapeutic interventions for the treatment of ISSHL, only a small number of controlled studies have been performed. Moreover, there is no clear consensus for the treatment. More than 60 protocols have been described. However, when the three most prominent and efficacious treatments (steroids, vasodilators and HBO2) were systematically reviewed by meta-analyses from the Cochrane Collaboration, only the use of HBO2 received a positive, objective, critical review (Cochrane Review, 2010). Both steroids and vasodilator treatments were found to have "no good evidence to suggest the effectiveness or lack thereof” in the treatment of ISSHL. By contrast, the Cochrane Review concluded that "for people with acute ISSHL, the application of HBO2 significantly improved hearing . . .” Multiple controlled studies have also demonstrated a greater degree of hearing improvement when patients receive early intervention with HBO2 and oral steroids concomitantly. The use of HBO2 for the treatment of ISSHL is Class IIa (AHA Evidence-Based Scoring System) with an "A” Level of Evidence (data derived from multiple randomized clinical trials). Patient selection criteria

Patients with moderate to profound ISSHL (≥ 41 dB) who present within 14 days of symptom onset should be considered for HBO2. While patients presenting after this time may experience improvement when treated with HBO2, the medical literature suggests that early intervention is associated with improved outcomes. The best evidence supports the use of HBO2 within two weeks of symptom onset.

Clinical management

Patients who present with ISSHL should undergo a complete evaluation by an otolaryngologist and audiologist, inclusive of appropriate audiological and imaging studies, to determine the degree and potential etiology of disease. Patients determined to have ISSHL and meet the selection criteria may benefit from HBO2. The recommended treatment profile consists of 100% O2 at 2.0 to 2.5 atmospheres absolute for 90 minutes daily for 10 to 20 treatments. The 2.4 ATA treatment pressure is probably most practical, especially for facilities with multiplace chamber operations. Patientswith no known contraindications to steroid therapy should also be treated concomitantly with oral corticosteroids. Continued consultation and follow-up with an otolaryngologist is recommended.

Utilization review

The optimal number of HBO2 treatments will vary, depending on the severity and duration of symptomatology and the response to treatment. Utilization review is recommended after 20 treatments.

Cost impact

There is no formal detailed cost analyses for ISSHL in the literature. However, the World Health Organization (WHO) has described the cost impact of hearing loss. Hearing impairment makes it difficult to obtain, perform and keep jobs, and the hearing impaired are often stigmatized and socially isolated. The cost of special education and lost employment due to hearing impairment imposes a heavy social and economic burden (WHO, 2010). Adult onset hearing loss is the most common cause of disability globally, and the third leading cause of years lost due to disability. Moreover, adult onset hearing loss is the 15th leading cause of burden of disease,and is projected to move up to 7th by the year 2030 (WHO, 2008). Although additional studies are recommended to further define the pathology and optimize the treatment of ISSHL, based on the current medical evidence, the use of HBO2 outweighs the risk. Furthermore, significantly improving a patient’s hearing and minimizing the social and economic burden of this disease outweighs treatment costs.

Introduction

Avascular necrosis (AVN), also referred to as aseptic osteonecrosis (AO), can develop in several osseous districts of the body. Most commonly described is avascular necrosis of the femoral head (AVNFH), a debilitating and progressively disabling condition with partially understood, wide-ranging etiology and pathogenesis. Pathology is chiefly caused by a reduced vascularization of a terminal vascular bed, such as the one perfusing the femoral head, or similar vascular distributions such as femoral condyles, humeral head, the talus, the calcaneus, the navicularis, and other bony structures. Hypoxic conditions mediate the condition and can improve with a course of hyperbaric oxygen (HBO2).

The Ficat classification is one of the most widely used staging systems for AVN of the femoral head. It classifies patients with osteonecrosis into four stages based on the appearance on a plain radiograph, at least before the advent of MRI, the ultimate golden standard for the specific case.

1. Pain but no radiographic anomalies
2. Increased density, cystic changes, or porosity
3. Flattening of the femoral head and crescent sign
4. Full collapse of the femoral head with decreased joint space

Many of the treatment options proposed aim to achieve joint preservation. However, when the radiological signs progress to advanced bone collapse in the articular capsule, the single mandatory surgery approach is a femoral head replacement with total hip arthroplasty (THA).

There are two possible opportunities for intervention with HBO2:

• Early stages of the disease (Ficat I and II): Complete recovery can be achieved with imaging and functional improvement, along with injury management and pain control.
• Pre-collapse stage of the joint (Ficat III, early stage): HBO₂ therapy may help delay disease progression, effectively “buying time” before the patient requires Total Hip Arthroplasty (THA), which is the typical clinical course without HBO₂ treatment.

All bones can develop an osteonecrotic lesion, but the segments most frequently affected are undoubtedly the terminal portions of the long bones (epiphyses), especially that of the femoral head. This pathology usually affects the age range of the most active population (40-50 years old), with repercussions both on the patient’s quality of life (as it is often progressively disabling, leading to femoral head collapse if left untreated and eventual surgery) and on the general economy as well (due to its reduction in the ability and work performance of those affected).