Hyperbaric Oxygen Therapy in the Management of ...

Yanagita N, Nakashima T (eds): Hyperbaric Oxygen Therapy in Otorhinolaryngology. Adv Otorhinolaryngol. Basel, Karger, 1998, vol 54, pp 14–32

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Hyperbaric Oxygen Therapy in the Management of Osteoradionecrosis of the Mandible Dale H. Brown a, A. Wayne Evans b, George K.B. Sandor c a b c

Department of Otolaryngology/Head and Neck Program, Hyperbaric Department, and Division of Oral and Maxillofacial Surgery, Toronto Hospital, University of Toronto, Ont., Canada

The history surrounding hyperbaric oxygen (HBO) therapy generally, and its use in mandibular osteoradionecrosis (ORN) specifically, is not new and can be traced back many years. Since Henshaw described compressed air in 1662 and Priestly’s discovery of oxygen a century later, HBO has been used for the treatment of many maladies. Mandibular ORN has been recognized as a complication of radiotherapy since the early part of this century. Regaud first provided a clinical discussion of ORN in 1922 and since that time a variety of treatment modalities have been used to arrest or reverse this entity [1, 2]. This discussion will comprehensively review ORN in the mandible; specifically dealing with its incidence, pathophysiology, clinical presentation and its diagnosis. Then we will look realistically at the management of ORN with HBO, its protocol and its results in arresting this disease.

Incidence In patients who are treated with radical radiotherapy for oral or oropharyngeal primary malignancies, the accepted incidence for ORN is stated to be around 14% [3]. However, it is the authors’ impression and the opinion of other authors that this incidence now in 1997 is much lower [14]. This is a direct result of more efficient use of radiation (dosimetry, portals, etc.) and

improved dental care and follow-up. This impression is further supported by the wide range of reported incidence in more recent series [4–10]

Medical Presentation All the patients presenting with ORN of the mandible have had radical radiation to the oral cavity and/or oropharynx. With this assumed prerequisite, certain patient factors probably increase ORN risk. These are conditions which may compromise micro-vascularity including diabetes, periodontal disease, hypertension, etc. In examining the radiation dosage administered, it can be seen that ORN can occur despite fairly low-dose radiation. In our series [22] the dosage ranged from 30 to 65 Gy; however, in our experience 95% received dosage schedules in the range of 50 to 55 Gy. This is generally lower than in other series, emphasizing our belief that ORN can still occur in a lower dose radical regime in the post-orthovoltage radiation era [8]. However, it logically follows that the higher the radiation dosage, the greater the risk of ORN [5, 6, 8] In our series [22], all patients received external beam irradiation with single daily dose fractionation. We cannot comment from our data regarding brachytherapy and hyperfraction. Only 8% of our patients who developed ORN had iridium implants. There is some belief that either of these factors may increase the incidence of mandibular ORN [11], in addition to high dose volume. Another interesting parameter to look at is the time range for the development of ORN from the time of primary radiation. There is a belief that the time to development of the problem is many years [9, 12]; however, our experience is not necessarily in keeping with this belief. Almost 50% of our cases with mandibular ORN presented in the first year after primary radiation. We had no cases of ORN after 5 years (fig. 1) [22]. In addition, radiotherapy complications do not seem to predispose to ORN of the mandible. Again in our series there were no complications at all (dysphagia, serous otitis media, mucositis) and there were no major complications in a series of 41 patients. No complications led to the cessation of radiotherapy [22]. It is also the authors’ belief that the primary pathology has no bearing in the occurrence of mandibular ORN. Fully 93% of the patients in our series had squamous cell carcinoma as expected. The site of tumor occurrence also does not play a role in the development of ORN of the mandible [22]. The mandibular sites of ORN in our series were symphysis (73%), body (12%), angle (10%) and ascending ramus (5%). In this group of 41 patients,

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Fig. 1. Time from radiation to development of osteoradionecrosis.

17% had more than one site of ORN of the mandible (5 patients with 3 sites; 2 patients with 2 sites) showing that multiple sites are a real possibility and dilemma [22]. In our patients, 80% presented with pain as the initial symptom and all patients had some visible exposed bone intraorally. Most of these patients had a significant segment of necrotic bone at presentation either by physical exam, panorex x-ray or by computed tomography. It can be speculated that patients have pain for a long period of time while the area of devascularized bone was increasing prior to presentation. There is a role for more aggressive followup and investigation of patients after radiation treatment in an attempt to detect ORN at an early stage, when we have a better ability to arrest or reverse the process [22]. Over the past decade, with increasing knowledge of this entity, many authors have tried to introduce clinical classification schemes [4, 11, 13, 14] which these authors encourage. This can only improve treatment protocols, patient selection and analysis of treatment results.

Diagnosis ORN of the mandible is defined as a nonhealing mucosal or skin opening with underlying exposed devitalized bone more than 1 cm in diameter. We do not put a time criteria to this definition; however, the area in question should have been originally closed. The diagnosis is therefore clinical but a biopsy must be carried out in order to rule out recurrent/residual malignant disease.

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Radiological findings further support the diagnosis and should include a panorex, plain mandibular radiographs and a computed tomogram showing bony erosion, discontinuity and possible pathological fracture. The use of bone scanning will be addressed later in this manuscript.

Pathophysiology of ORN The Physiologic State of Host Cells following Irradiation Following irradiation the host cells undergo a series of responses which can include histologic remodeling to a less functional and less resilient tissue. The remodeling exhibits clinically evident texture and appearance changes externally in skin which has been irradiated several years previously. Underlying this, the less visible effects of radiation on the highly radiosensitive vascular tissue also demonstrate radiation induced histologic remodeling which results in radiation fibrosis [34]. An important underlying issue associated with such changes is slowing of mitotic activity or complete loss of mitotic potential of these vascular endothelial cells. This results in loss of capillary budding potential and thus progressive reduction of tissue vascularity over time. The loss of vascularity and reduced proportion of vessel wall cells containing nuclei can easily be visualized microscopically on pathology specimen. This is of particular concern in the mandible where there are fewer choices for arterial supply compared to the adjacent maxilla. To explore this fragile perfusion of the mandible further measurement of tissue hypoxia has been performed in patients with mandibular osteoradionecrosis using transcutaneous oximetry [45]. In the center of an irradiated field measurements as low as 5 mm Hg oxygen tension has been recorded and quite typically 5–10 mm [46] (noting that values of less than the normal venous level of 40 mm Hg are indicative of pathology). These measured oxygen levels increase by perhaps 5 mm Hg for each centimeter as one moves distally from the focus of the radiation beam to the edge of the field. Thus, there is a gradual reduction in perfusion as one nears the center of the radiation field. Development of such perfusion defects are dose dependent and relatively predictable although multiple host factors will alter the degree of biological effect in each case. It is generally agreed that tissue doses below 5,000 cGy infrequently display the clinical complication of tissue necrosis. The commonly witnessed result of the above processes has been referred to by Dr. Robert Marx as ‘3H’ tissue which is: (a) hypovascular; (b) hypocellular, and (c) hypoxic. Such chronically hypoxic tissues are prone to a variety of complications. These tissues become unable to perform routine maintenance functions, defend


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themselves against infection or tolerate the metabolic demands of wound healing either traumatically or post-surgically. Tissue Repair The well-understood process of normal wound healing proceeds in an orderly fashion in many ways similar to other familiar biochemical pathways cascades. In recent years, the research focus has progressed to exploring the subtle control mechanisms for this process. Let’s look at the response to tissue insult in normal tissue (fig. 2). For example, a simple skin laceration will precipitate Hageman factor activation, which induces several cascades including complement, plasminogen, kinin, and clotting. In the process, platelet aggregation results in the release of a number different platelet derived growth factors. These, as well as degradation products from the other cascades act to direct the activities of a macrophage, neutrophil, fibroblast, epidermal cell and perhaps most importantly, the capillary endothelial cells. The neutrophil and macrophage play a pivotal role in infection control whereas the latter three cell varieties (fibroblast, epidermal cell and capillary endothelial cell) are the key to new tissue development. Both of these processes are essential for wound healing to occur. Of course, the controls for the various cell functions are much more complicated than described herein, and in the case of radiation compromised tissue (because of the radiation effect on vascularity) our focus becomes the control acting on the capillary endothelial cells and how it can be encouraged to increase vascularity through angiogenesis. In the exploration of angiogenesis control, platelet-derived angiogenesis factors as well as various chemical messengers originating from the macrophage have emerged as key ingredients in the successful stimulation of capillary endothelial cells to initiate mitosis, and thus new vessel formation through capillary budding. One of these, macrophage angiogenesis factor has been isolated by Knighton [47] and is produced by macrophages following hypoxic exposure or in the presence of lactate. One might reasonably ask why normal angiogenesis does not automatically occur in hypoxic irradiated tissue, which has suffered radiation-induced vascular insufficiency. As previously noted, Marx has demonstrated in irradiated tissue that due to the radiation beam scatter amongst other factors, there is no abrupt change in oxygen tension over the field. This is to be contrasted with the steep oxygen gradient which could be demonstrated at the edge of a laceration in healthy tissue. The problem here is that in such a setting, the injury may be inapparent to the macrophage and thus go unnoticed. Work by Hunt and others [48] has revealed that a ‘minimal oxygen gradient’ is required to generate signals of sufficient intensity to induce angiogenesis. Coworkers [49, 50] have determined that a minimal gradient of 20 mm oxygen

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Fig. 2. Normal wound healing processes (Knighton) [47].

per cm is required to stimulate macrophage chemotaxis to the hypoxic zone and coax the macrophage to secrete its angiogenesis factor. Following repair, once the oxygen gradient between healthy and hypoxic tissue becomes too shallow, the macrophage senses that no further repair is required and moves on, capillary budding stops and vascular density becomes static. It is thus essential that the macrophage recognize that the injured tissue is hypoxic before it will produce factors which stimulate capillary budding.


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The gradient of higher to lower oxygen levels in irradiated tissue may be much below a threshold recognizable by the macrophage and thus, insufficient to initiate angiogenesis. Although such might prevail when breathing room air, a shallow oxygen gradient, however, can be magnified with the use of increased levels of inspired oxygen such that a larger gradient can be developed and thus stimulate angiogenesis. The role of hyperbaric oxygen is thus to magnify the gradient and signal the macrophage into stimulating capillary budding. The ability of HBO to stimulate angiogenesis has been demonstrated in an irradiated rabbit model which revealed an angiogenesis dose response from 21% oxygen (room air) through 3 atm of pure oxygen [51]. The complexities of multiple feedback control factors involved in encouraging maximal angiogenesis are far from completely elucidated and at this point, literally dozens of factors have been implicated as having a role to play.

Management: Rehabilitation of ORN Use of Hyperbaric Oxygen: ‘What Is Hyperbaric Oxygen Therapy?’ HBO therapy is a method of treating certain disease by delivering oxygen at pressures above those that can be achieved at one atmosphere, or sea level (normobaric pressure). In order to achieve these ’hyperbaric’ pressures, a patient, much like deep sea divers or compressed air workers, has to be placed inside a pressure chamber. Thus, the total ambient pressure can be increased to two or three times normal. The patient then breathes 100% oxygen at the higher ambient pressure for a predetermined period. Both acute lifethreatening and chronic conditions are treated. In this manner, oxygen is used as a ‘drug’ and the hyperbaric chamber is the dosing apparatus. Tissue Effects of Hyperbaric Oxygen Hyperoxygenation. An abnormally elevated arterial oxygen concentration in excess of 1,000 mm Hg can easily be demonstrated from blood gas specimens taken while in the hyperbaric environment. This permits diffusion of this highly concentrated oxygen into the tissue, primarily at the capillary level. Diffusion of gases from capillaries into interstitial tissue is proportional to the square root of the oxygen concentration in the capillary. Replenishment of Intracellular Energy Stores. In fatigued or damaged muscle tissue restoration of ATP levels by hyperbaric oxygenation following significant hypoxic injury has been associated with findings of increased tissue survival [52]. New Tissue Production. Angiogenesis occurs through the seemingly paradoxical stimulation by intermittent hypoxia. Fibroblast proliferation to form a collagen lattice to support the neovascular network is extremely oxygen depend-

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ent [53]. Quantitative bone production is also augmented under hyperoxic conditions [54]. Quality of bone and collagen are improved [55]. Host Defenses. Leukocyte oxidativeness likely is dependent on the generation of high energy oxygen radicals; markedly impaired at tissue pO2 of =30 mm Hg [56]. Hyperbaric Protocols. Generally, the practical limits of HBO use in humans is limited by oxygen toxicity. Like most pharmaceuticals, there is a therapeutic range whereby the desired effect is obtained while avoiding drug toxicity. This is also true in the case of the administration of oxygen. The benefit gained by increasing the concentration of reactive oxygen species (assists in stimulating increased tissue growth and oxidative phosphorylation) can be overdone, leading to over stimulation of the CNS and thus oxygen toxicity is seen as CNS irritability. If continued high dosage of oxygen persists this toxicity progresses, eventually resulting in grand mal seizure. Such toxicity is easily resolved, with no adverse CNS effects, simply by reducing the oxygen concentration by resuming air breathing. This dose effect can be predicted. For example, at 2 ATA oxygen toxicity is unlikely to be evident with less than 3 h of exposure; whereas at 6 atm its window is reduced to a few minutes. Thus, clinical hyperbaric oxygen exposure protocols have been designed to provide oxygen at pressures which permit good penetration of the dissolved oxygen deeply into the tissues while avoiding the risks of oxygen toxicity. It should be noted that sustained hyperoxia is not an objective since differential positive effects of intermittent hyperoxia and hypoxia have been demonstrated to stimulate various differential cellular process involved in new tissue production [57–59]. With the above factors in mind several hyperbaric protocols had been successfully utilized in the treatment of osteoradionecrosis. Dosing schedules have involved reaching maximum pressure of between 2 and 2.5 atm absolute for a duration of 90 to 120 min. Perhaps the most commonly used is that recommended by Dr. Robert Marx of the University of Miami. This protocol specifies 2.4 atm absolute for a period of 90 min on a daily basis. Using this protocol, permanent gains in vascular density in such tissue have been predictably achieved. Clinical studies have demonstrated that hypoxic tissue (fig. 3) treated daily with hyperbaric oxygen therapy will achieve a vascular proliferation over a course of 20 treatments. In Marx’s original work describing a rigid osteoradionecrosis management protocol (reported in 1983) the process of tissue preparation involved sequential courses of HBO at various states (which could eventually result in 90 or more treatment sessions by the completion of cancellous bone grafting and soft tissue flap reconstruction). Because of the demonstrable long-term effect of HBO-induced revascularization this has since been modified to include a single but complete course of 30 preoperative hyperbaric oxygen treatments.


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Fig. 3. Illustrations depicting the lag and proliferative phases of oxygen-gradient-mediated angiogenesis.

The current algorithm of Marx which enjoys widespread application is summarized in fig. 4). Protocols for oxygen treatment in the hyperbaric chamber have developed around the above principles so as to provide a dosage of oxygen which is small enough to be well tolerated in the vast majority of patients while providing sufficient stimulation of the various cellular components to achieve both cell division as well as maximal production of cellular products such as high quality collagen and bone mineralization.

Oral Hygiene and Dental Therapy Local wound care and good oral hygiene plays a major role in the treatment of ORN. This promotes healing and may prevent bacterial superinfection. This includes rigorous use of hydrogen peroxide and/or chlorhexidene oral rinses and external wound packing. One must get the patient to commit to a smoking cessation program and limit/stop alcohol consumption. Initially it was believed that the pathogenesis of ORN was radiation, trauma, and infection [15, 16]. Trauma to the soft tissues overlying the bone was thought to permit oral pathogens to enter demineralized bone. The next step in the sequence was thought to be osteomyelitis in the radiated bone [17]. These concepts have been challenged, and this has led to newer concepts in the pathophysiology of osteoradionecrosis [18].

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Fig. 4. Management of osteoradionecrosis: Wilfred-Hall staging algorithm [20].


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Microorganisms most likely act as contaminants in ORN. The role of trauma was questioned by Daly et al. [19]. Currently, it is believed that radiation leads to the formation of hypoxic-hypocellular-hypovascular tissue [18]. This tissue, including bone and soft tissue, has lost its ability to repair and heal. In hypoxic, injured tissues, macrophages are not stimulated to reorganize the wound, and fibroblasts fail to lay down new collagen, resulting in chronic nonhealing wounds. Antibiotic use in the management of ORN has not been clearly defined [20]. Based on our current understanding of ORN, prolonged empiric antibiotic use cannot be justified. Five (12%) of the 41 patients received longterm antibiotic prescriptions, and 30 (73%) received greater than 2 weeks of intravenous antibiotics. In all cases, the records did not clearly indicate why this therapy was administered. These patients did not appear to have an improved rate of healing of their radionecrotic bone. In our patients a variety of antibiotics were tried for various lengths of time. Antibiotic coverage is recommended when obvious evidence of infection is present. Prophylactic antibiotic use may also be justified prior to surgery. Since these patients by definition have poorly vascularized bone, and usually have segments of completely devascularized bone, antibiotics may not infiltrate the area where needed. The use of antibiotics may also create resistant organisms, making the treatment of clearly documented infections more difficult. The use of antibiotics, the type and reason for use is very indeterminate in the literature; however, every author uses antibiotics to some degree [11, 13, 14]. The value of dental extractions in the management of ORN remains controversial [19]. Clearly, the patient’s dental condition prior to irradiation treatments has an effect on the incidence of ORN. Some authors believe that dental removal of both carious and healthy teeth prior to irradiation decreases the incidence of ORN [15, 17]. Various authors have proposed that postradiation extraction may decrease the risk of ORN [16]. However, this is not currently accepted [21]. The 41 patients in our study had extraction of all diseased teeth prior to radiotherapy. The patients received regularly scheduled dental examination postoperatively, and further extractions were performed on any new diseased teeth [22]. Surgery Surgery plays an important role in the management of ORN with removal of all necrotic bone. The surgical procedure may include small local debridement, sequestrectomy, or resection of large segments of the mandible. It has been our experience that in the group of patients with severe ORN (i.e. large amount of exposed/necrotic bone, severe symptoms, fistulae, gross radiological changes) of which all needed surgery (by definition), only 20%

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Fig. 5. Number of operations required for control of osteoradionecrosis.

required large surgical reconstruction. The rest (80%) needed only local surgery with HBO, although some of these needed more than one operation to debride bone and get wound closure [22] (fig. 5). Marx and others [11, 13, 14, 23, 24] showed that reconstruction with particulate bone and cancellous marrow grafts or subperiosteal grafting shows good results when used in combination with HBO. If possible, the original architecture/contours of the mandible should be maintained for both cosmetic and dental occlusal objectives. In situations where the defect is small and most of the mandible is structurally intact, one could argue for the use of nonvascularized particulate cancellous bone to fill the defect. The risk here involves the previously discussed danger of perfusion insufficiency in fueling the metabolically active process of bone remodeling in this tissue as the grafted bone becomes incorporated in and adds to the structural integrity of the mandible. In this situation the use of hyperbaric oxygen has been effectively used to stimulate normal angiogenesis resulting in gains in perfusion which permanently adds to the metabolic capacity of the region. Thus, with adequate angiogenic preparation of the tissue by following a standardized protocol (fig. 4), the postoperative metabolic demands can often be met to ensure healing, thus future integrity of the work, while maintaining a structural form which is optimal for future occlusal dental considerations. There are, of course, imitations to such uses of the above cancellous bone approach even with the support of hyperbaric oxygen; however, both approaches likely have their place. It is the authors’ preference of reconstruction to use free vascularized bone grafts in segmental resections and not particulate grafting (we have not required its use to date [22]). Cancellous bone grafts can include the insertion


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of a portion of fibula or radius where the mandible previously resided restoring form and function. Our favorite donor sites for free tissue transfer would be either free iliac crest bone (bone only needed) or free fibula osteocutaneous (bone and skin needed). This provides healthy nonirradiated bone with its own blood supply to replace a segment of devascularized bone and soft tissue. Based on an analysis of our patients, two groups emerged. The first group is that of mild osteoradionecrosis. These patients (15% in the present series) have minor symptoms, minimal radiographic changes, and small amounts of exposed bone. HBO may be all that is necessary to cure these patients [22]. This correlates with the experience of Marx (stage 1 responders – fig. 4). The second group are those patients with severe osteoradionecrosis. These patients (85% in our series) have a large amount of exposed bone, severe symptoms with complications such as fistulas, and gross radiographic changes. In these patients, HBO plays a role in management; however, these patients need additional surgical treatment [22]. The division of patients into mild or severe ORN may have some role in clinical judgment. If the patient falls into the category of severe ORN, the patient will definitely need an operation (i.e. stage 2 or 3 of the Marx protocol) (table 2) and, therefore, HBO to attempt cure is not justified. Rather, the established 30 preoperative treatments followed by the appropriate surgery with a shorter postoperative course of 10 HBO treatments is more rational. One last surgical consideration is osseointegration in previous ORN involved bone. We have a small but growing experience with osseointegrated implant treatment in this patient group (largely due to cost); but implant surgery in combination with HBO is now a real possibility [61]. Many more implants are now being used in post-ORN patients [14] with excellent success. With the use of free vascularized bone in segmental resections of ORN [62] one has an excellent recipient site for osseointegrated implants. Vascularized tissue transfer should supply the metabolic demands of new bone growth and the high turnover found at the titanium implant bone interface [63–65]. Early work in the application of osseointegration in previously irradiated tissues [66, 67] addressed the high failure rate of bone anchored implants in previously irradiated tissue, over the 30-year history of the use of such devices (Branemark endosseous dental and craniofacial implants). However, a significant reduction in such failures has been realized by providing adjunctive support for such procedures with hyperbaric oxygenation in randomized control study patients [61, 68, 69] and is further supported by ongoing work now [70]. This work also showed that in implant failures osteoradionecrosis was avoided in the hyperbaric-treated group, again supporting Marx’s previous work demonstrating hyperbaric oxygenation repair process at work prophylactically to avoid the natural history of developing overt osteoradionecrosis

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Table 1. Rigid end point criteria of Marx [46]

1 2 3 4 5 6

Continuity Aleveolar bone height Osseous bulk Maintenance of bone Soft tissue deficiencies eliminated Facial form

lesions. An associated incidental finding of a significant increase in the bone formation of hyperbaric oxygen treated normal controls is a finding of significance, which deserves further exploration. A recently popular concept developed from the above Scandinavian experience is the establishment of the Craniofacial Osseointegration and Maxillofacial Prosthetic Rehabilitation Unit (COMPRU) which relies on hyperbaric oxygen in treatment of high-risk cases of multidisciplinary head and neck reconstruction [70]. This team performs various implant procedures and requires hyperbaric oxygen availability for pre- and postoperative treatment in high-risk cases where the tissue has been radiated. Their gains in success have been impressive.

Prognosis The literature over the past 10–15 years definitely supports the use of HBO in the management of ORN of the mandible [11, 13, 14, 21, 22, 24–34]. In addition, several studies indicate HBO in the prevention of ORN [35, 36]. However, many questions remain unanswered in spite of the volumes of literature now available on this subject. Review of many of the clinical studies to date show inherent problems and flaws in each case including few patient numbers, inconsistent endpoints, inconsistent methods and criteria, and no denomination in any study. Marx lists six endpoint objectives and the definitions are perhaps the most rigid developed (table 1). Because of the limited number of cases seen by any single centre per year, it is difficult to achieve convincing statistical power when studying patient outcomes. The most recent reviews dealt with study numbers of 26 [11], 29 [13], 17 [14], and 41 [22] from our experience in Toronto. Each of these studies showed excellent success rates. Aitasalo et al. [14] with a combination of preand postoperative HBO had only one failure of the 17 patients he treated. van Merkesyn et al. [13] had a resolution rate of 69% although 2 of their 29 patients received no HBO (therefore should not have been included) and actually would have a better success rate than stated. McKenzie et al. [11]


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report 50% resolution of ORN with HBO × surgery, while a further 30% had improved status following therapy. This is in keeping with our own findings [22] which showed 15% complete resolution with HBO alone while a further 68% showed significant improvement (based on our definition) with HBO in conjunction with surgery. Thus overall HBO resulted in a radiologic and clinical significant improvement in 83% of the patients treated. From our data [22], we concluded there may be a role for lengthy followup and investigation of patients who have received radiation to the mandible in order to detect ORN at a time when HBO alone can arrest the disease. Early recognition of ORN is imperative to prevent progression of disease and to allow treatment with HBO alone, thus avoiding major surgery. There is a place for major free vascularized bone grafting in a number of ORN cases; however, there remains a need to study the outcome of free vascularized bone grafting alone in ORN versus this surgery plus HBO. Another issue that stems from these conclusions is how one actually follows the patient. Obviously close clinical follow-up is a foregone conclusion but what investigations should one use, and how frequently? Aitasalo et al. [14, 23] supported the use of bone scans for the initial diagnosis of clinical necrosis, although these scans were less useful for monitoring progress as they remained abnormal for long periods of time. Epstein et al. [4] felt a gallium scan may be a useful tool for monitoring as they noted a normalization of previously abnormal gallium scans which correlated with clinical disease resolution. However, the literature is varied on bone scan use [37–44] and only future study will hopefully answer these questions. The work of Marx and others over the past two decades has helped clarify the rehabilitation potential of pharmacologic doses of oxygen in radiationcompromised tissue. Through this we have gained some appreciation of the judicious use of a rather elegant intervention associated with minimal hazards and as a result, the prognosis of the affected patient population has improved. Thus, in the management of radiation-compromised tissue our objectives may be summarized: (1) maximize tissue salvage with the use of HBO to arrest the degenerative process; (2) identify those who can completely resolve nonsurgically with HBO; (3) identify those who require minimal surgery; (4) facilitate successful minimally invasive surgery to those who require it; (5) minimize the number and cost of HBO. We are currently guided by studies which estimate the risk of wound failure primarily based upon history of significant radiation dosage. If indicated, we then appropriately rehabilitate the tissue nonsurgically to their maximum microvascularity using established hyperbaric oxygenation algorithms (often in preparation for surgical wounding). In some cases, postoperative hyperbaric oxygen is also indicated.

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The implicit assumption in this, our current approach, however, is that tissue damage and rehabilitation requirements of all patients fit neatly into a few categories. This may not be precisely accurate. With ample supporting evidence to the rationale of an HBO medicated revascularization process now in existence, exploration of additional refinements of Marx’s protocols are in order, perhaps challenging the assumption that all ORN cases should respond optimally to the same HBO Rx protocol. Thus what remains for future exploration is perhaps improved measurement of the degree of tissue compromise in individual patients since this is the key underlying problem we later deal with when surgical intervention becomes necessary. Our current evidence [22] indicates that the natural history of perfusion deterioration as a consequence of radiation damage can be arrested if treated at an early stage. With this in mind it may be possible to nonsurgically treat patients earlier in the natural history of disease if we could select those who had developed perfusion defects for treatment before a long-standing bony erosion is established. The use of transcutaneous oxymetry (TCOM) may be worthy of revisiting. This diagnostic tool is enjoying more extensive use of late as an adjunct to clinical assessment in patient selection and monitoring of patient progress in the management of other perfusion compromised tissues usually involving the limbs. As such this tool assists not only in determining the degree of tissue ischemia but also the margins of the affected tissue through a mapping technique. Portions of the affected tissue are serially monitored for the improvements in vascularity in response to treatment in a similar fashion to the previous work of Marx (fig. 3). The experience gained assessing peripheral limb problems with this relatively common tool may be transferable back to the head and neck arena again. This may include more precise determination of degree and pattern of ischemia pretreatment through detailed mapping with TCOM or other means. Portions of affected tissue could be serially monitored for improvements in vascularity through TCOM measurements. The potential modification of protocols to provide adequate pre-operative hyperbaric support has been somewhat explored by Aitasalo providing a significantly abbreviated protocol of 5–7 pre- and postoperative treatments, yet achieving excellent results in a small study. One must bear in mind however that Aitasalo is not working with the same model as Marx in that Aitasalo uses microvascular-free periosteal grafting, a technique which bears partial but not identical relevance to the recipient bed preparation objectives of the protocol of Marx. (Oximetry studies would ideally accompany such new protocols.)


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Benhaim P, Hunt TK: Natural resistance to infection: Leukocyte functions. J Burn Care Rehabil 1992;13:287–292. Tuncay: Oxygen tension regulates osteoblast function. Am J Orthodont Dentofac Orthoped 1994; 105:457–463. Makihara N, Nakashima T, Suzuki T: Effect of hyperbaric oxygenation on bone in HEBP-induced rachitic rats. Undersea Hyperbaric Med 1996:23:1–4. Iwase T, Kuroda D, Lui S: Bone composition and metabolism after hyperbaric oxygenation in rats with 1-hydroxyethylidene-1, 1-bisphosphonate-induced rickets. Undersea Hyperbaric Med 1996;23: 5–9. National Institutes of Health Consensus Development Panel: Consensus statement: Oral complications of cancer therapies. NCI Monogr 1990;9:3–8. Granstro¨m G, Bra˚nemark PI, Tjellstro¨m A, Fornander J: Bone-anchored reconstruction of the irradiated head and neck cancer patient. Otolaryngol Head Neck Surg 1993;108:334–343. Barber HD, Seckinger RJ, Hayden RE, Weinstein GS: Evaluation of osseointegration of endosseous implants in radiated, vascularized fibula flaps to the mandible: A pilot study. J Oral Maxillofac Surg 1995;53:640–644. Granstro¨m G, Hansson A, Johnsson K: Hyperbaric oxygen can increase bone to titanium implant surface strength after irradiation. XVIIth Ann Meet EUBS, Sept 14–19, 1992, Basel, 1993, pp 151– 155. Johnsson K, Hansson A, Granstro¨m G: The effects of hyperbaric oxygenation on bone-titanium implant interface strength with and without preceding irradiation. Int J Oral Maxillofac Implants 1993;8:415–419. Nelson L, Albrektsson T, Granstro¨m G, Rocker HOE: The effect of hyperbaric oxygen treatment of bone regeneration. Int J Oral Maxillofac Implants 1988;3:43–48. Granstro¨m G, Bergstro¨m K, Tjellstro¨m A, Bra˚nemark PI: A detailed analysis of titanium implants lost in irradiated tissues. Int J Oral Maxillofac Implants 1994;9:653–662. Taylor TD, Worthington P: Osseointegrated implant rehabilation of the previously irradiated mandible. J Prosth Dent 1993;69:60–69. Granstrom G: The use of hyperbaric oxygen to prevent implant loss in the irradiated patient. Adv Osseointegration Surg 1993;28:336–345. Granstrom G, Jacobsson M, Tjellstrom A: Titanium implants in irradiated tissue: Benefits from hyperbaric oxygen. Int J Oral Maxillofac Implants 1992;7:15–25. Wolfaardt JF, Wilkes GH, Parel SM, Tjellstrom A: Craniofacial osseointegration: The Canadian experience. Int J Oral Maxillofac Implants 1993;8:197–204.

Dr. Dale H. Brown, FRCSC, Department of Otolaryngology/Head and Neck Surgery, Toronto Hospital, 200 Elizabeth St., EN7-234, Toronto, Ont. M4G 2C4 (Canada)

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