Using Hyperbaric Oxygen to Treat Diabetic Foot Ulcers: Safety and Effectiveness

Hyperbaric oxygen therapy is no longer considered a “fringe” treatment. A quick Internet search shows that hyperbaric oxygen therapy is an increasingly popular treatment option for a variety of injuries and disorders. Hyperbaric treatment centers are appearing even in relatively small communities throughout the United States, Canada, and Europe. The primary mechanism of action of hyperbaric oxygen—enhancement of tissue oxygenation—makes this therapy particularly useful for the resolution of hypoxic conditions such as traumatic crush injuries, necrotizing fasciitis, gas gangrene, carbon monoxide poisoning, and anemia due to extensive blood loss. It has also been used with various degrees of success to treat many other disorders, including migraine headaches, morbidity due to radiation damage, multiple sclerosis, cerebral palsy, ulcerative colitis, and anorexia nervosa.Approximately 17 million persons in the United States (6.2% of the population) have diabetes, and an additional 1 million cases are diagnosed annually.1,2 The prevalence of diabetes among adults is expected to increase to 9% by 2025.3 Among patients with diabetes, 60% to 70% have some degree of nerve damage, termed diabetic neuropathy.4 Poor glycemic control, diabetic neuropathy, and peripheral vascular disease, in conjunction with comorbid foot trauma, can result in the formation of a diabetic foot ulcer. Diabetic foot ulcers develop at some point in approximately 15% of patients with diabetes.5 Sequelae of the ulcers may include infection, gangrene, osteomyelitis, and ultimately amputation.6,7 More than half the patients undergoing lower limb amputation in the United States have diabetes.8 More than 80% of amputations in patients with diabetes are preceded by nonhealing foot ulcers.9Diabetic foot wounds are defined as any break in the cutaneous barrier, usually extending through the full thickness of the dermis.10 Diabetic foot ulcers can be generally classified as either neuropathic or ischemic11 (Table 1). A diabetic foot wound that remains unhealed for 1 month is associated with poor outcomes, including osteomyelitis, gangrene, and amputation.10Diabetic foot ulcers are associated with significant morbidity and mortality. The risk of death is 2.4 times greater for patients with diabetes who have foot ulcers than for patients with diabetes who do not.12 Further, diabetic foot complications are the most frequent cause of hospitalization in patients with diabetes, accounting for up to 25% of all admissions among patients with diabetes.13 The goals of therapy include improvement in function, infection control, and avoidance of amputation.Diabetic foot ulcers are thought to result from multiple pathophysiological mechanisms.11 Risk factors for diabetic foot ulcers are delineated in Table 2.8,12–15 The occurrence of diabetic neuropathy is the factor most consistently associated with foot ulcers.7 The decrease in sensory input from the lower limbs due to neuropathy increases the likelihood of foot injury and reinjury, with little awareness on the part of the patient. Pedal injury can come from sources of heat or cold as well as poorly fitting shoes. Once the foot is injured, the ulcer often becomes chronic because of rein-jury and hypoxia. Microvascular and macrovascular complications of diabetes diminish the blood flow to the extremities, limiting the gradient of oxygen pressure in the tissue (Figure 1). Wound healing involves a complex series of events initiated by chemoattraction of macrophages, production of growth factors, fibroblast hyperplasia, and production of collagen. Oxygen is an essential controlling factor for bacterial killing, fibroblast growth, angiogenesis, collagen synthesis, epithelialization, and other biochemical processes essential for wound healing (Table 3).16–19 Ischemia may contribute to 30% to 40% of foot ulcers.7Standard care of diabetic foot ulcers includes pressure reduction (via bed rest, casts), debridement of devitalized wound tissue, moist dressings, and management of infection with topical or systemic antibiotics.7,10,20,21 Unfortunately, none of these therapies effectively increases oxygen delivery to the affected tissue. Hyperbaric oxygen therapy may be a noninvasive alternative to surgical revascularlization for the treatment of diabetic foot ulcers.In hyperbaric oxygen therapy, patients breathing 100% oxygen are placed in a chamber pressurized to 2 to 3 times atmospheric pressure. This pressure is equivalent to diving to approximately 15 m (50 ft) in seawater. In use since 1943, hyperbaric oxygen therapy is considered the treatment of choice for decompression sickness and severe carbon monoxide poisoning. The Undersea and Hyperbaric Medical Society has identified 13 diseases as approved indications for hyper-baric oxygen therapy, including gas gangrene, crush injuries, and enhancement of healing in selected problem wounds.22Two systems for hyperbaric oxygen therapy are currently available: monoplace and multiplace chambers. In each instance, patients breathe pure oxygen while exposed to barometric pressures greater than normal atmospheric pressure. Monoplace chambers are hollow cylinders compressed with pure oxygen that allow 1 patient to lie supine during hyperbaric therapy. Multiplace chambers accommodate up to 6 patients at once; each patient is given an individual breathing source of 100% oxygen via a hood or mask19 (Figure 2). Hyperbaric oxygen given in this manner, often referred to as systemic hyperbaric oxygen therapy, should not be confused with topical oxygen therapy or pure oxygen inhaled at ambient atmospheric pressure.In hyperbaric oxygen therapy, the physical properties of gases under pressure are taken advantage of to expose tissues to greater concentrations of oxygen than would otherwise be possible.23 Boyle’s law asserts that the volume of a quantity of gas is inversely proportional to the ambient pressure surrounding it. Henry’s law states that the amount of gas that can dissolve in a liquid at a given temperature is proportional to the partial pressure of that gas (Figure 3). Exposure to 2 to 3 times normal atmospheric pressure in a hyperbaric chamber concentrates gases the patient is exposed to by a factor of 2 to 3 (Boyle’s law) and increases the amount of dissolved gases in the patient’s bloodstream by a factor of 2 to 3 (Henry’s law).24 Increasing the partial pressure of oxygen has essentially no effect on the amount of oxygen bound to hemoglobin because hemoglobin is already approximately 97% saturated at sea level in room air. However, exposure to 3 atm of pressure increases the amount of oxygen dissolved in the plasma from 0.32% to 6.8% by volume, a quantity great enough to sustain life even in the total absence of hemoglobin.25 Therefore, treatment with 100% oxygen during hyperbaric therapy essentially hypersaturates the bloodstream with oxygen, allowing tissues to achieve levels of oxygenation that would otherwise be impossible. Under hyperbaric conditions, the diffusion distance of oxygen from the vasculature to wound tissue increases by a factor of 2 to 3.19 The partial pressure of oxygen in normal tissue is approximately 40 mm Hg. The partial pressure of oxygen in hypoxic wounds increases from 10 to 20 mm Hg under normobaric conditions to 200 mm Hg after hyperbaric oxygen therapy.26,27 Figures 4A and 4B depict typical results of hyperbaric oxygen therapy.Ten studies16,28–36 have been done to date to assess the effectiveness of hyperbaric oxygen therapy in the treatment of 989 patients with diabetic foot ulcers (Table 4). In all cases, hyperbaric oxygen therapy was used as an adjunct to standard wound care.When all the trials that used foot amputation as a primary outcome variable are considered, amputation was prevented in from 82% to 95% of patients in the groups receiving hyperbaric treatment. When data from all controlled trials (both retrospective and prospective) are combined and averaged, hyperbaric oxygen therapy resulted in a mean limb salvage rate of 89%, compared with prevention of amputation in 61% of patients who received conventional therapy alone. This difference translates to a relative risk reduction of 0.74 attributable to hyperbaric oxygen therapy. In other words, the patients with diabetes in these studies who underwent adjunctive hyperbaric treatment had approximately one fourth the risk of limb amputation compared with the patients who received conventional therapy only. On average, the calculated number of patients who must receive hyperbaric oxygen therapy in order to prevent 1 amputation (ie, the number needed to treat) is 3.6.Despite limitations in the power of the studies because of the relatively small sample sizes in most instances, hyperbaric oxygen treatment resulted in a significant reduction in amputation rates in all comparative trials. Thus, adjunctive hyperbaric oxygen therapy is superior to conventional ulcer therapy. However, most of the patients studied in these trials had necrotic foot ulcers that were refractory to standard therapy. Also, most of the subjects had ulcers that were primarily ischemic. These facts limit the applicability of these results to those patients with diabetes who have ischemic ulcers complicated by profound peripheral vascular disease. Whether hyperbaric oxygen therapy will be as effective in patients with diabetes who have foot lesions that are predominantly neuropathic remains to be determined.Absolute contraindications to hyperbaric oxygen therapy include untreated pneumothorax and treatment with certain chemotherapeutic agents (doxorubicin, bleomycin, and cisplatin) or disulfiram.37 Relative contraindications include seizure disorders, emphysema, upper respiratory tract infections, and a history of thoracic surgery, spontaneous pneumothorax, or surgery for otosclerosis.37In general, if pressures do not exceed 3 atm (3.04 × 105 Pa) and the length of therapy is less than 2 hours, hyperbaric oxygen therapy is considered safe.38 Other than pressure on the ears (easily managed by decongestants, yawning, or the Valsalva maneuver), the most common adverse effect is a reversible nearsightedness. Myopia associated with hyperbaric therapy usually resolves completely approximately 6 weeks after discontinuation of the therapy. The remaining adverse effects are rare; these may include ear, sinus, or tooth pain from changing pressures of gases in the chamber, an occasional dry cough, a temporary burning sensation under the sternum, and feelings of claustrophobia related to being in a restricted space. A very slight increase in seizure risk has been noted, particularly in patients with a high fever or history of epilepsy.37Hyperbaric oxygen therapy is expensive, but the costs are reimbursable under Medicare and many insurance plans. A 30-session protocol typically costs more than $9000. However, this expense should be viewed in light of the total costs associated with therapeutic failure: the costs for osteomyelitis, amputation, and subsequent rehabilitation.As our population ages, the prevalence of lower extremity amputations in patients with diabetes continues to increase, accounting for nearly $2 billion and an estimated 2600 patient-years of hospital stay annually in the United States alone.39 In a recent analysis, Ramsey et al6 determined that the overall economic impact attributable to a newly diagnosed diabetic foot ulcer was $27 987 for a 40- to 65-year-old man the first 2 years after diagnosis. The cost for pedal amputation ranges from $18 760 to more than $40 000.29,40,41 These figures do not include rehabilitation expenses, which range from $40 000 to $50000.42Management of diabetic ulcers of the lower extremity in inpatients cost Medicare an average of $14 400 per episode in 1996.43 Improving the healing rate would obviously save healthcare dollars. It remains to be seen if the rather substantial costs of hyperbaric oxygen therapy will ultimately result in overall cost savings by avoiding the expenses of amputation and rehabilitation. However, the relatively low number needed to treat of 3.6 suggests that spending $32400 on hyperbaric oxygen therapy would prevent 1 amputation and the resultant rehabilitation, which would cost approximately $90000. These dollar figures do not take into account the significant psychological impact of amputation. Thus, it seems that hyperbaric treatment of ischemic foot wounds in patients with diabetes would be cost-effective.Foot ulcers are a significant source of morbidity, mortality, and diminished quality of life for patients with diabetes. Ulcer development is often due to a combination of diabetic neuropathy and peripheral vascular disease, which decreases the supply of oxygen to the affected extremity. Hypoxia can cause otherwise trivial lesions to progress rapidly to infection, gangrene, and limb amputation. Hyperbaric oxygen therapy increases the amount of oxygen dissolved in the plasma, allowing tissues to achieve levels of oxygenation that would otherwise be impossible.Hyperbaric oxygen therapy is adjunctive treatment and will never replace good wound care.19 The American Diabetes Association recommends hyperbaric oxygen therapy as adjunctive treatment for severe and limb- or life-threatening wounds unresponsive to other treatments, particularly if ischemia is present that cannot be corrected by vascular surgery.10 A review of the available literature reveals that the mean limb salvage rate is 89% after hyperbaric oxygen therapy, compared with 61% after conventional treatment. The importance of oxygen in wound healing was highlighted in the study by Kalani et al,36 in which the mean trans cutaneous oxygen tension in the wound was significantly higher in patients who healed than in those patients in whom hyperbaric therapy was unsuccessful and who ultimately lost a limb. Albeit costly, hyperbaric oxygen therapy is a reasonable, cost-effective adjunct to standard wound care for patients with ischemic diabetic foot ulcers that have not healed after 1 month, especially for patients with significant vascular disease affecting the lower extremity.We thank Ms Dana Solomon for manipulation of the hyperbaric chamber photographs.

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