Non Healing Wounds Like Diabetic Foot Ulcers Can Benefit From HBOT

Non healing wounds or problem wounds such as diabetic ulcer wounds, vascular insufficiency ulcers (ulcers with poor circulation), compromised amputation sites, traumatic wounds – all share the common problem of tissue hypoxia – a low tissue oxygen level, usually related to impaired blood circulation.

Problem and non healing wounds are failing to respond to established medical and surgical management. Such wounds usually develop in compromised hosts with multiple local and systemic factors contributing to inhibition of tissue repair.

Fifty percent of all lower extremity amputations in the United States are due to diabetes and non healing wounds, at a cost of more than one billion dollars per year.

It is well known that many diabetics suffer circulatory disorders that create inadequate levels of oxygen to support non healing wounds repair.

Diabetic foot ulcers and non healing wounds are one of the major complications of diabetes and an excellent example of the type of complicated wound which can be treated with hyperbaric oxygen.

When hyperbaric oxygen treatment is used in conjunction with standard wound care, improved results have been demonstrated in the healing of difficult or limb threatening non healing wounds as compared to routine wound care alone.

Mississauga--March 16/2005--Jack Hunter lost his right leg from below the knee and several toes on his left foot due to complications stemming from diabetic ulsers. He is now undergoing treatment in a hyperberic chamber which promotes faster healing with pure oxygen. His doctor thinks that 75% of amputations due to diabetic ulsers and non healing wounds could be avoided with the preventative use of the Hyperbaric Chamber.

Photo courtesyof Glenn Lowson

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Enhancement Of Healing In Selected Non Healing Wounds

By Robert A. Warriner III, M.D., FACA, FCCP, CWS and Harriet W. Hopf, M.D.

Incidence And Prevalence Of Problem Non Healing Wounds

Problem and non healing wounds represent a significant and growing challenge to our healthcare system. The incidence and prevalence of these wounds are increasing in the population resulting in growing utilization of healthcare resources and dollars expended. 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 and non healing wounds in patients with diabetes contribute to over half of lower extremity amputations in the United States in a group at risk representing only 3 per cent of the population.¹

In response to this challenge specialized programs have emerged designed to identify and manage these patients using a variety of new technology to improve outcomes. Hyperbaric oxygen treatment has been increasingly utilized in an adjunctive role in many of these patients coinciding with optimized patient and local wound care.

Hypoxia In Wound Healing Failure

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 non healing 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 healing wounds 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.

The hypoxic nature of all non healing wounds has been demonstrated³, and the hypoxia, when pathologically increased, has correlated with impaired healing wounds⁴ and increased rates of wound infection. Local oxygen tensions in the vicinity of the wound are approximately half the values observed in normal, non-wounded tissue.^{5, 6, 7}

The rate at which normal wounds heal has been shown to be oxygen dependent. Fibroblast replication, collagen deposition⁸, angiogenesis^{9, 10, 11}, resistance to infection^{12, 13}, and intracellular leukocyte bacterial killing^{14, 15} 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.^{16, 17}.

Measurement of Non Healing Wounds 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 Scheffler¹⁸ and its application to wound healing problems by Sheffield.^{19, 20}

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 permeabililty, and oxygen diffusion. The electrode is typically about 0.3mm from the capillary network in normal skin²¹. 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 (18). PtcO₂ is a more accurate reflection of changes in perfusion than is measurement of ankle brachial index²².

Although 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^22-31 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^32-33. The addition of provocative testing with lower extremity elevation or dependency^{34, 35} or following occlusion induced ischemia and recovery³⁶ or with 100% oxygen breathing³⁷ may increase the sensitivity of the test as a screening tool for detecting occult lower extremity arterial insufficiency.

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 salvage³⁸. 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 if hyperbaric oxygen. This positive predictive value is consistent with those reported by others in both arterial insufficiency and diabetic lower extremity wounds^39-41.

When evaluating problem chronic or acute non healing wounds where local hypoxia is suspected to play a role in wound healing failure, baseline PtcO₂ measurements should be made breathing sea level air to define the presence and degree of periwound hypoxia. Provocative testing with 30 degree elevation of the lower extremities may enhance the sensitivity of testing to identify occult peripheral vascular disease^{34, 35}.

If hypoxia is identified, PtcO₂ measurement made while breathing 100% oxygen at sea level or preferably 100% oxygen during hyperbaric oxygen treatment may indicate who is likely to respond successfully to treatment. Testing can also be repeated following lower extremity angioplasty or revascularization to assess the physiological benefit of such interventions.

The laboratory evidence for hypoxia playing a major role in wound healing failure is not in dispute and has been discussed above. Clinical studies identifying the risks of wound or amputation flap healing failure⁴² define periwound hypoxia as a primary determinant of future 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. Unfortunately there is a lack of direct clinical trial data linking periwound hypoxia as a selection criteria 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^{43, 44} 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 Non Healing Wounds

Regardless of the primary etiology of problem and non healing 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 hypoperfused 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. 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. 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.

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. Two groups of induced responses occur:

1. Improved leukocyte function of bacterial killing^{45, 46}, antibiotic potentiation^{48, 49}, and enhanced collagen synthesis⁸ occur during periods of elevated tissue PO₂.
2. Suppression of bacterial toxin synthesis⁵⁰, blunting of systemic inflammatory responses⁵¹, and prevention of leukocyte activation and adhesion following ischemic reperfusion^52-54 are effects that may persist even after completion of hyperbaric oxygen treatment.

In addition, vascular endothelial growth factor (VEGF) release is stimulated⁵⁵ and platelet derived growth factor (PDGF) receptor appearance^56-58 is also induced. The net result of serial hyperbaric oxygen exposures is improved local host immune response, clearance of infection, enhanced tissue growth and angiogenesis⁵⁹ with progressive improvement in local tissue oxygenation, and epithelialization of hypoxic wounds.

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Diabetic Lower Extremity Wounds, the Prototype Hypoxic Non Healing Wounds

Lower extremity ulcers and amputations are an increasing problem for people with diabetes. Up to 6 per cent of all hospitalizations for diabetics include a lower extremity ulcer as a discharge diagnosis. When present, an ulcer increased hospital length of stay by an average of 59% compared to diabetics admitted without lower extremity ulcers. Finally, once an amputation occurs, nine to 20% of diabetic patients will experience an ipsilateral or contralateral amputation within 12 months and 28-52% within five years¹. The cost of care for a new diabetic foot ulcer has been calculated to be $27,987 in the two years following diagnosis⁶⁰.

The pathophysiology of diabetic foot ulceration, faulty healing, and lower extremity limb loss has been well described^{42, 61, 62}. It involves the progressive development of a sensory, motor, and autonomic neuropathy leading to loss of protective sensation, deformity increasing plantar foot pressures, and alternations in autoregulation of dermal blood flow. Diabetics show earlier development and progression of lower extremity peripheral arterial occlusive disease with a predilection for the trifurcation level vessels just distal to the knee. Impaired host immune response to infection and possible cellular dysfunction all contribute to the clinical outcomes described above.

Management, likewise, has been extensively described^63-66 and includes careful attention to identification and management of infection, aggressive surgical debridement, evaluation and correction of vascular insufficiency ambulatory off-loading, and glycemic control^{67, 68}. While a full discussion of these interventions is beyond the scope of this review, they form the basis of effective diabetic foot ulcer management and must be applied consistently if adjunctive interventions are to provide an additive value. Other interventions have recently been advocated including topical application of a recombinant human platelet derived growth factor (PDGF-BB, becaplermin)⁶⁹, bioengineered human mono layer fibroblast grafts^70-72 and bi-layer fibroblast and keratinocyte^{73, 74} grafts, and negative pressure wound therapy (wound vac)^{75, 76}. Clearly, regardless of the interventions applied, limb salvage rates improve when care is applied in a multidisciplinary setting using comprehensive protocols for care⁷⁷.

Local wound hypoxia plays a pivotal role in diabetic wound healing failure and limb loss as evidence by the report by Pecoraro⁴² that when periwound PtcO₂ values were below 20 mmHg they were associated with a 39 fold increased risk of primary healing wounds failure. While aggressive distal lower extremity bypass grafting and lower extremity angioplasty have contributed to increased non healing wounds repaair 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 in the setting of minimal or insufficiently corrected blood flow.

Other Potentially Hypoxic Wounds

Venous Stasis Ulcers

Compression therapy with multilayer external compression bandaging techniques remains the mainstay of management of venous stasis ulcers of the lower extremity^{89, 90}. Recent evidence suggests that bioengineered tissue grafts⁹¹ used in combination with standard compression bandaging techniques may shorten time to repair non healing wounds. While one prospective, blinded, randomized clinical trial of hyperbaric oxygen treatment in leg ulcers of undefined etiology⁹² showed a statistically greater reduction in wound size at six weeks compared to control wounds, hyperbaric oxygen treatment is not indicated in the primary management of venous stasis ulcers of the lower extremities. Hyperbaric oxygen may be required to support skin grafting in patients with concomitant peripheral arterial occlusive disease and hypoxia not corrected by control of edema.

Pressure Ulcers

The management of decubitus ulcers has been well described elsewhere⁹³ and emphasizes pressure relief, surgical debridement, treatment of infection, nutritional support, and surgical closure for large ulcers. Other interventions such as negative pressure wound therapy (wound vac) may be beneficial. Hyperbaric oxygen treatment is not indicated in routine decubitus ulcer management. It may be necessary for support of skin grafts or flaps showing evidence of ischemic failure, when the ulcer develops in the field of previous radiation treatment for pelvic or perineal malignancies, or when progressive necrotizing soft tissue infection or refractory osteomyelitis is present.

Arterial Insufficiency Ulcers

The primary treatment of refractory ischemic wounds of the lower extremities is improvement in blood flow by angioplasty or surgical revascularization. However, hyperbaric oxygen treatment may be of benefit in those cases where persistent hypoxia remains after attempts at increasing blood flow or when wound failure continues despite maximum revascularization⁸⁰. Hyperbaric oxygen treatment may also be required in support of skin grafting in this setting⁹⁴.

Hyperbaric Oxygen Treatment Protocols

Treatment protocols vary depending on the severity of the problem and the type of hyperbaric chamber used. In larger multiplace chambers, treatments are delivered at 2.0 to 2.5 ATA for 90 to 120 minutes once or twice daily.In monoplace chambers patients are usually treated at 2.0 ATA. Patients with serious infections may require hospitalization for intravenous antibiotics and better diabetes control. Hyperbaric oxygen treatment in such cases is usually rendered twice daily for 90 minutes. Once stabilized most of these patients can be treated on a once daily basis as outpatients. When infection is controlled, blood flow optimized (wherever possible), other interventions that may hasten tissue growth and wound closure such as negative pressure wound therapy (wound vac), bioengineered tissue grafts, or surgical reconstruction or closure can be used in combination with adjunctive hyperbaric oxygen treatment to hasten recovery. The October 2000 Office of the Inspector General report to the Department of Health and Human Services⁹⁵ identified that active physician oversight of hyperbaric oxygen treatment led to improved outcomes.

Utilization Review

Hyperbaric oxygen treatments are performed at 2.0 to 2.5 ATA for 90 to 120 minutes of oxygen breathing. The initial treatment schedule is dictated by the severity of the disease process. In the presence of limb-threatening infection after debridement or incompletely corrected peripheral arterial occlusive disease, patients may require twice daily treatments. Once stabilized, treatment frequency may decrease to once daily. Utilization review is required after the initial 30 days of treatment and at least that frequently thereafter.

Cost Impact

Hyperbaric oxygen therapy as an adjunct to medical and surgical treatment of difficult problem, chronic non healing wounds, particularly diabetic ulcer and other lower extremity wounds, has been shown to be cost effective in limited reviews, especially when compared to major lower extremity amputation^{96, 97}. Preventing a below the knee amputation by salvaging a ray resection or transmetatarsal amputation of the foot or preventing an above the knee amputation by preserving a below the knee amputation represents a satisfactory outcome in these high risk patients. Wounds healed with adjunctive hyperbaric oxygen treatment have also demonstrated excellent durability⁹⁸.