Hypoxia and Wound Healing Failure
Problem 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 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. 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. HBOT 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.
The hypoxic nature of all wounds has been demonstrated, and the hypoxia, when pathologically increased, correlates with impaired wound healing 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. The rate at which normal wounds heal has been shown to be oxygen dependent. Fibroblast replication, collagen deposition, angiogenesis, resistance to infection, and intracellular leukocyte bacterial killing 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.
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.
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 and its application to wound healing problems by Sheffield. 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 45 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. 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.
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 for predicting failure to heal a wound without intervention, failure to heal a planned amputation, and failure to respond to HBOT, 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 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. The addition of provocative testing with lower extremity elevation or dependency or following occlusion induced ischemia and recovery or with 100% oxygen breathing 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 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. 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
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 and antibiotic potentiation, have been demonstrated.