Evidence Shows Efficacy of Topical Oxygen Therapy for Diabetic Foot Ulcers Advances

With the burden of wounds impacting 10.5 million Medicare beneficiaries, improvements in wound treatments, technology, and delivery of care need to be addressed. When hard-to-heal or nonhealing wounds fail to progress toward healing within an appropriate amount of time, advanced therapies may need to be utilized to jumpstart the healing process. Advanced therapies may include biological matrices, topical agents, or topical oxygen therapy (TOT). Oxygen plays a crucial role in various cellular functions, such as collagen synthesis, angiogenesis, and antimicrobial activity. Ensuring an adequate oxygen supply to the wound is essential for the wound to heal.

In a recent consensus document published in the Journal of Wound Care, 9 expert panel members convened to assess the clinical evidence supporting the use of topical oxygen in wound healing; this group sought to develop evidence-based treatment algorithm for its use in hard-to-heal wounds, such as diabetic foot ulcers (DFU). Within their article, the authors provide TOT with an overview, best available evidence, ways to incorporate into clinical practice, along with the patient’s perspectives, its cost-effectiveness, and the gaps in evidence. To properly assess the literature, the experts rated the quality of evidence per the American Diabetes Association (ADA) Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system, which uses the ratings of A, B, or C depending on the quality of evidence. For the purposes of their evaluation, A denotes clear evidence from adequately powered randomized controlled trials (RCT), B includes supportive evidence from cohort studies, C consists of supportive evidence from studies that are poorly controlled or uncontrolled, and D uses the lowest level of expert consensus or clinical experience.

Assessing oxygen levels in a wound is key to understanding what intervention is required and when. A lack of oxygen in the wound can stall the healing process, but there are methods that can be used to measure the level of oxygen in the wound to evaluate the treatment efficacy. These include near-infrared spectroscopy, tissue oxygen tension, transcutaneous oxygen tension measurement, and remission spectroscopy. These methods vary in their parameters, mechanisms, advantages, and disadvantages.

Per the panel’s definition, TOT is “the administration of oxygen applied topically to wounds by either mechanical or non-mechanical means to promote tissue healing.” This mode of oxygen therapy differs from hyperbaric oxygen therapy (HBOT) in that TOT is applied topically versus a patient inhaling the oxygen within a hyperbaric chamber. TOT allows an individual (clinician or self-delivery) to utilize the treatment in various settings (hospital, outpatient, home) rather than fixed to the HBOT chamber in a specialized facility. However, it is important to note that TOT and HBOT are two distinct therapies that are complementary to each other—and could be sequentially used. The evidence base for TOT demonstrates efficacy in high quality RCTs and systematic reviews. Due to the quality of those studies and their positive results, TOT was granted the highest level of evidence rating (Grade A) for Standards of Care guideline by the ADA in 2023. The International Working Group on the Diabetic Foot (IWGDF) also recommended considering TOT as an adjunct treatment for hard-to-heal DFUs. With this, the panel supported the adjunctive use of TOT for all hard-to-heal wounds and stated that some products have completed adequate studies to affirm clinical efficacy. However, they indicate that more data are needed on additional wound types as well as additional studies for more TOT products that have not yet been studied or are understudied.

With TOT, there are various modalities available for use, such as continuous delivery of oxygen (CDO aka cTOT), disposable CDO, higher cyclical pressure oxygen, low constant pressure oxygen, hemoglobin spray, and oxygen dressings.

As the authors note, not all TOT modalities are the same and have shown different clinical outcomes. The modalities differ in their delivery, treatment time, treatment frequency, and ADA grade. For scoring the aforementioned modalities, the panel members assessed the most recent or highest-grade studies from each option. Regardless of the method used, the authors report that proper wound assessment—including evaluating wound depth, size, and infection status—must be conducted to determine the most suitable oxygen therapy approach.

For CDO, both options deliver oxygen from a wearable device and are worn continuously (ie, 24/7); however, where CDO scored an ADA grade of A, disposable CDO was only graded as C.

CDO devices blanket the wound with a continuous low pressure of pure oxygen. According to the report, “oxygen is generated from the surrounding air using compression-stack electrochemical oxygen generator units”; CDO devices are small, rechargeable, wearable, and silent. The oxygen is delivered to the wound bed via a cannula to an oxygen diffuser or diffusion dressing. The patient can use this device for the entire duration of their wound therapy.

Disposable CDO also delivers continuous oxygen to the wound, but the system is only intended for use up to 15 days, at which point the device is then disposed of and is not rechargeable. The disposable CDO device is lightweight, small, wearable, and silent. Per the report, these devices “deliver a continuous low flow of pure oxygen via a cannula, with an open end placed within a moist occlusive wound dressing.”

For higher cyclical pressure oxygen (HCPO) devices, the intermittent treatment consists of 90 minutes daily, for 5 days per week; this modality scored an A grade. These devices have variable pressure that cycles between 10 mbar and 50 mbar and use a computer-controlled concentrator to combine oxygen with humidification (if needed). HCPO devices deliver a high flow of oxygen to a disposable plastic chamber applied around the wound; these can resemble a boot or patch. Like wearable oxygen devices, HCPO is conveniently able to be used at home however does not allow mobility during therapy.

Low constant pressure oxygen (LCPO) is delivered for 60 to 90 minutes per day for 3 to 7 days per week; this modality received a grade of C. LCPO devices deliver a relatively high flow of low-pressure oxygen from a concentrator to a disposable chamber. Unfortunately, no high-quality RCTs are available in the literature, and its use is mainly supported by case series or uncontrolled trials.

Hemoglobin spray treatment can be used 24 hours per day for 7 days, and it scored a grade of B per the ADA. The authors note that “hemoglobin molecules increase the local delivery of oxygen by facilitating diffusion, rather than by a pharmacological or metabolic effect.” With a B grade, this TOT device still needs large, well-designed RCTs to affirm its efficacy.

The last of the modalities is oxygen dressings, which are continuous-release dressings and hydrogel dressings; this TOT modality received a grade of C based off 1 prospective comparative study. With continuous release, pure oxygen contained in an occlusive dressing dissolves when in contact with moisture and then releases the oxygen across a semipermeable membrane. The hydrogel dressing releases the oxygen from chemical reactions on combining the parts of a hydrogel primary dressing.

To optimize TOT in clinical practice, the authors recommend incorporating TOT as an appropriate adjunctive therapy when wounds fail to heal or reduce in size by 50% after 4 weeks of standard-of-care treatments. They also note that TOT should be considered earlier versus later in hard-to-heal wounds, as indicated by evidence provided in their report. TOT could have the potential to be a first-line therapy as clinical evidence continues to grow. The panel provided an algorithmic approach to integrating TOT into clinical practice by which assessing the wound with noninvasive vascular studies and initiating standard of care and reassessing at 4 weeks is initially employed. Depending on whether the wound has healed, stalled, or only partially reduced in size, the patient is either discharged, considered for TOT and assessed 1 to 2 weeks later, or continues to receive standard of care and reassessed 1 to 2 weeks later, respectively. Importantly, the wound should be frequently and adequately debrided and monitored.

In their report, the authors also address patient perspectives on TOT: “TOT is easily self-administered by patients or caregivers at home or long-term care after a brief initial training on appropriate application, thereby facilitating patient activation in their self-care.” Although there is little qualitative research for patients receiving TOT, some reports have shown positive patient experiences with TOT devices owing to their ability to manage their therapy and a reported reduction in wound-related pain. Future research, per the panel’s recommendations, should measure TOT-associated patient-centric outcomes, the patient’s quality of life, TOT advantages from the patient perspective, and TOT-associated health literacy.

In terms of the economics of TOT, the panel noted that improved rate and speed of wound healing will lower long-term costs associated with wound care and hard-to-heal wounds. The available cost-efficacy evidence shows the most promise in DFUs, as that wound type has been the most widely studied. Studies on economic outcomes are lacking; further data are needed With the increasing interest in the role oxygen plays in wound healing, the evidentiary gaps in knowledge of TOT will likely decrease as further real-world data are published.

In conclusion, due to the increased amount of highest-level evidence, the panel acknowledged the clinical and scientific interest in the crucial role of oxygen in wound healing. The panel emphasized the significance of oxygen in wound healing and agreed to recommend TOT as an adjunct therapy that accelerates wound healing. While also providing insights related to incorporation and optimization of TOT in clinical practice, the panel stressed the importance of individualized treatment plans and patient engagement to achieve the best possible outcomes. With the added benefit of empowering patients via the ease of accessibility and patient education, TOT use could be maximized to help address disparities in health care in rural locations or in primarily minority localities.

The Wound Healing Society has awarded a "Level I" recommendation to topical oxygen therapy, marking a groundbreaking advancement in wound care. The full clinical insights are here: https://bit.ly/whs22023guidelines