Retrospective Analysis of the Effect of Vaporous Hyperoxia Therapy as an Adjunct to Standard Wound Care in Chronic Wounds

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From 2014 to 2019, the number of Medicare beneficiaries with a wound increased from 8.2 million to 10.5 million.¹ Each year, approximately 18.6 million people are affected by a DFU worldwide, including 1.6 million people in the United States.^2,3 The lifetime incidence of developing a DFU is 34%.⁴ DFUs place a substantial burden on patients, families, caretakers, and the health system in general, accounting for greater than 80% of all lower extremity amputations,⁵ and constituting at least one-third of the annual direct costs for diabetes annually in the United States.⁶ Furthermore, the 5-year mortality rate for individuals with a DFU is 30%; this rate surpasses 50% for those who undergo a major amputation.⁷ 

Yet despite significant effort and increased attention given to preventing amputations, major challenges exist in the development of safe and effective treatments for chronic wounds. For example, the average healing rate of DFUs treated with standard wound care is as low as 31%.⁸ This underscores the importance of pursuing wound research that not only involves RCTs but also accounts for real-world data or evidence. In fact, according to a recent study published in JAMA, when design and measurements are closely emulated, real-world evidence has the potential to reach similar conclusions as RCTs.⁹ Furthermore, real-world evidence presents an opportunity to include a greater number and variety of wounds and different populations into the dataset, thereby increasing the overall knowledge of a potential treatment.

VHT (Vaporox) is a patented, FDA 510(k) Class II (#K212121)–cleared technology that has been clinically validated as a safe and effective adjunct treatment for healing skin wounds, including DFUs, venous leg ulcers, postoperative wounds, decubitus  wounds, amputation sites, skin grafts, burns, frostbite, and gangrene. VHT enhances wound healing by hypersaturating and oxygenating tissue in an automated, dual-modality system. With VHT, a low-frequency, noncontact, nonthermal, ultrasonic mist that alternates with COT is administered to the wound. Gentle hydrating vapor and concentrated oxygen then surround the wound, allowing the elements to be passively absorbed into the tissue.¹⁰ Combining the effects of ultrasound therapy to deliver a hydrating mist and COT, VHT provides a wound healing environment for chronic DFUs that increases angiogenesis and fibroblast formation while reducing bioburden, which promotes rapid wound healing (internal data). In a recent study, the addition of VHT to standard wound care for the treatment of chronic DFUs in 29 patients led to an 83% healing rate by 20 weeks, with an average time for wound closure of 9.4 weeks.¹⁰ 

The aim of this retrospective chart review is to evaluate the effect of VHT for the treatment of chronic wounds. By expanding the population to include a greater variety of wound types and etiologies, the effect of VHT can be assessed on a larger scale than previously done. 

A retrospective chart review of patients with chronic wounds treated with VHT in conjunction with standard wound care was performed. The primary end point in the study was complete healing (defined as complete epithelialization) of wounds treated with VHT and standard of care at 16 weeks. Secondary end points included time to heal in weeks, PAR, PVR, and resource utilization based on the average number of treatments administered. 

From February 28, 2020, through August 30, 2022, eligible adult patients at multiple outpatient centers who presented with chronic wounds refractory to standard of care for longer than 4 weeks received VHT treatment in addition to standard wound care. For inclusion, the patient had to be able to maintain reasonable nutrition, hydration, and adequate home care between treatment visits; and had to be able to understand and follow basic wound care instructions, or had a caregiver who could assist. Exclusion criteria included one-time visits, Wagner grade 4 and 5 DFUs, having sepsis symptoms, having a wound with cancerous etiology, acute skin conditions, wounds in which the end could not be probed, wounds treated with more than 5 CTPs, pregnant patients, and patients who lacked capacity to provide legal consent. 

The study protocol adhered to the Declaration of Helsinki and was reviewed by Western Institutional Review Board (WO#1659331), which approved a request for waiver of authorization for use and disclosure of protected health information and determined the study to be exempt under 45 CFR §46.104(d)(4). Eligible patients were assigned to the treatment group if they provided written informed consent for VHT treatment and agreed to the use of their treatment data in a redacted, HIPAA-compliant format.

The study sponsor provided the VHT devices (Figure 1) as well as all materials and supplies needed at each treatment visit, and was responsible for device cleaning and maintenance. Each treatment visit included a comprehensive wound assessment, including wound area and volume measurements using a standardized metric ruler, digital photographs, and Wagner classification for DFUs, as well as patient monitoring, laboratory tests, debridement as needed, and offloading (as appropriate). At the initial visit, patient demographics, comorbidities, and wound age were additionally recorded. 

There were 2 weekly treatment visits for at least 4 weeks and until the wound healed or the end of the 16-week treatment period. Before VHT was administered, the wound was debrided (if needed) and wound measurements were taken. Arterial ulcers were also revascularized as needed before VHT treatment began. During each treatment, the index foot was placed in the treatment chamber and the patient underwent less than 1 hour of VHT, during which the device alternated 4 cycles of a proprietary ultrasonic mist for 9 minutes and then 5 minutes of COT. After the treatment session concluded, the wound was dressed with moist dressings. DFUs, PIs, arterial ulcers, and burns all received offloading with felt-to-foam modalities, a controlled ankle motion walking boot, or diabetic shoes. Burns received silver alginate and were dressed with a dry, sterile dressing. Each patient was to receive 2 VHT treatments per week, in adherence to the study protocol. Therefore, any patient who did not receive on average 1.7 to 2.3 treatments per week was withdrawn from analysis. Patients who did not complete at least 4 weeks of treatment were also withdrawn.

Providers collected patient and wound data and wound photographs at point of care using an electronic medical record system that collects data and generates forms for patient consent, wound registration, treatment, and patient and wound release in a HIPAA-compliant cloud database. A data visualization tool pulled and filtered study data to generate outcomes data. The study statistician (M.J.C.) analyzed data using SPSS version 28 (IBM Corporation). Descriptive statistical methods summarized study data and included mean (SD) for continuous variable data (median [IQR] values for nonnormal distribution), and frequencies and percentages summarized categorical variable data. Time to heal analysis was conducted using the Kaplan-Meier approach. Resource and treatment variables were analyzed using treatment length. For those patients discharged prematurely from treatment, reasons were listed categorically. 

The electronic medical records of 249 patients were retrospectively screened for study eligibility; 206 (83%) were initially excluded for not receiving on average 1.7 to 2.3 treatments per week or not completing at least 4 weeks of treatment. Forty patients with 53 chronic wounds were analyzed in this study. Table 1 summarizes patient demographics and characteristics. About half (52.5%) of the patients were 65 to 74 years old; the majority were male (65%). The mean (SD) comorbidity count per patient was 4.6 (2.5), with diabetes, peripheral neuropathy, hypertension, and peripheral vascular disease being the most common comorbidities. The mean (SD) number of wounds per patient was 1.6 (0.8).

Table 2 summarizes wound characteristics. The vast majority of wounds were DFUs (n = 47 [88%]). At baseline, the mean wound area was relatively large at 5.6 cm², with an average age of 8 months, whereas the median wound area was 1.5 cm² and the median wound age was 2 months. The majority of DFUs were Wagner grade 2 (n = 32 [68.1%]). 

Twenty-seven patients (68%) completed VHT treatment and had a mean (SD) treatment length of 81 (78.9) days (median: 60; IQR: 76.5). Among the 13 patients who withdrew from the study, 7 (54%) were deemed ineligible after they were ultimately treated with more than 5 CTPs. VHT treatment was not related to any of the reasons for early termination of the study. The other 6 patients withdrawn stopped treatment early due to death (n = 1), hospitalization (n = 1), surgery (n = 1), nonadherence to the study protocol (n = 1), and other reasons (n = 2). 

The mean (SD) number of VHT treatments applied per patient was 22.9 (20.8); the median was 18 (IQR: 21). Patients received on average (SD) 2.2 (0.71) treatments per week (median: 2; IQR:5.3). Five patients were additionally treated with fewer than 5 CTPs, including 1 with dehydrated human amnion/chorion membrane (CTP1), 2 with human connective tissue matrix (CTP2), and 3 with human amnion membrane grafts (CTP3). The wounds of all 5 patients treated with combination VHT/CTP therapy healed.

A total of 33 of 53 wounds healed by 16 weeks (62%), and 40 of 53 (75%) healed at 1 year, including 35 of 47 DFUs (74%). The mean time to heal within 1 year was 14.5 weeks (95% CI, 9.9-18.1), while the median time to heal was 8.9 weeks (95% CI, 7.6-10.1). Figure 2 depicts the Kaplan-Meier plot. 

The mean (SD) PAR at 16 weeks among healed wounds was 69% (156.7%) (Figure 3). The mean (SD) PVR at 16 weeks among healed wounds was 82% (70.3%) (Figure 4). 

Heterogeneous case examples of wounds healed after VHT treatment in this study are depicted in Figures 5-8. In Figure 5, a case of a large DFU with a baseline area of 36 cm³ is summarized. Figure 6 shows a complex patient with a DFU and 7 serious comorbidities, who also received 1 CTP while undergoing VHT treatment. Figures 7 and 8 depict cases involving a PI and an arterial ulcer, respectively.

In this retrospective review, 62% of chronic wounds treated with VHT healed by 16 weeks, with an average time to closure of 14.5 weeks over 1 year. At 16 weeks, the mean PAR was 69% and the mean PVR was 82%. These findings suggest that VHT accelerates healing in problem wounds, and the findings are consistent with the results from a previously published report in which VHT was used to treat 36 patients with chronic DFUs.¹⁰ In that study, the adjunctive use of VHT with standard of care achieved an 83% healing rate by 20 weeks, with an average healing time of 9.4 weeks. In the current study, a variety of wound types and etiologies beyond DFUs were included to assess the real-world impact of VHT, which could explain subtle differences in the overall healing rates and time to closure. Furthermore, the average wound area at baseline in the current study was 5.6 cm² and much larger than the wounds enrolled in the previous VHT study, which had a mean baseline area of over 3 cm².¹⁰

Previously, oxygen was shown to enhance wound healing by increasing vascular endothelial growth factor expression and by promoting angiogenesis.¹¹ A multinational, multicenter, double-masked RCT reported a superior healing rate among patients with chronic DFUs who received adjunctive oxygen therapy compared with standard of care alone (41.7% [15 of 36] and 13.5% [5 of 37], respectively).¹² Likewise, ultrasound therapy has demonstrated an ability to improve wound healing rates by altering the activity of the cell membrane via cavitation and microstreaming.¹³ In a meta-analysis of 463 chronic wounds treated with noncontact, low-frequency ultrasound therapy, 41.7% healed and the average PAR was 85.2%.¹⁴ 

VHT combines a low-frequency, noncontact, nonthermal ultrasonic mist with concentrated oxygen to optimize the therapeutic benefits of both treatments and enhance wound healing. In VHT, the mist penetrates the microcapillaries and allows tissue reperfusion without directly applying pressure to the wound site.¹⁰ Ultimately, VHT serves to optimize wound bed preparation and is especially useful for facilitating the response of the wound bed to the application of CTPs, as demonstrated by the 5 patients who healed following combination VHT/CTP therapy. This retrospective analysis also suggests that VHT alone has an accelerated effect on wound closure, as evidenced by the fact that 40 wounds completely healed.

The type of retrospective review presented herein is generally limited by an inability to control for patient selection bias, and it is not possible to assess all the factors that contribute to wound healing. In addition, a relatively small number of patients was enrolled. However, the heterogeneity and severity of the cases evaluated in this study generate real-world evidence and represent the wound care challenges faced daily in clinical practice. Patients had nearly 5 comorbidities each, some wounds were highly complex (Figure 6), and very large wounds were included (Figure 5). Thus, it is not surprising that one-third of patients did not complete this study; importantly, however, none of the early terminations were related to VHT. VHT appears to be both safe and beneficial to wound healing. Furthermore, while the majority of wounds enrolled were DFUs, PIs and arterial ulcers also healed after VHT (Figures 7, 8). Based on these findings, further investigation of the use of VHT on chronic wounds is warranted, especially larger, prospective RCTs that compare VHT with standard of care and other advanced modalities, as well as evaluation of the use of VHT as combination therapy with CTPs. 

In this retrospective study, the use of VHT with standard of care appeared to optimize wound bed preparation and accelerate healing rates, with the majority of wounds closed before 16 weeks. VHT also appears to boost healing rates in wounds that are also treated with CTPs; however, this finding warrants further investigation. The use of VHT as an adjunctive therapy for chronic wounds appears to be safe and effective in a real-world population with multiple comorbidities and various wound types. A future RCT with a large sample size is recommended to fully assess the comparative effect of VHT on the healing of chronic wounds.