Monitoring the Effect of Continuous Topical Oxygen Therapy With Near-Infrared Spectroscopy: A Pilot Case Series in Wound Healing

© 2024 HMP Global. All Rights Reserved.

Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of Wounds or HMP Global, their employees, and affiliates.

Aerobic respiration is the process that most living things use to generate energy. In humans and animals, the mitochondria in cells utilize oxygen during cellular respiration to break down glucose to synthesize high-energy ATP.¹ ATP is needed to power life-sustaining cellular functions. When oxygen is plentiful aerobic metabolism occurs, producing 36 ATP molecules to fuel cells.¹ Without adequate levels of oxygen, cells convert to anaerobic metabolism, which produces only 2 ATP molecules.¹ This lack of adequate oxygen levels, or hypoxia, and the resultant low levels of ATP produced will eventually lead to cellular dysfunction and tissue necrosis.¹ From hemostasis through the remodeling phase of wound healing, wounded tissues are in a hypermetabolic state and have an increased need for oxygen as the energy demand needed for tissue repair and regeneration is increased.²

Following injury, poor blood circulation, edema, injured microcirculation, and contraction of vessels in traumatized tissue limit oxygen distribution to the wound, thereby reducing the wound's capacity to heal.^3-5 Adequate tissue perfusion is a known predictor of wound healing. Oxygen plays a key role in tissue repair and regeneration. Multiple processes, including oxidative killing of bacteria, cellular signaling and proliferation, collagen deposition, and angiogenesis, are heavily dependent on the presence of adequate levels of oxygen.^2,6

In patients with chronic wounds, oxygen levels are often insufficient. Systemic disease states and other comorbid conditions can contribute to poor macro- and microcirculation, low levels of growth factors, and cellular inactivity. Hypoxia of wounded tissues contributes to the disruption of the healing cascade seen in hard-to heal, chronic wounds.⁶ Treatment with supplemental oxygen as part of an evidence-based protocol may support wound healing. The use of clinically relevant objective measures to identify and track hypoxic wounds and their response to adjunctive oxygen therapy is key to understanding the benefits of supplemental oxygen.

TOT as a means of supplying supplemental oxygen to wounded tissue has been well documented in the literature. Furthermore, high-quality clinical evidence now supports the use of cTOT as an effective adjunct therapy to support faster healing compared with standard of care alone across multiple patient cohorts and wound types.^7-16 The NATROX O2 (Inotec AMD Ltd) cTOT device delivers continuous oxygen directly to the wound bed 24 hours a day, 7 days a week.¹⁷ This United States Food and Drug Administration–cleared and CE-marked device consists of an oxygen generator, 2 rechargeable batteries, and an oxygen delivery system that connects to the oxygen generator to provide oxygen directly to the wound bed (Figure 1). The cTOT system is easy to use, lightweight, and portable, allowing the patient to perform activities of daily living uninterrupted. The treatment is easy to use in a wide range of care settings and for a variety of chronic wound types.

NIRS imaging technology is a validated tool used to evaluate functional StO₂ in acute and chronic wounds.¹⁸ Oxygenated hemoglobin and deoxygenated hemoglobin have separate and distinct spectral signatures in the visible and near-infrared light spectrums. To calculate StO₂, NIRS measures the absorption of red and near-infrared wavelengths, which varies based on the oxygen-carrying status of hemoglobin. Using a proprietary algorithm, the NIRS device is able to unmix the spectral signatures to determine the proportion of oxygenated hemoglobin and deoxygenated hemoglobin in the sampled tissue.^19,20

The SnapShotNIR (Kent Imaging) is a commercially available NIRS device that is noncontact, handheld, and mobile, offering repeatable immediate images illustrating site-specific quantifiable levels of tissue oxygenation (Figure 2).

By using differing optical signals based on the proportion of oxygenated hemoglobin in the tissue capillary bed, oxygen saturation of the tissue is calculated.²⁰ These images provide the health care practitioner a measure of functional blood flow to the wound and surrounding tissues.^19,21

In this prospective, single-site, single-arm, pilot case series, the authors evaluated the effectiveness of the proprietary cTOT device in increasing tissue oxygenation and supporting wound area reduction in patients with chronic nonhealing wounds of various etiologies. It was hypothesized that the administration of cTOT over 5 consecutive weeks would result in an increase in oxygenated hemoglobin in the wound bed and a decrease in total wound area. The commercially available NIRS device was used to objectively measure the StO₂ of the wound bed at each TV.

Patient recruitment

Five patients from the lead author's (W.C.'s) clinical practice were enrolled in this pilot case series. The study was conducted in accordance with Health Insurance Portability and Accountability Act guidelines, adhered to tenets of the International Conference on Harmonization E6 Good Clinical Practice and the Declaration of Helsinki, and received ethics approval by the institutional review board at Richmond Heights Hospital. Prior to study enrollment, all patients provided written informed consent to publish the case details and associated de-identified image assessments. No compensation was provided for participation. Patients had a variety of chronic wound etiologies, including venous leg ulcers, diabetic foot ulcers, and trauma wounds. All wounds were considered nonhealing prior to inclusion, because they had not achieved at least 50% wound area reduction after at least 4 weeks of treatment with standard of care. Previous wound management varied and included debridement, off-loading, compression bandages, alginates, collagen, gelling hydrofibers, and foam dressings. All patients had an ankle-brachial index greater than or equal to 0.9 mm Hg, but less than or equal to 1.3 mm Hg. All wounds were negative for clinical signs and symptoms of infection.

Wound tissue oxygenation measurement

The NIRS imaging device was used to provide immediate image capture and objective point-of-care site-specific information to objectively track changes in tissue oxygenation. An NIRS image of the wound, as well as an StO₂ calculation from the standardized central point within the wound bed, were obtained each week along with standard manual wound measurements. Final images and wound measurements were obtained at TV 5, signaling the end of the study, or upon wound resolution if complete healing occurred prior to TV 5.

Wound assessment and treatment

Prior to the initiation of cTOT, baseline manual wound measurements and a NIRS image were obtained. The cTOT device was applied to each subject's wound per manufacturer instructions for use. Subjects were seen once weekly in the clinic for 5 consecutive weeks. Subsequent weekly NIRS wound images were obtained from the center of the wound to track oxygenated hemoglobin in the tissues, along with wound measurements. All wounds were debrided to remove devitalized tissue per the clinician's discretion and were bandaged with inert semiocclusive dressing materials to manage exudate and promote a moist wound healing environment. Patients whose wound did not heal within the 5-week pilot study period were followed in the lead author's wound clinic until complete epithelialization was achieved.

Three male and 2 female patients participated in this study. The mean patient age was 75.8 years. The median baseline wound age was 32 weeks, with a baseline median surface area of 8.95 cm² prior to enrollment (Table 1).

Wound progression and healing

There was a general trend toward wound area reduction in all 5 subjects during the 5-week study period, with 3 patients achieving full epithelialization as shown by wound area in square centimeters (Table 2) and percentage wound area reduction (Figure 3). One wound (patient 1) healed rapidly within 3 weeks of treatment despite exhibiting delayed healing for the previous 22 weeks. In patients 5 and 2, complete wound healing was seen at weeks 4 and 5, respectively. Two patients required longer treatment times, but complete wound closure was noted at week 9 for patient 3 and at week 11 for patient 4.

Tissue oxygenation

StO₂ measures obtained from the wounded tissue illustrated a relative increase over the 5-week period in all patients (Table 3). Generally, the greatest change in StO₂ occurred during the first week of treatment, and small yet notable changes occurred in the remaining weeks. The aggregated trends in tissue oxygenation and relative wound surface area over the treatment period are displayed in Figure 4, demonstrating the reduction in wound area with improved tissue oxygenation.

Case example: patient 4

Patient 4 was an 85-year-old male with a nonhealing venous ulcer on the gaiter region of the left leg. The ulceration duration was 64 weeks. Past medical history included peripheral venous disease, venous insufficiency, venous stasis dermatitis, non-insulin dependent diabetes, hypertension, and degenerative joint disease.

The wound had previously been managed with compression therapy and wound dressings, including silver alginates, collagen, and foam. The wound did not enter a healing trajectory; it remained static. Prior to enrollment in the present study, ankle-brachial index of 1.07 was recorded, which is within the normal parameters.

At presentation (ie, baseline) the wound measurements were 9.2 cm × 2.8 cm × 0.2 cm, and per NIRS the StO₂ was 65% (Figure 5A, B). Eighty percent of the wound bed was covered with sloughy nonviable tissue. The patient was treated with debridement, cTOT, a semiocclusive dressing, and multilayer compression therapy. He was seen for weekly bandage changes and wound assessments.

By week 3, the wound measured 8.0 cm × 2.0 cm × 0.1 cm, the NIRS StO₂ was 79%, and the wound bed was completely free of slough, with signs of new granulation tissue (Figure 5C, D). At the week 5 end of study visit, the wound continued to display a significant reduction in wound size, measuring 7.0 cm × 1.4 cm × 0.0 cm, with a NIRS StO₂ measurement of 83% (Figure 5E, F). After completion of the study period, the patient continued treatment in the lead author's clinic. Full wound resolution was achieved at 11 weeks (Figure 6).

The wound healing cascade is an intricate process that is activated when tissues are subject to injury. Oxygen is essential throughout all phases of wound healing.²² StO₂ is an important biomarker in determining the healing potential of a wound.²³ The development of nonhealing chronic wounds is typically multifactorial, but tissue hypoxia is commonly a contributing factor, especially in patients with diabetes and venous disease.

Wounds that enter a healing trajectory move orderly through the phases of wound healing thanks to robust cellular activity supporting angiogenesis, organization of the extracellular matrix, and deposition of cross-linked collagen, leading to wound contracture.²⁴ Conversely, nonhealing or stalled wounds often exhibit prolonged inflammation, low cellular activity, poor neovascularization, a disorganized matrix, and limited collagen deposition.²⁴ Following injury, disrupted microcirculation, edema, and contraction of vessels in traumatized tissue all limit oxygen distribution to a wound.³ These physiologic processes can be further compounded by patient comorbidities.

Oxygen plays an essential role in every step of the wound healing process. Adequate levels of oxygen are needed for oxidative killing of bacteria, cellular signaling and proliferation, collagen deposition, and neovascularization.²⁵ It stands to reason that treatments resulting in the turnabout of hypoxia would support faster healing.

Dating to the 1960s, HBOT is among the first documented treatments to use supplemental oxygen for the management of nonhealing wounds.²⁶ With HBOT, the patient is subjected to high-pressure (2 atm–3 atm) 100% oxygen to augment oxygen levels in the blood and tissue.²⁶ For HBOT to be most effective, adequate arterial perfusion should be present to transfer oxygen to the wounded tissue. Additionally, HBOT requires 90-minute treatments 5 days a week.²⁶ In most areas, HBOT is only available in specialist centers. Most HBOT chambers are not portable; thus, it is not a suitable treatment for home or community use.

Small, portable, battery-powered oxygen generators are now available that allow cTOT to be applied directly to the wound base at normospheric pressure. cTOT is an innovative treatment that can be used to treat a broader cross-section of patients throughout various sites of service to support healing outcomes. The evidence base for cTOT is rapidly increasing, with high-quality randomized controlled trials highlighting the effect this therapy has over standard of care.^12,27,28 As a result, many expert guidelines now recommend the use of cTOT as an important adjunct to standard of care.^29,30

The positive effect of cTOT was observed in the present study, with 3 of 5 wounds healing within the 5-week study period despite their previous recalcitrance. All patients in the present case series presented with multiple systemic conditions and challenging wounds of long duration. Additionally, the increases in wound tissue oxygenation noted via NIRS at each weekly assessment provided a trackable metric to support the continued used of cTOT throughout the study period.

The major limitation of this observational study is that it is a single-site, single-arm, pilot study with a small sample size. In addition, the study period was limited to 5 weeks, which may not allow for determination of the full benefit of cTOT. The results of this case series lend credence to the idea that cTOT supports increases in tissue oxygenation. Future studies should include larger recruitment and a longer duration of follow-up.

The current study confirms that cTOT offers an effective, noninvasive chronic wound treatment as a key adjunct to standard of care in nonhealing wounds of multiple etiologies and that use of cTOT may expedite wound healing by improving microcirculation and oxygenated hemoglobin. Moreover, the NIRS proved to be a quite user-friendly point-of-care imaging device when used to highlight the need for intervention and track weekly wound progress, and it provided objective information concerning improvement in tissue oxygenation.

Authors: Windy Cole, DPM, CWSP^1,2; and Emma Woodmansey, PhD²

Acknowledgments: The authors would like to thank Tyler Vermeulen, Product Research Specialist, Kent Imaging, for his support with data analysis. 

Affiliations: 1Kent State University College of Podiatric Medicine, Independence, OH, USA; 2Natrox Wound Care, Cambridge, UK

ORCID: Cole, 0000-0002-0692-3469; Woodmansey, 0000-0002-2054-2240 

Disclosure: Dr Cole and Dr Woodmansey are paid employees of Natrox Wound Care.

Correspondence: Windy Cole, DPM, CWSP; Kent State University College of Podiatric Medicine, 7000 Euclid Ave, Suite 101, Cleveland, OH 44103 USA; wcole4@kent.edu

Manuscript Accepted: March 20, 2024