Background: Chronic wounds are a growing problem internationally, termed a silent epidemic. To combat this epidemic, it is not sufficient to rely on traditional wound care treatments alone, but to look to innovative and alternative therapies. The indispensable role of oxygen in wound healing is well-discussed in the literature, and in the past two decades the topical application of oxygen has shown promising results in the healing of chronic wounds. However, the toxic effects of oxygen are usually not appreciated and can often lead to wound necrosis and gangrene in wounds with compromised blood supply. While wounds with adequate blood supply contain free radical quenchers (catalase, superoxide dismutase and reduced glutathione) which neutralize the free radicals (reactive oxygen species) released as a by-product of the Krebs cycle, wounds with deficient blood supply are deficient in free radical quenchers and are further damaged by exposure to oxygen as a result of reperfusion injury/oxygen toxicity. Topical hyperbaric oxygen (THOT ®) uses low oxygen tensions in the hyperbaric range to stimulate angiogenesis, while preventing excessive oxygen toxicity. The result is the induction of marked angiogenesis, with increasing capacity for quenching reactive oxygen species, resulting in wound healing of ischemic wounds. Case Presentation: This case report describes a 95-year-old Caucasian female who presented with a stage IV chronic necrotic ulcer on her lower left leg. Surgical pathology results revealed calcifying vasculopathy, which is thought to be responsible for deficient blood supply to the leg, leading to a necrotic, chronic leg ulcer of her left leg. After traditional wound therapies were unsuccessful, she was considered for leg amputation. The introduction of adjunctive treatment with topical hyperbaric oxygen therapy saw complete healing of the wound within 15 weeks. The wound remained closed, without the presence of scar tissue, with no signs of wound breakdown at three-month and six-month follow-ups. Conclusions: Chronic hypoxic wounds with vascular insufficiency are considered “unlikely to heal” and tend to lead to limb amputation. The use of THOT ® technology, with low hyperbaric oxygen tensions to neutralize free radicals released by the Krebs cycle when oxygen contacts the wound, prevents oxygen toxicity and results in angiogenesis necessary for wound healing. In this way, THOT ® treatment was able to convert the hypoxic “unlikely to heal” wound considered for limb amputation into one which healed, with limb salvage. The results of this case report demonstrate the potential for complete healing of chronic hypoxic wounds even in complex cases with multiple confounding factors preventing wound healing, using a cost-effective treatment that is easily accessible to patients.
Chronic wounds, defined as wounds that fail to heal, are placing an increased burden on a health care system already encumbered by increased patient morbidity, an aging population, and rising health care costs [
The antidote for the chronic wound epidemic involves the identification of innovative yet simple, accessible, and cost-effective interventions. The benefits of oxygen and its key role in wound healing are discussed extensively in the literature, and this evidence points to the simple solution of oxygen therapy as an adjunct treatment for wounds. Oxygen is required for tissue repair and regeneration, necessary in nearly every phase of the wound healing process. Not only is it a component of cellular metabolism, yielding energy for use by the cells in the repair process, but it is also essential for the synthesis of protein and the production of blood vessels and collagen—vital materials in wound repair and quality healing [
Chronic wounds tend to be hypoxic, or lacking oxygen within the wound tissue [
Besides hypoxia’s deleterious effect on fibroblast proliferation and sustained angiogenesis, it also directly inhibits antimicrobial activity, compromising the tissues’ ability to fight infection [
Oxygen’s indispensable role in tissue repair has precipitated investigation of oxygen as a wound care intervention. Hyperbaric oxygen therapy is widely known, but the past two decades have seen the rise of an innovative form of oxygen therapy involving the topical application of oxygen to the open wound [
Based on transcutaneous oxygen partial pressure measurements (TcPO2), hypoxic wounds (TcPO2 0 - 30 mm Hg) are identified by the presence of yellow necrotic slough (TcPO2 13 - 30 mm Hg) or black gangrene (TcPO2 0 - 13 mm Hg). Necrotic wounds with TcP02 between 0 - 30 mm Hg are considered “unlikely to heal” [
Unopposed oxygen free radicals or reactive oxygen species, a normal byproduct of oxidative phosphorylation (Krebs cycle) form the basis of reperfusion injury [
In this case report, we report complete healing of a hypoxic, non-healing leg wound in 15 weeks with THOT®. The patient had been scheduled for amputation. Our hope is that it will prompt further clinical studies and case reports, as well as focus the spotlight further on a simple, yet effective, wound care therapy which should be considered by health care professionals when prescribing treatment regimens.
A 95-year-old Caucasian female scheduled for amputation presented with a stage IV non-healing necrotic leg wound. Per the medical records, the patient could not recall a specific injury or event that precipitated the wound. Her past medical history included: osteoarthritis, bradyarrhythmia with pacemaker placement, gastroesophageal reflux disease, osteoporosis, hyperlipidemia, hypertension, urinary incontinence, hysterectomy, and polymyalgia rheumatica.
The patient had been treated through a local wound care center, where her treatment included weekly sharp debridement and daily dressing changes with application of Santyl and gentamicin to the wound bed. Topical hydrocortisone and Silvadene were also implemented at a later stage. Despite these efforts, the wound continued to deteriorate, and the probability of the wound healing was documented as “quite small” by one of the wound care center physicians and the patient was discharged due to an assessment of “inability to heal”. The facility recommended that the patient be evaluated for a below-the-knee amputation. The patient’s family referred the patient to a surgeon for alternative treatment options due to poor healing with the current treatment regimen in order to prevent amputation.
When first evaluated by the surgeon, the patient’s left lateral leg wound had been present for several months. On initial assessment, the surgeon described the wound as measuring 6 cm in diameter, with necrotic eschar over the wound base (
A surgical excision was performed, down to the muscular fascia, for removal of the necrotic tissue. The operative report detailed that the necrotic tissue in the ulcer involved the subcutaneous fat and extended to the muscular fascia, although the fascia itself and muscle were viable. The patient’s wound after surgical debridement is shown in
The surgical pathology report listed a diagnosis of calcifying vasculopathy with histologic findings consistent with calciphylaxis: “Histologic sections demonstrate partially ulcerated skin and subcutaneous tissue with granulation tissue and numerous small to medium arteries exhibiting occlusive endoluminal calcifications.” There was no evidence of vasculitis in the biopsy. Cultures obtained at the time of surgery were positive for two strains of Pseudomonas aeruginosa (few) and the gram stain was positive for white blood cells (rare) and gram-negative bacilli (few). Susceptibility results showed no evidence of drug resistance among the P. aeruginosa strains identified in the wound.
To enhance the patient’s healing post-surgery, the surgeon prescribed Topical Hyperbaric Oxygen Therapy (THOT®), to be delivered via the Numobag® Kit following surgical debridement The prescription was initially written for 12 Numobag® Kits (a 3-week supply), with 4 refills. In addition to THOT®, the surgeon’s plan of care recommendations included:
· Gentamycin ointment to wound bed
· Evaluation of calcium/parathyroid hormone metabolism (calciphylaxis diagnosis)
· Sodium thiosulfate (calciphylaxis diagnosis)
Topical hyperbaric oxygen therapy with oxygen pressures delivered at the therapeutic range (THOT®) is delivered via a patented device known as the Numobag®. Oxygen is administered via an 84” × 48” pleated polyethylene bag. The open end is taped around the chest at the level of the nipple, allowing multiple ulcers to be simultaneously treated. Using pressures validated by instruments specially designed for measuring low pressures (Sandia, National Labs, Albuquerque, New Mexico), intrabag pressures were maintained within a narrow range (1.004 to 1.013 atmospheres) at all times, as well as ensuring a 15 L/min flow rate. Per Numobag® protocol, the patient received THOT® for 4 hours a day, 4 consecutive days per week. In between, the ulcers received regular dressing changes. All treatment was clinically managed in the patient’s home. A home-care nurse was trained to administer THOT® following the Numobag® Kit protocol.
Strict infection control measures were implemented, including the use of sterile dressing materials and daily linen changes. The wound was complicated by a significant amount of purulent exudate, as evident in
As reported in the culture obtained during the initial surgical procedure, the wound was found to be colonized with Pseudomonas aeruginosa (
During weeks 1 - 5 of THOT® treatment (Figures 6-10), necrotic tissue was observed to form after debridement, albeit in decreasing amounts from 70% of wound surface (
Weekly measurements of wound size over time show improvements in ulcer size, as documented in
The patient was contacted for weekly follow-ups during the first two months after completing THOT®, and again at six months post-treatment, reporting each time that the site of the preexisting wound remained healthy and fully healed.
In this case study, the patient’s wound was covered by a grey/black necrotic slough (
It has been previously shown that in THOT® treated wounds, because there was abundant angiogenesis [
The healing of the necrotic wound in our patient is primarily due to the adequacy of the vascularization induced by the THOT® treatment. This allows the vascularized granulation tissue to fill the space occupied by the necrotic/dead tissue in the dermis and deep fascia and allow for re-epithelialization of the healing wound. Even after the wound is healed, many changes continue to take place within the newly healed wound. 1) The new collagen fiber, which is secreted as single short fiber by dermal fibroblasts, lengthens and becomes thicker by cross-linking using S-S bonds. This makes the wound stronger and may take 3 months or more to occur. 2) Blood vessels and capillaries shrink in size and become fewer in number—they may take up to 1 - 1.5 years to decrease in number. 3) The epidermis thickens, and the stratum corneum matures, and becomes less scaly. During this period remodeling of the tissues take place and inflammation decreases following wound repair (Figures 20-27).
Various methods of topical oxygen therapy exist, gaining traction over the past two decades. Some therapies deliver the oxygen at a normobaric pressure, while others, such as the one utilized in this case report, deliver the gas under a pressure slightly higher than atmospheric pressure and hence qualify as a “hyperbaric” oxygen treatment. In contrast to traditional hyperbaric oxygen therapy delivered in a chamber, topical hyperbaric oxygen therapy (THOT®) is more portable, accessible, promotes patient comfort and quality of life, and carries significantly less risk of oxygen toxicity due to its lower pressure utilized and mode of delivery (topical rather than systemic). Pressures utilized by hyperbaric oxygen chambers are significantly higher (2 atmospheres) compared to THOT®, with consequently higher risk of oxygen toxicity and reperfusion injury.
A review of the literature on topical hyperbaric oxygen therapy (THOT®) demonstrates convincing support for the efficacy of the therapy in healing wounds, as well as reveals the need for further clinical validation through well-designed randomized controlled studies. The effects of topical hyperbaric oxygen therapy were evaluated on stage II to IV ulcers in bed-ridden patients at a long-term care facility in one prospective randomized controlled clinical study (18). The study looked at 40 patients with 79 ulcers in total. The control group (50 ulcers) received standard wound care, which included pressure reduction techniques, antibiotic treatment, sharp debridement, and dressing changes as indicated. The treatment group (29 ulcers) received THOT® using a medical device and treatment regimen nearly identical to the one detailed in this case report. Results revealed healing in 90% of the ulcers receiving topical hyperbaric oxygen, while the standard wound care group saw only 22% achieve full healing. Tissue samples biopsied from the ulcers showed significantly increased capillary density in treatment group compared to the standard wound care group (p < 0.001). Of note, 28 of the 29 ulcers in the THOT® group, had no evidence of clinical scarring, in contrast to the observance of some degree of clinical scarring in 49 of the 50 ulcers in the standard wound care group. This study included a cost analysis which revealed impressive cost-savings for the THOT® group: at 4 weeks, stage II ulcers saw 81.3% savings compared to the standard wound care group, stage III ulcers saw 37.9% savings, and stage IV ulcers saw 36.1% savings [
The efficacy of THOT® on chronic diabetic foot ulcers was examined in a prospective, controlled study conducted at a single wound clinic [
In a cohort study which compared THOT® to traditional hyperbaric oxygen therapy, 57 patients with chronic wounds were analyzed—32 receiving treatment in hyperbaric chambers, and 25 receiving topical oxygen therapy. Though enrollment was not randomized, the statistical approach to calculate treatment efficacy on wound closure was identical in both groups. Those treated with THOT® saw significant wound closure (p = 0.001), while those who received traditional hyperbaric oxygen therapy did not demonstrate significant improvements in wound closure (p = 0.150). Additionally, through analysis of tissue edge biopsies, topical oxygen therapy was associated with a higher VEGF expression [
In addition to the Heng study referenced above, other studies have examined the cost savings of topical oxygen therapy. One case study series reported an average weekly cost of $700 for the form of topical oxygen therapy utilized to treat pressure ulcers in patients with spinal cord injuries [
The Numobag® was developed through more than twenty years of clinical research and is FDA-approved. It is a thin, transparent, disposable membrane that covers the legs and approximately 75% of the human torso. Designed for single-use, each bag is composed of a polyethylene material that is considered “extremely clean”, although not sterile. Tubing is used to connect the bag to an oxygen source. Once inflated fully, the Numobag® Kit delivers 100% medical-grade oxygen directly to the open wound at a pressure of 1.03 to 1.05 ATA, as according to the device’s protocol.
Hypoxic wounds covered by black or yellow necrotic tissue are associated with insufficient blood supply leading to low TcPO2 values. Because of insufficient blood supply and the inability to neutralize oxygen free radicals, these wounds suffer reperfusion injury when exposed to oxygen in the air, with reformation of necrotic slough after debridement. These wounds are considered “non-healing” and usually require limb amputation. Our patient with a non-healing leg wound covered by black necrotic slough, with recurrent yellow slough formation following debridement, was considered “non-healing” and scheduled for amputation. With THOT®, the formation of new blood vessels with increased free radical quenching properties enabled the wound to heal because the tissues were no longer subjected to reperfusion injury.
The healing of the hypoxic non-healing wound with THOT® in our patient is an example that non-healing hypoxic wounds that may lead to limb amputations can be converted to non-hypoxic wounds capable of healing, with avoidance of amputation and increased limb salvage. In addition, the lack of excessive scar tissue in wounds healed with THOT® may prevent wound breakdown after healing.
On top of the successful results, THOT® was a cost-effective option that promoted the quality of life of the patient and her support system. The treatment allowed the patient to remain in the comfort of her home and lessened the burden on caregivers who would have otherwise transported her to frequent wound care appointments. The medical device employed to deliver THOT® in this case report has been used to effectively treat a variety of wounds, including burns, pressure injuries, diabetic ulcers, and necrotizing fasciitis, in the home, hospital, long-term care, and clinic setting. Today’s chronic wound epidemic needs versatile therapies such as THOT®, warranting further research and randomized controlled clinical studies to build the evidence base for this alternative treatment option. It must be emphasized that in our patient, without undergoing THOT®, amputation would have proceeded as scheduled.
The authors would like to thank the patient and her family for their enthusiasm and encouragement of the publication of this case report.
Ethics Approval and Consent to ParticipateThis case report was performed in accordance with international ethical rules.
Consent for PublicationWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Numotech, Inc. donated the Numobag® Kits during the complete course of treatment.
Competing InterestsThe patient was referred for treatment with Hyperbaric Oxygen Therapy at Wound Care Center but was disqualified due to pre-existing conditions.
Availability of Data and MaterialsData sharing is applicable to this article as datasets were generated or analyzed during the current study. Data support the results were extracted from the patient’s medical records.
Author’s ContributionsAH: management of the patient’s THOT® clinical care team, review of the literature, data collection and analysis, and drafted the manuscript. SCB, RAD: served as part of the patient’s clinical care team directly administering the topical hyperbaric oxygen therapy, data acquisition and analysis, revision of the manuscript. PMR: clinical consultant for the patient’s THOT® clinical care team, data analysis, revision of the manuscript. VDL, MCYH Data analysis, manuscript preparation.
All authors read and approved the final manuscript.
Castillo Benitez, S.C., Alduey Duran, R., Matos-Ruiz, P., Heng, M.C.Y. and Vander Laan, T.L. (2019) A Disruptive Treatment to Prevent Amputation and Enhance Limb Salvage in an Elderly Patient. Journal of Cosmetics, Dermatological Sciences and Applications, 9, 129-154. https://doi.org/10.4236/jcdsa.2019.92012
USD: United States dollar
THOT®: topical hyperbaric oxygen therapy
ATA: atmospheres absolute (standard atmosphere of pressure at sea level)
VEGF: vascular endothelial growth factor
ABI: ankle brachial index