Topical Oxygen and Hyperbaric Oxygen Therapy Use and Healing Rates in Diabetic Foot Ulcers

Objective. Hyperbaric oxygen therapy (HBOT) and topical oxygen therapy (TOT) are widely used treatments to facilitate wound healing, and both are approved by the US Food and Drug Administration (FDA). This study compares the efficacy of TOT and HBOT in wound healing in an urban population. Based on an extensive literature search by the author, these 2 therapies have not previously been compared. Material and Methods. Using data compiled from a community medical center at an outpatient wound care clinic, a retrospective review comparing healing rates of diabetic foot ulcers utilizing HBOT or TOT was performed, where all the wounds were healed. The study encompassed a 15-month time period (July 2011 to October 2012), and a total of 11 patients for TOT and 11 patients for HBOT were included. All wound measurements included length, width, and depth of the wound in centimeters. Age, gender, ethnicity, body mass index, hemoglobin A1c levels, smoking status, flow dynamics (arterial and venous), and neuropathic status were obtained. The exclusion criteria included nondiabetic ulcers, diabetic ulcers at or above the ankle, venous stasis ulcers, and the use of advanced wound care or acellular matrices utilized in conjunction with oxygen therapy. Results. Twenty-two healed wounds were examined; 11 treated with TOT and 11 treated with HBOT. The study endpoints were overall wound closure for ≥ 1 month. The data was then compiled to compare the rate of closure between the 2 modalities. The wounds treated with HBOT closed faster than those treated with TOT, with average days to closure being 47.09 vs 61.82, respectively. The average rate of closure for HBOT was 0.063 cm³/day and the average rate of closure for TOT was 0.004 cm³/day. Conclusions. The 11 wounds studied using HBOT closed in fewer days and had a faster rate of closure than the 11 wounds studied using TOT. Hyperbaric oxygen therapy creates higher levels of oxygen absorption by the blood, thereby causing hyperoxygenation in the tissues and perhaps leading to this faster rate of closure.

  Diabetic foot ulcers are a worldwide problem and a major cause of morbidity. The annual global incidence of ulcerations and amputations is as high as 10.7% and 1.8%, respectively.¹ The financial burden of diabetic foot ulcers is substantial considering that an uncomplicated ulcer can cost $8,000 to treat, an infected ulcer can cost $17,000, and the cost of an amputation can reach $45,000.² Diabetes is the seventh leading cause of death in the United States, with more than 233,000 deaths per year.³

  The etiology of diabetic foot ulcers is multifactorial, often resulting from neuropathy, ischemia, and/or infection. Peripheral neuropathy in the lower extremity typically manifests as a stocking-distribution loss of sensation and subsequent foot deformity. Ultimately the plantar pressures of the foot become redistributed and increased pressure points lead to ulcerations. Additionally, people with diabetes can develop autonomic neuropathy causing hyperkeratotic formations and dry skin, which makes the patient vulnerable to infections.1 Patients with diabetes also face impaired cellular and humoral immunity, which can exacerbate infections. Wound healing can be impaired if the patient with diabetes suffers from lower extremity ischemia due to peripheral vascular disease (PVD). Factors that can augment oxygen delivery to the tissue include supplemental oxygen, warmth, and sympathetic nerve blocks.^4,5

  Wound healing is comprised of 3 major phases: inflammatory, proliferative, and maturation, all of which are oxygen dependent.⁶ The inflammatory phase, which occurs 1-7 days after the initial insult, consists of an influx of platelets and leukoctyes, the release of cytokines, and coagulation.⁷ The proliferative phase, which takes place 5-20 days after injury, involves the production of collagen fibers, angiogenesis, and wound contraction.⁷ The last phase of wound healing, maturation, takes place 3 weeks to several years following trauma and includes deposition of collagen and a return to a pre-injury state.⁷ Oxygen is required for the synthesis of collagen, enhancement of fibroblasts, angiogenesis, and leukocyte function.² Furthermore, oxygen enhances the leukocyte bactericidal effect, including the killing of aerobic Gram-positive and Gram-negative organisms and is cytotoxic to anaerobes.⁸

  Oxygen delivery is a crucial element involved in wound healing and it is widely recognized that limited oxygenation can lead to a chronic nonhealing ulcer. Hypoxia related to vascular disruption is a rate-limiting step in the healing of wounds. The pO₂ of a dermal wound ranges from 0-10 mmHg at the periphery, while the pO₂ in the arterial blood is about 100 mmHg.⁵ If the wound pO2 drops below 20 mmHg, nicotinamide adenine dinucleotide phosphate oxidase (NADPH), an enzyme that generates reactive oxygen species (ROS) to signal propagation and promote healing, ceases to function.⁹ This helps explain why a wound may fail to heal in an ischemic lower extremity.

  Impaired oxygen delivery to a wound can greatly inhibit the healing cascade. Acutely, a hypoxic state encourages angiogenesis; however, a chronic ulcer causes death and dysfunction of tissue.⁵ Oxygen and its reactive derivative hydrogen peroxide are known to induce angiogenic responses, such as vascular endothelial growth factor (VEGF) expression, and attribute to the acceleration of vessel growth.⁵ It has also been observed that oxygen triggers differentiation of fibroblasts to myofibroblasts, which are the cells responsible for wound contraction.⁵

  Collagen deposition, which is also oxygen dependent, is another primary step in wound healing. Collagen provides the matrix for angiogenesis and tissue remodeling.⁹ Enzymes, such as prolyl hydroxylase, lysyl hydroxylase, and lysyl oxidase, are involved in the synthesis of collagen and require oxygen.⁹ More specifically, prolyl hydroxylase allows the procollagen peptide chains to assume their triple helix configuration. Without this formation, the procollagen peptide chains accumulate in the rough endoplasmic reticulum and are emitted as nonfunctional protein.⁹ It is this formation that ultimately leads to the tensile strength required for wound healing. Jonsson et al¹⁰ clinically demonstrated that increasing wound oxygenation results in increased collagen deposition and tensile strength. A group of 33 postoperative patients were treated with supplemental oxygen (4L/min via nasal cannula for 12 hours a day for 3 days) and it was discovered there was 2 times as much collagen deposited in their wounds vs those with no supplemental oxygen.¹⁰ Therefore, supplemental oxygen can enhance collagen deposition, which translates to increased wound tensile strength. This phenomenon has not been as thoroughly investigated in the healing of chronic wounds; however, it has been postulated that the failure of healing a chronic wound is due at least in part to poor collagen deposition and remodeling from hypoxia.¹¹ Ultimately, oxygen enhances neutrophil killing ability, stimulates angiogenesis, and enhances fibroblast activity and collagen synthesis.¹²

  Factors such as arterial occlusion, hypotension, hypothermia, and peripheral venous congestion can limit wound healing.⁶ Given that enhanced oxygen induces events in wound healing, oxygen therapies including hyperbaric oxygen therapy (HBOT) and topical oxygen therapy (TOT) have been used clinically.

  Hyperbaric oxygen therapy is defined by the Undersea and Hyperbaric Medical Society as a treatment where the patient breathes 100% oxygen, with the chamber being pressurized > 1 atmosphere absolute (ATA).¹ Hyperbaric oxygen therapy has multiple mechanisms of therapeutic effect including bacteriostatic effects, hyperoxygenation, and restoration from hypoxia.¹³ Patients who are eligible for HBOT often have 1 of the following ailments: acute carbon monoxide poisoning, decompression illness, gas gangrene, acute traumatic peripheral ischemia, crush injuries, necrotizing fasciitis, acute peripheral insufficiency, compromised skin grafts, osteomyelitis, cyanide poisoning, Actinomyces infection, soft tissue radionecrosis, osteoradionecrosis, and nonhealing diabetic wound of the lower extremity.¹⁴ First documented in 1662, the therapy now consists of a monoplace chamber with pure oxygen delivery under pressure, or a multiplace chamber with oxygen delivered under pressure with compressed air and oxygen delivered via mask, head tent, or endotracheal tube. Pressures applied while in the chamber are usually 2 to 3 ATA, with patients typically receiving 10-30 treatments.¹⁵ Treatments are typically 1.5-2 hours long, 5 days per week, and require the patient to travel to specialized facilities that are under the supervision of a physician.

  A randomized, double-blind, controlled clinical trial supporting the use of HBOT as a therapeutic option in the healing of 18 chronic diabetic foot ulcers was demonstrated by Abidia et al in 2003.¹⁶ This study revealed that the HBOT group had a 63% healing rate and the control group had a 28% healing rate over the course of 6 months.¹ Most recently in 2012, Londahl¹³ examined all the published controlled trials with follow-up times between 3 months and 3 years, consisting of 108 patients in double-blind randomized controlled studies and 208 patients in nonrandomized controlled studies. The results ultimately found that healing rates were higher in patients treated with adjunctive HBOT (54% vs 24%) in randomized controlled studies. The results also demonstrated higher healing rates in patients treated with adjunctive HBOT (77% vs 25%) in nonrandomized controlled studies when compared to placebo or multidisciplinary wound care alone.¹

  The benefits of HBOT are numerous, however there are some contraindications that must be considered when using this treatment. These include opthalmopathies (eg, cataract formation); central nervous system toxicity and seizures; ear trauma (eg, otitis media or tympanic rupture), pulmonary barotraumas and pneumothorax; fetal complications from pregnancy (eg, spina bifida); claustrophobia; and fire incidents.¹ Therefore, patients with recent ear or sinus surgery, seizure disorders, febrile disorders, upper respiratory infections, emphysema, thoracic surgery or pneumothorax, pacemakers, optic neuritis, hyperthermia, claustrophobia, and pregnancy should be excluded from this therapy.

  Topical oxygen therapy represents a less explored and less expensive modality in wound healing compared to HBOT. In an effort to address some drawbacks to HBOT, TOT was introduced in the 1960s.¹⁷ Topical oxygen therapy is a low-pressure treatment that applies oxygen directly to the wound site at 1.03 atmospheres of pressure.⁴ Since oxygen is applied directly to the wound site and there is no additional inspiration of oxygen, there is a decreased oxygen penetration of the tissue it is being delivered to in comparison to HBOT.⁶ Topical oxygen therapy is FDA approved for diabetic ulcers, venous insufficiency, postsurgical infections, gangrenous lesions, pressure ulcers, skin grafts, burns, frostbite, and amputations. It is applied in the comfort of a patient’s home and consists of a sterile, single-use, disposable, gas-impermeable chamber with adhesive edges applied as a boot or bag administered around the affected extremity or wound. Treatments of topical oxygen for all patients consist of one 90-minute session per day for 4 consecutive days, with a rest period of 3 days; cycle is repeated until the wound is healed. The advantage of this system is that it has a low cost and does not involve systemic oxygen, which can place a patient at risk for oxygen toxicity.⁴

  A study performed by Fries et al⁵ demonstrated that TOT increases VEGF expression in wounds and vessel formation via the use of pig models. Four female pathogen-free domestic pigs each had 5 wounds placed on their backs, for a total of 20 wounds. Each wound consisted of a 2.5 cm x 2.5 cm excised full-thickness piece of skin.⁵ Half of the wounds were treated with TOT using 100% oxygen at 1 atmosphere of pressure for 3 hours per day for the first 7 days of wounding; the other half of the wounds were treated with room air, dressed with a transparent dressing (Tegaderm, 3M, St. Paul, MN), and allowed to heal by secondary intention.⁵ Compared with the wounds treated with room air, those treated with TOT had higher levels of VEGF protein expression and greater blood vessel density, with pO₂ levels almost 4 times higher than the room air group.⁹

  There are some limiting factors involved with TOT and optimal conditions should be met to use this treatment. For instance, necrotic debris should be removed from the wound surface prior to treatment and the patient should be kept well hydrated.⁹ All wound dressing must be removed during treatment and no petroleum-based dressings can be used because they create a barrier to oxygen penetration. The therapy should also not be applied to patients with limb ischemia as indicated by a transcutaneous oxygen measurement ≤ 25 mmHg or large wounds with average initial wound area of 25.3 cm², mainly because the patient would not respond to the therapy because there is an increase in diffusion distance for the oxygen, therefore decreasing its effectiveness.⁹ Furthermore, this therapy is very user dependent, as it is done in the privacy of one’s home and is not directly supervised by a physician; therefore, the patient’s ability to comply with treatment recommendations must be taken into consideration.

  After obtaining exemption from the Institutional Board Review at Wyckoff Heights Medical Center (Brooklyn, NY), a retrospective chart review was completed of patients who received wound treatment using either TOT (TO2, GWR Medical, Inc, Chadds Ford, PA) or HBOT at a community medical center in an outpatient setting from July 2011 until October 2012. All diabetic foot ulcers treated with oxygen therapies were included as long as they remained healed with complete wound closure for at least 1 month. Prior to treatment, arterial and venous studies were performed as needed and appropriate treatments were conducted as deemed necessary. Exclusion criteria included nondiabetic ulcers, diabetic ulcers at or above the ankle, venous stasis ulcers, and concurrent use of any advanced therapies or acellular matrices used in conjunction with oxygen therapy.

  Moreover, the parameters for HBOT treatment include patients with type I or type II diabetes with a wound classified as Wagner Grade III or higher with a failed adequate course of standard therapy for more than 4 weeks, a laboratory workup (ie, complete blood count, sedimentation rate, and hemoglobin A1c) with recent vascular studies including transcutaneous oxygen measurements, and a recent chest X-ray and electrocardiogram. Using a disposable ruler, the length, width, and depth of each wound were recorded in centimeters by taking the greatest length of the wound head-to-toe and the greatest width of the wound side-to-side, with these 2 measurements taken perpendicular to each other. A clean cotton-tipped applicator was placed into the wound and then the marked area was measured against a ruler device, in centimeters, to determine the depth. These measurements were then complied to determine the area of each wound. All wounds were measured from the start of treatment to closure as documented in the patient’s official medical record. Comorbidities as well as smoking status, body-mass index (BMI), age, gender, ethnicity, hemoglobin A1c levels, flow dynamics (arterial and venous), and neuropathic status were documented. In conjunction with oxygen therapy, all included wounds were managed with additional conservative measures, such as a surgical shoe to off-load the wound, and topical therapies including an antimicrobial alginate dressing, silver sulfadiazine, calcium alginate dressings, or collagenase. Furthermore, wounds underwent excisional debridement during routine exams as needed.

 Twenty-two patients were included in the current study, with 11 undergoing HBOT and 11 receiving TOT. Data is summarized in Tables 1 and 2.

  There were a total of 5 women and 17 men with an average age of 58.6 years (range, 44-78). Thirty-two percent of all patients reported smoking. Patients had an average BMI of 28.57 and an average A1c of 8.9. Most were both neuropathic (68%) and reported having PVD (70%). Ulcers were present in the following locations: plantar (8), hallux (3), digits (4), dorsal (1), and amputation sites (6).

  Of the 11 patients treated with TOT, 4 were female and 7 were male with an average age of 55.2 (range, 44-73). Twenty-seven percent were smokers. Patients had an average BMI of 29.23 and an average A1c was 8. More than 90% of the patients were neuropathic and more than half (54.5%) had PVD. The locations of the ulcers for this particular cohort included hallux (2), plantar (7), digit (1), and amputation site (1).

  Of the 11 patients treated with HBOT, 1 was female and 10 were males with an average age of 62 (range, 52-78). Thirty-six percent of patients were smokers. Patients had an average BMI of 28.2 and an average A1c of 9.9. Forty-five percent were neuropathic and almost 90% of those reported experienced PVD. A majority of patients in this cohort had amputations (7 of the 11) with the remainder of ulcers located on the hallux (1), plantar (2), and dorsal ulcer (1).

  The average number of days to closure and average wound volume was assessed. The data revealed an average wound volume for HBOT of 2.986 cm³ and average number of days to closure of 47.09. For TOT, the average wound volume was 0.268 cm³ and the average number of days to closure was 61.82. Despite larger wound volume in the HBOT cohort, these wounds healed more quickly. Rate of closure in the HBOT cohort was 0.063 cm³/day compared with the TOT cohort closure rate of 0.004 cm³/day as seen in Figure 1. The distribution of rates of closure for each patient can be visualized in Figure 2.

  This study represents preliminary data and, to the author’s knowledge, is the first of its kind to compare the rate of closure of TOT vs HBOT. The results may suggest that wounds in patients treated with HBOT are more likely to heal in a shorter duration of time than wounds in patients receiving TOT, considering the rate of closure for HBOT was 0.063 cm³/day and for TOT was 0.004 cm³/day in the current study (Figure 1). The average number of days for closure utilizing HBOT was 47.09 and the average number of days of closure for TOT was 61.28. Furthermore, the average volume of wounds included in HBOT (2.986 cm³) was more than 10 times larger than the average volume of wounds included in TOT (0.268 cm³). Despite the HBOT group having 2 outliers with considerably faster rates of closure compared to the majority of those included in the study (Figure 2), the rate of closure for HBOT compared to TOT would still be greater even if the 2 outliers were excluded (0.0113 cm³/day). The results must be interpreted within the context of the study design.

  While there is no study that directly compares the rate of closure of these 2 modalities, previous studies conducted on HBOT and TOT suggest both forms of therapy are effective treatments for wounds. Hyperbaric oxygen therapy has been shown to have as high as a 77% healing rate on 208 patients in a nonrandomized controlled study.¹ Topical oxygen therapy has also proved to have many benefits suggested by a study performed by Fries et al,⁵ which demonstrated increases in VEGF in wounds and vessel formation.⁹ Both HBOT and TOT encourage the stimulation of fibroblast proliferation and differentiation, increase collagen formation and cross-linking, encourage the stimulation of leukocyte microbial killing, and increase neovascularization.⁶

  It is widely reported that the high economic cost of HBOT to patients is of concern and TOT is a less expensive treatment. It is also important to consider the patient’s comfort and convenience.⁴ Hyperbaric oxygen therapy requires a patient travel to a wound care facility, provided there is a facility within a reasonable distance, multiple times a week. Topical oxygen therapy is performed in the patient’s home and does not require travel to a specialized facility. However, TOT is user dependent. There are also limited studies linking TOT and the healing of wounds. When deciding which treatment is best, it is always important to examine the patient’s lifestyle to determine the most feasible plan.

  The treatment of diabetic foot ulcers can be extremely challenging considering that the cause of ulcers is multifactorial in nature and best treated by a team approach. Standard therapies are important to consider when trying to heal a wound and include off-loading of the ulcer, management of infections, appropriate dressing changes and, when needed, excisional debridement. Hypoxia is a common limitation to healing in chronic ulcers and maintaining an appropriate level of oxygen in these wounds continues to be a challenge.

  There are limitations to this study that should be noted. The study was conducted at an outpatient teaching facility and, due to the nature of this setting, patients may not have been routinely seen at each visit by the same physician. This could have affected weekly measurements and documentations. In addition, the wounds studied all had complete closure and perhaps results would have varied if nonhealing ulcers were examined. Statistically, more wounds in the TOT group were neuropathic (68%) compared to the HBOT group (45%), which could have delayed the rate of healing of wounds in the TOT group. Furthermore, the sample size is small.

  Some wounds utilized in this study had conjunctive applications of topical therapies including an antimicrobial alginate dressing, silver sulfadiazine, calcium alginate dressings, or collagenase, which may have influenced the healing of wounds. Some wounds also had excisional sharp debridements, which may have contributed to healing rates. The wounds measured in the HBOT treatment group were larger on average than those in the TOT treatment group, which may represent a bias. The patient population was also complex in that all patients involved have diabetes; and several are smokers with elevated BMI’s, A1c levels, and complications of PVD. Thus, when evaluating the effectiveness of wound healing, it is important to account for these comorbidities.

  While hyperbaric and topical oxygen therapies resulted in complete reepithelialization, it is important to note that HBOT had a faster rate of closure when compared to TOT, as well as a shorter number of days to closure. Each modality has its pros and cons, and it is essential to choose the best course of treatment based on the patient’s needs. Wound healing is a complex process that may involve a culmination of various techniques, which should be specific to the nature of each wound.

  The author would like to thank Dr. Ronald Guberman and Dr. Angela Miele for mentoring her while working on this paper.

The author is from the Wyckoff Heights Medical Center, Brooklyn, NY.

Address correspondence to:
Brittany Winfeld, DPM, CWS
Wyckoff Heights Medical Center
374 Stockholm Street
Brooklyn, New York 11237
bek221@gmail.com

Disclosure: The author discloses no financial or other conflicts of interest.