Treating Diabetic Foot Ulcers With HBOT And Topical Oxygen

Diabetes mellitus continues to be a global health threat. The Centers for Disease Control and Prevention (CDC) estimates that 9.3 percent of the United States population has diabetes.¹ The CDC estimates that by 2030, diabetes will affect more than 360 million people worldwide.¹

With uncontrolled diabetes comes the increased risk of the development of diabetic foot ulcers (DFUs). An estimated 15 percent of patients affected by diabetes will suffer from a DFU in their lifetime.² It is important to note that about 20 percent of patients with diabetes admitted in the hospital are admitted for DFUs. The presence of DFUs increases the risks of infection, gangrene, amputation and even loss of life. Patients with diabetes are 15 times more likely to sustain an amputation in comparison to people without diabetes.² Based on these statistics and the patients we see every day in practice, it is essential that we have a thorough understanding of the various treatment options available for DFUs.

There are various risk factors associated with the development of DFUs. These include diabetic neuropathy, peripheral vascular disease, foot deformities, previous diabetic foot ulceration or lower extremity amputation, and increased plantar pressures to an insensate foot. Researchers have reported that the most common causes of a DFU are minor trauma, neuropathy and foot deformity.^2,3

It is our goal as practitioners to determine the cause of the ulceration and design a treatment plan that will heal the wound. There are various treatment modalities that we utilize for DFUs. Initially, conservative therapy includes debridement and offloading. It is important to debride the wound, essentially removing all necrotic tissue and subsequently converting a chronic wound into an acute wound. In addition to the removal of infected skin, debridement facilitates the delivery of growth factors into the wound.

In addition to debridement, offloading is another important conservative modality that plays an important role in wound healing. Offloading modalities aim to relieve pressure from the wound site. This includes total contact casting, which distributes pressure over the foot, relieving pressure from the wound site and thus facilitating healing. In addition, therapeutic shoes with accommodative inserts become important in preventing ulcerations.^4-7

When conservative therapy has failed and there is less than 50 percent of wound closure by four weeks, Sheehan and colleagues state that clinicians should consider advanced treatment.⁸ In many instances, biomechanical factors play an important role in the development of a DFU. Limited mobility at the ankle joint or in the foot may lead to varying deformities ranging from ankle equinus to hammertoe deformities.⁴ In these cases in which conservative therapy has failed, it is important to consider surgical options and correcting the foot deformity leading to increased pressure.

However, some patients are not good candidates for surgery. This includes patients with uncontrolled diabetes, additional comorbidities, a history of smoking, peripheral arterial disease (PAD) and several other factors. In addition to surgery to correct biomechanical factors, revascularization may be needed for a lot of our patients but they may not be the best candidates for revascularization. In these cases, authors have suggested that oxygen therapy may be helpful. This includes hyperbaric oxygen therapy (HBOT) and topical oxygen therapy.^9,10  

A Closer Look At How Oxygen Factors Into Wound Healing

The lack of prospective studies on oxygen therapies has made the topic very controversial. In order to understand how these therapies work, it is important to understand the role of oxygen in wound healing.
Oxygen plays an important role in every step of the wound healing phase. Starting with the inflammatory phase of wound healing, moving into the proliferative phase and ending with the remodeling phase, the skin requires an increased amount of oxygen.

Various cellular and biomechanical processes occur in the wound healing phases, and they require an adequate supply of oxygen.⁴ These processes range from the control of an infection to the signaling pathways to the remodeling of collagen. Many of the patients with non-healing DFUs either have PAD or suffer from neuropathy. In cases of neuropathy, the insensate foot may sustain repetitive trauma, leading to a non-healing wound. When it comes to PAD, there is a decreased supply of oxygen to the wound, leading to a non-healing chronic wound. For patients with neuropathy, there is thickening of the basal membrane and endothelial capillary swelling, which also prevents an adequate supply of oxygen from reaching the wound and may subsequently prevent a diabetic wound from healing. It therefore becomes apparent that oxygen plays a critical role in wound healing.¹¹

What The Research Says About HBOT

The clinical use of oxygen therapy to facilitate wound healing began in the 1960s with the use of HBOT. Hyperbaric oxygen therapy involves placing the patient in a compression chamber, where the pressure within the chamber increases and the patient receives 100 percent oxygen. The thought process is that this delivers increased partial pressure of oxygen to the tissues. With this treatment, pressures increase to between 2.0 and 2.5 ATA for a duration of an hour or two hours once or twice a day.⁹ Hyperbaric oxygen treatment requires up to 30 sessions.⁹

Normally, most of the oxygen carried in blood is bound to hemoglobin and some of the oxygen is carried in solution. In the use of hyperbaric treatment, there is an increased amount of oxygen dissolved in the plasma component of blood. Since the oxygen is in solution, it is able to reach areas where red blood cells may not be able to and can provide oxygenation in areas that may have impaired hemoglobin concentration.¹² Researchers suggest that HBOT improves wound healing by amplifying oxygen gradients along the periphery of ischemic wounds, promoting the oxygen-dependent collagen matrix formation needed for angiogenesis.¹²

However, the use of HBOT has been very controversial due to the lack of high quality randomized controlled trials (RCTs), increased cost and associated risks, including the side effects of systemic oxygen therapy. In a recent Cochrane Systematic Review, authors found that HBOT improved the healing of chronic ulcers significantly in the short term but not in the long term.¹³ The review reported several flaws in trials, indicating that while HBOT may be promising, better quality RCTs are needed.

Similarly, in a systematic review, Game and colleagues reviewed the use of HBOT, but limited controlled studies or poor quality studies prevented the authors from reaching a confident conclusion regarding HBOT.¹⁴ Stoekenbroek and coworkers concluded in their systemic review on HBOT that there is some evidence for the use of hyperbaric oxgyen in diabetic ulcers, but larger trials of higher quality are needed before implementing HBOT in routine clinical practice.¹⁵ In another study done by Santema and colleagues, they conclude that while there are studies suggesting HBOT may improve the healing of chronic wounds, there is little evidence suggesting the economic effectiveness of the therapy.¹⁶

These studies suggest that HBOT may play a role in the healing of DFUs but there needs to be better quality studies to determine long-term healing and amputation rates.  

What You Should Know About Topical Oxygen In The Treatment Of DFUs

Unlike HBOT, topical oxygen aims to provide a local increase of oxygen at the wound site, therefore decreasing the risks associated with systemic oxygen delivery.¹⁰ Although the exact mechanism of topical oxygen is unclear, it is suggested that topical oxygen doesn’t rely on the vascular system to provide oxygen to the site. The theory is that topical oxygen increases the local concentration of oxygen at the wound bed by increasing the solubility and dissolution of oxygen through an increase in oxygen partial pressure. A study by Gordillo and colleagues found that topical oxygen induces the expression of vascular endothelial growth factor (VEGF), which stimulates angiogenesis at the wound site.¹⁷   

Until recently, there have not been prospective studies regarding the use of topical oxygen for DFU. However, a recent article by Yu and coworkers presents the first randomized control study determining the effectiveness of topical oxygen in non-healing diabetic ulcers in comparison to those patients using the best standard of care practice in combination with topical oxygen.¹⁸ In the small study, 20 patients received either the standard treatment or a combination of standard treatment and topical oxygen therapy. The standard therapy consisted of weekly sharp debridement with a surgical blade, use of antimicrobial dressings and offloading with a total contact cast or Aircast (DJO Global). The topical oxygen therapy consisted of the use of a portable oxygen concentrator, which allows for the delivery of continuous topical oxygen by processing oxygen from the air and delivering it continuously to the ulcer bed through a dressing. The authors note that the advantage of this system is that one can use it while the patient is mobile and in conjunction with other dressings and offloading devices.

The patients in both groups were matched for age, wound size, duration of wound prior to treatment, ankle brachial index (ABI) results and HgA1c.¹⁸ The wounds were classified according to the University of Texas classification system. The authors found that patients with grade 1 ulcers healed completely after eight weeks in both the control and treatment groups. None of the patients with grade 2 ulcers healed in the control group while all of the patients in the treatment group with grade 2 ulcers healed. Fifty percent of grade 3 ulcers healed in the treatment group while none of the grade 3 ulcers healed in the control group. Grade 3 ulcers that did not heal in the treatment group had bone involvement and were more severe.

The results of this small study seem to suggest that topical oxygen can be beneficial in the healing of DFU in conjunction with standard care.¹⁸ Although the cohort size in the study by Yu and coworkers was small, it is a well designed study and we can appreciate that topical oxygen may at least warrant research in the healing of DFUs that have failed the standard treatment and fall into the category of grade 1 and 2 ulcers. Further randomized control trials with a greater patient population are warranted.

In Conclusion

Although there is a standard of practice for DFUs including debridement, offloading and surgical treatment, the use of oxygen therapy has been very controversial. A review of the literature has led to the conclusion that HBOT may prove beneficial for chronic wounds but the cost of the therapy as well as the lack of well designed studies prevent some clinicians from utilizing HBOT. The recent study by Yu and coworkers shows topical oxygen therapy may be promising.¹⁸ However, further studies are still warranted before oxygen therapy can become part of routine practice for DFUs. 

Dr. Mohamed is a second-year resident with the New York City Podiatric Medicine/Metropolitan Hospital Program.

Dr. Khan is an Associate Professor in the Department of Podiatric Medicine at the Temple University School of Podiatric Medicine in Philadelphia.

References

1. Centers for Disease Control and Prevention. Diabetes. Available at https://www.cdc.gov/chronicdisease/resources/publications/aag/diabetes.htm .
2. Yazdanpanah L, Nasiri M, Adarvishi S. Literature review on the management of diabetic foot ulcer. World J Diabetes. 2015;6(1):37-53.
3. Monterio M, Boyko E, Ribeiro J, Dinis M. Predictive factors for diabetic foot ulceration: a systematic review. Diabetes Metab Res Rev. 2012; 28(7):574-600.
4. Fontaine J, Lavery L, Hunt N, Murdoch D. The role of surgical off-loading to prevent recurrent ulcerations. Int J Lower Ext Wounds. 2014; 13(4):320-334.
5. Lebrun E, Tomic-Canic M, Kirsner RS. The role of surgical debridement in healing of diabetic foot ulcers. Wound Repair Regen. 2010;18(5):433–438.
6. Cavanagh PR, Bus SA. Off-loading the diabetic foot for ulcer prevention and healing. J Vasc Surg. 2010;52(3Suppl):37S–43S.
7. Mueller MJ, Diamond JE, Sinacore DR, et al. Total contact casting in treatment of diabetic plantar ulcers. Controlled clinical trial. Diabetes Care. 1989;12(6):384–388.
8. Sheehan P, Jones P, Caselli A, et al. Percent change in wound healing of diabetic foot ulcers over a four-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care. 2003; 26(6):1879-82.
9. Dissemond J, Kroger K, Storck M, Rise A, Engels P. Topical oxygen wound therapies for chronic wounds: a review. J Wound Care. 2015; 24(2):53-62.
10. Blackman E, Moore C, Hyatt J, Railton R, Frye C. Topical wound oxygen therapy in the treatment of severe diabetic foot ulcers: A prospective controlled study. Ostomy Wound Manage. 2010; 56(6):24-31.
11. Kimmel H, Grant A, Ditata. The presence of oxygen in wound healing. Wounds. 2016;28(8):264-270.
12. Gill AL, Bell CN. Hyperbaric oxygen: its uses, mechanisms of action and outcomes. QJM. 2004;97(7):385–395.
13. Kranke P, Bennett MH, Martyn-St James M, et al. Hyperbaric oxygen therapy for chronic wounds. Cochrane Database Syst Rev. 2015; 6:CD004123.
14. Game F, Apelqvist J, Attinger C, et al. Effectiveness of interventions to enhance healing of chronic ulcers of the foot in diabetes: a systematic review. Diabetes Metab Res Rev. 2016; 32(1):154-68.
15. Stoekenbroek R, Santema TB, Legemate D, et al. Hyperbaric oxygen for the treatment of diabetic foot ulcers: a systematic review. Eur J Vasc Endovasc Surg. 2014; 6(47):647-55.
16. Santema TB, Stoekenbroek R, van Steekelenburg LC, et al. Economic outcomes in clinical studies assessing hyperbaric oxygen in the treatment of acute and chronic wounds. Diving Hyperb Med. 2015; 45(4):228-34.
17. Gordillo, Gayle M. Topical oxygen therapy induces VEGF expression and improves closure of clinically presented chronic wounds. Clin Exper Pharmacol Physiol. 2008; 35(8):957–964.
18. Yu J, Lu S, McLaren A, Perry J, Cross K. Topical oxygen therapy results in complete wound healing in diabetic foot ulcers. Wound Repair Regen. 2016; 24(6):1066-1072.