Optimizing Oxygen Therapy in Your Clinical Wound Practice

May - June 2022

Optimizing Oxygen Therapy in Your Clinical Wound Practice

Editorial Summary

This article provides a concise overview of the role of oxygen therapy in your clinical wound practice. Oxygen is required at almost every step of the wound healing process1. Oxygen is an essential building block of cells and tissues, required for synthesis of energy, proteins, and collagen. If these building blocks are not present, tissue building, and wound healing simply cannot occur9. Oxygen is also involved in many wound healing processes, such as oxidative killing of bacteria and angiogenesis9.

Introduction

Chronic and hard to heal wounds are a silent epidemic, affecting a large percentage of the global population1. 1-2 of every 100 adults will suffer from a chronic wound in their lifetime, many suffering from multiple wounds and recurrences, and these rates will only increase with our ageing population2. In developed countries, wound care accounts for ~3% of total health care expenditures3. This translates to annual estimated costs of more than 97 billion dollars in the United States3 and 5.3 billion pounds in the UK4. The most effective way to reduce these costs is simply to heal wounds with chronicity that are considered ‘non-healing’. Yet, in practice, healing these wounds is far from simple. Despite the enormous range of readily available bandages, ointments, antimicrobial solutions, and advanced therapies targeted to wounds, the current standard of care heals less than 40% of chronic wounds by 12 weeks5. The remaining wounds continue to be a burden to both the patients and the healthcare system.

What Types of Wounds are Suitable?

Diabetic ulcers, vascular ulcers (venous or arterial), and pressure injuries are all chronic wounds. The pathologies underlying chronic wounds can differ widely. However, common shared features include prolonged or excessive inflammation, persistent infections, and the inability to respond to reparative stimuli6,7 Adults with vascular disease and/or diabetes are at highest risk for chronic leg and foot wounds. The ischemic (reduced tissue perfusion) and/ or hypoxic lower limb conditions which result

from these conditions reduces availability of both oxygen and nutrients, making these wounds especially hard to heal. These wounds last on average 12 to 13 months, but this varies widely; many will remain open for years or never heal6,7, and up to 30% of Diabetic Foot Ulcers (DFUs) go on to amputation8. Even when they do heal, wounds recur in 60-70% of patients, decrease quality of life, and are a significant cause of morbidity6,7

Oxygen is required at almost every step of the wound healing process1. Oxygen is an essential building block of cells and tissues, required for synthesis of energy, proteins, and collagen. If these building blocks are not present, tissue building, and wound healing simply cannot occur9. Oxygen is also involved in many wound healing processes, such as oxidative killing of bacteria and angiogenesis9. Yet, both wound perfusion and blood oxygen levels are frequently insufficient in patients with chronic wounds due to poor circulation, vascular disruption, and vasoconstriction, thereby reducing the wound’s capacity to heal.Novel wound care therapies that specifically address these underlying issues are sorely needed. Fortunately, there is a growing body of evidence to support the benefits of supplementary oxygen therapy on wound healing10-12.

When physiological constraints hinder adequate oxygenation, various methods can be used to direct exogenous oxygen to the wound in a therapeutic context. Skin wounds can receive oxygen from the blood stream via perfusion and from oxygen uptake through the skin13. Raising oxygen concentrations can, by itself, trigger healing responses through the mechanisms

Dr Aliza Lee Clinical Research Investigator, Department of Veterans Affairs Salem VA, United States

outlined earlier.

Severe impairments in lower limb vascular networks, suffered by many patients with wounds, often necessitate surgical efforts to improve these oxygen delivery networks and prevent amputation14,15

Direct repair of perfusion can therefore have a profound effect on restoration of tissue oxygenation. Revascularization via arterial bypass surgery, venous ablation, angioplasty, and stenting are methods that attempt to correct the lower limb large vessel network15. When successful, the benefits are clear; limbs on the path to amputation are often saved by these procedures14,16. However, surgical interventions improve flow primarily in larger arteries; they often cannot overcome deficiencies in the microvasculature, which is a root cause of poor tissue oxygenation in hard to heal wounds17,18.

Therefore, many wounds remain slow to heal after these procedures and wound recurrence is very common17,19. Benefits of adjunctive oxygen therapy on wound healing in this group have been reported20

How to Deliver Oxygen to the Wound

Improved wound oxygenation can be achieved with the use of supplementary oxygen. This can be delivered either systemically or topically, depending on your patient’s needs.

In some patients, systemic Hyperbaric Oxygen Therapy (HBOT) can be very effective at increasing wound oxygen to above physiological levels, resulting in a pharmacologic dose21. As these pharmacological doses are systemic, i.e., not directed at the wound, effectiveness of hyperbaric oxygen is somewhat dependent on adequate blood perfusion. The vascular system must direct and deliver the pharmacologic oxygen levels to the wound. This is hampered in the large percentage of patients with wounds

in which perfusion is compromised by peripheral artery disease or chronic venous insufficiency. Still, when adequate arterial blood flow to the wound is present, adjunctive hyperbaric oxygen in patients with lower limb chronic wounds has been shown to elevate wound oxygen levels21, improve wound healing rates22, and reduce limb amputation rates23. In addition to the elevated oxygen levels, there is evidence to suggest that hyperbaric therapy may increase angiogenesis and antioxidant response24 and decrease inflammation25. Despite these reported benefits, practical limitations and adverse effects have hindered the global adoption of hyperbaric oxygen as a wound therapy.

Systemic HBOT is costly, not widely available, and requires patients to be confined to a full body chamber for at least 90 minutes a day, 5 days a week for the duration of the treatment26 These lifestyle-limiting chambers are not portable, and therefore cannot be used for supplying continuous oxygen therapy to the patient in an outpatient setting. Furthermore, the number of hyperbaric sessions a patient can tolerate is limited; middle ear barotrauma has been observed in two-thirds of patients after just seven days of systemic hyperbaric treatment27,28. Consequently, hyperbaric oxygen chamber usage is limited to very short periods of the week (approximately 5%)26, which in turn limits the ability to raise oxygen levels in wounds for any sustained period.

The pre-clinical and clinical studies provide ample evidence to support Topical Oxygen Therapy (TOT) use. Pre-clinical models involving excisional dermal wounds in pigs exposed to TOT had increased wound tissue pO2 (partial pressure of oxygen); within 4 minutes oxygen had diffused into the wound tissue and elevated the local pO2 from 5 mmHg to over 40 mmHg (a 10-fold increase in pO2 after 4 minutes)26. Low pressure topical oxygen, in contrast to HBOT, can diffuse locally at the wound bed, deep into the tissue and elevate

“The pre-clinical and clinical studies provide ample evidence to support Topical Oxygen Therapy (TOT) use.”

“TOT can be delivered either intermittent or continuous. The main difference is intermittent systems tend to be pressurised systems whereas continuous TOT are portable low flow systems. These systems are particularly relevant today, because they are home care based, offering an alternative for wound patients particularly during COVID-19.”

local tissue partial pressures with repeated treatments accelerating wound closure. TOT induces vascular endothelial growth factor expression and improves closure of chronic wounds27. Oxygen levels have also been shown in both animal and human studies to significantly increase growth factors related to the formation of angiogenesis; Vascular Endothelial Growth Factor (VEGF), Basic Fibroblast Growth Factor (FgF-2) and PlateletDerived Growth Factor (PDGF)27. Several controlled TOT studies in humans have showed significantly lower reoccurrence rates at 36 months post healing in the TOT group28,29 (better interlinked collagen and resultantly more patent tissue). TOT on the hind limb wounds of rats under ischemic conditions had shorter healing times, more accumulation of collagen fibers, and many more new vessels compared to the control group30. The results of the experiment showed that TOT therapy improved ischemic wound healing.

TOT can be delivered either intermittent or continuous. The main difference is that intermittent systems tend to be pressurised systems, whereas continuous TOT are portable low flow systems. These systems are particularly relevant today, because they are home care based, offering an alternative for wound patients particularly during COVID-19.

TOT improved healing of even advanced (Texas Grade III) DFUs31, or wounds that had been open for up to 88 weeks prior to topical oxygen therapy32. A recent Randomized Controlled Trial (RCT) with 54% of patients over age 65, demonstrated statistically significant healing rates in the continuous diffusion TOT treated patients33. Over 52% of those patients healed within the 12-week therapy period, representing a 71% greater healing rate and 73% greater reduction in wound size compared to the control group33. Kauffman et al., (2018) reported the results of a large trial in chronic ulcers of mixed aetiology34. The authors noted

an optimum treatment effect if the continuous diffusion device was used for >25 days, including an 83% reduction in wound area and a 47% wound closure rate in venous leg ulcers, and a 74% reduction and 57% wound closure rate in arterial foot ulcers. The effects of the continuous delivery of oxygen to the wound have also been examined mechanistically: Hunter et al., (2019) used 16S rDNA sequencing to examine the effect of topical oxygen on chronic wound microbiomes. The authors reported a significant shift in bacterial flora from anaerobic to aerobic (oxygen utilizing) genera after 2 weeks of continuous treatment with the TOT system35. The authors postulated based on their results that topical oxygen can promote healing via disruption of the bacterial biofilms that form in chronic wounds35. A sham-controlled, double-blind randomized controlled trial demonstrated that, at both 12 weeks and at 12 months, adjunctive cyclical pressurized TOT therapy was superior in healing chronic DFUs compared with optimal SOC alone36 with a fourand-a-half-fold increased likelihood of healing achieved at 12 weeks. Clinically, the durability of healing as measured by index ulcer recurrence at 12 months was sixfold better than that in the sham group36. Home based cyclical pressurized topical wound oxygen therapy, when used with or without other adjunctive treatments, is associated with significantly reduced frequency of wound-related hospitalization and amputation for patients afflicted with DFU37 That study found 8.9 times greater likelihood of hospitalizations in the non-oxygen therapy arm compared to oxygen, and similarly 4.9 times greater likelihood of amputation in the nonoxygen arm compared to the oxygen therapy arm37

Conclusion

We know oxygen plays a significant role during every phase of wound healing from angiogenesis and revascularization to cell membrane and energy production, it promotes growth factor

Optimizing Oxygen Therapy in Your

signaling transduction, collagen synthesis, cell proliferation and re-epithelization, and it even is involved in antibacterial activities and bacterial biofilm. Just like wound care products and dressings, there are various options available. Knowing your patient, their needs, available resources, and support level, you can confidently select an oxygen delivery system that will enhance your wound care outcomes.

References

1. Sen CK. Wound healing essentials: let there be oxygen. Wound Repair Regen 2009;17:1-18.

2. Gottrup F. A specialized wound-healing centre concept: importance of a multidisciplinary department structure and urgical treatment facilities in the treatment of chronic wounds. American journal of surgery 2004;187:38S-43S.

3. Nussbaum SR, Carter MJ, Fife CE, et al. An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds. Value Health. 2018;21(1):27-32.

4. Guest JF, Ayoub N, McIlwraith T, et al. Health economic burden that wounds impose on the National Health Service in the UK. BMJ Open. 2015 5(12):e009283.

5. Fife CEE, K.A; Carter, M.J. Publicly Reported Wound Healing Rates: The Fantasy and the Reality. Advances in wound care. 2018; 7(17).

6. Frykberg RG, Banks J. Challenges in the Treatment of Chronic Wounds. Adv Wound Care (New Rochelle). 2015;4(9):560-582.

7. Richmond NA, Maderal AD, Vivas AC. Evidence-based management of common chronic lower extremity ulcers. Dermatol Ther. 2013;26(3):187-196.

8. Stockl K, Vanderplas A, Tafesse E, Chang E. Costs of lower-extremity ulcers among patients with diabetes. Diabetes Care. 2004;27(9):2129-2134.

9. Gottrup F, Hunt TK, Hopf HW. Role of oxygen in wound healing and infection. Journal of wound technology 2010; 9: 6-10

10. Shivshankar T, Singh T, Golledge J. Topical oxygen therapy for diabetes‐related foot ulcers: A systematic review and meta‐analysis. Diabetic Medicine 2021 38: e14585.

11. Tawfick WA, Sultan S. Technical and clinical outcome of topical wound oxygen in comparison to conventional compression dressings in the management of refractory nonhealing venous ulcers. Vasc Endovascular Surg. 2013 47(1): 30-37.

12. Eggleton PB, Smerdon, G.R. Safety and efficacy of hyperbaric oxygen therapy in chronic wound management: current evidence. Chronic Wound Care Management and Research. 2015 2(12).

13. Stucker M, Struk A Altmeyer P et al The cutaneous uptake of atmospheric oxygen contributes significantly to the oxygen supply of human dermis and Epidermis Journal of Physiology2002 538(3):985–994

14. Almasri J, Adusumalli J, Asi N, et al. A systematic review and meta-analysis of revascularization outcomes of infrainguinal chronic limb-threatening ischemia. J Vasc Surg. 2018;68(2):624-633.

15. Conte MS. Diabetic revascularization: endovascular versus open bypass--do we have the answer? Semin Vasc Surg. 2012;25(2):108-14.

16. Goodney PP, Tarulli M, Faerber AE, Schanzer A, Zwolak RM. Fifteen-Year Trends in Lower Limb Amputation, Revascularization, and Preventive Measures Among Medicare Patients. JAMA Surg. 2015;150(1):84–86.

17. Forsythe RO, Brownrigg J, Hinchliffe RJ. Peripheral arterial disease and revascularization of the diabetic foot. Diabetes ObesMetab. 2015;17(5):435-44.

18. Wollina U, Abdel-Naser MB, Mani R. A review of the microcirculation in skin in patients with chronic venous insufficiency: the problem and the evidence available for therapeutic options. Int J Low Extrem Wounds. 2006;5(3):169-80.

19. Stoekenbroek RM, Santema TB, Legemate DA, et al. Hyperbaric oxygen for the treatment of diabetic foot ulcers: a systematic review. Eur J VascEndovasc Surg. 2014;47(6):647-55.

20. Rhodes JM, Gloviczki P, Canton LG, et al. Factors affecting clinical outcome following endoscopic perforator vein ablation. Am J Surg. 1998;176(2):162-7.

21. Smith BM, Desvigne LD, Slade JB et al. Transcutaneous oxygen measurements predict healing of leg wounds with hyperbaric therapy. Wound Repair Regen. 1996;4(2):224-229.

22. Abidia A, Laden G, Kuhan G, et al. The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial. Eur J Vasc Endovasc Surg. 2003;25(6):513-518.

Variables to consider while deciding which oxygen delivery system to choose from include: activity level, wound impacting factors; patient comfort levels, economic impact on your patient; geographic location, capable participation level; compliance/ adherence to therapy, number of wounds and severity; presence of active infection, and dressing compatibility.

23. Faglia E, Favales F, Aldeghi A, et al. Adjunctive systemic hyperbaric oxygen therapy in treatment of severe prevalently ischemic diabetic foot ulcer. A randomized study. Diabetes Care. 1996;19(12):1338-1343.

24. Sureda A, Batle JM, Martorell M, et al. Antioxidant Response of Chronic Wounds to Hyperbaric Oxygen Therapy. PLoS One. 2016;11(9):e0163371.

25. Thom SR. Effects of hyperoxia on neutrophil adhesion. Undersea Hyperb Med. 2004;31(1):123-131.

26. Winfield B. Topical Oxygen and Hyperbaric Oxygen Therapy Use and Healing Rates in Diabetic Foot Ulcers. Wounds. 2014;26:E39-E47. Fries RB, Wallace WA, Roy S, Kuppusamy P, Bergdall V, Gordillo GM, Melvin WS, Sen CK. Dermal excisional wound healing in pigs following treatment with topically applied pure oxygen. Mutat Res. 2005 Nov 11;579(1-2):17281. doi: 10.1016/j.mrfmmm.2005.02.023. Epub 2005 Aug 18. PMID: 16105672.

27. Blanshard J, Toma A, Bryson P, et al. Middle ear barotrauma in patients undergoing hyperbaric oxygen therapy. Clin Otolaryngol Allied Sci. 1996;21(5):400-403.Gordillo GM, Roy S, Khanna S, Schlanger R, Khandelwal S, Phillips G, Sen CK. Topical oxygen therapy induces vascular endothelial growth factor expression and improves closure of clinically presented chronic wounds. Clin Exp Pharmacol Physiol. 2008 Aug;35(8):957-64. doi: 10.1111/j.14401681.2008.04934.x. Epub 2008 Apr 21. PMID: 18430064; PMCID: PMC2574754. 28. Karahatay S, Yilmaz YF, Birkent H, et al. Middle ear barotrauma with hyperbaric oxygen therapy: incidence and the predictive value of the nine-step inflation/deflation test and otoscopy. Ear Nose Throat J. 2008;87(12):684-688. 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 Jun;56(6):24-31. PMID: 20567051.

29. Tawfick W, Sultan S. Does topical wound oxygen (TWO2) offer an improved outcome over conventional compression dressings (CCD) in the management of refractory venous ulcers (RVU)? A parallel observational comparative study. Eur J VascEndovasc Surg. 2009 Jul;38(1):125-32. doi: 10.1016/j.ejvs.2009.03.027. Epub 2009 May 22. PMID: 19464933.

30. Rao C, Xiao L, Liu H, et al. Effects of topical oxygen therapy on ischemic wound healing. J Phys Ther Sci. 2016;28(1):118-123. doi:10.1589/jpts.28.118

31. Yu J, Lu S, McLaren AM, Perry JA, Cross KM. Topical oxygen therapy results in complete wound healing in diabetic foot ulcers. Wound Repair Regen. 2016;24(6):1066-1072.

32. Hayes PD, Alzuhir N, Curran G, Loftus IM. Topical oxygen therapy promotes the healing of chronic diabetic foot ulcers: a pilot study. J Wound Care. 2017;26(11):652-660.

33. Serena TE, Bullock NM, Cole W et al. Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled trial. J Wound Care 2021; 30: Suppl.5 S7-14.

34. Kaufman H, Gurevich M, Tamir E, Keren E, Alexander L, Hayes P. Topical oxygen therapy stimulates healing in difficult, chronic wounds: a tertiary centre experience. J Wound Care. 2018;27(7):426-433.

35. Hunter P, Greco E, Cross K, Perry J. Topical Oxygen Therapy Shifts Microbiome Dynamics in Chronic Diabetic Foot Ulcers. Wounds. 2020;32(3):81-85.

36. Frykberg RG, Franks PJ, Edmonds M, Brantley JN, Téot L, Wild T, Garoufalis MG, Lee AM, Thompson JA, Reach G, Dove CR, Lachgar K, Grotemeyer D, Renton SC; TWO2 Study Group. A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study. Diabetes Care. 2020 Mar;43(3):616-624. doi: 10.2337/dc19-0476. Epub 2019 Oct 16. PMID: 31619393.

37. Yellin JI, Gaebler JA, Zhou FF, Niecko T, Novins O, Ockert A, Krzynowek D, Garoufalis MG, Lee AM, Frykberg RG. Reduced Hospitalizations and Amputations in Patients with Diabetic Foot Ulcers Treated with Cyclical Pressurized Topical Wound Oxygen Therapy: Real-World Outcomes. Adv Wound Care (New Rochelle). 2021 Dec 6. doi: 10.1089/ wound.2021.0118. Epub ahead of print. PMID: 34714167.

“Knowing your patient, their needs, available resources, and support level you can confidently select an oxygen delivery system that will enhance your wound care outcomes.”