Guidance Documents

Oxygen Therapy and Wound Management: Thinking Outside the Chamber

Editorial Summary

Oxygen is a vital component of basic and advanced wound healing. It plays a major part in intricate cellular processes involved with healing all types of wounds. Understanding the pathophysiology of a hypoxic situation at the tissue level is vital in establishing the types of wounds that will benefit from oxygen therapy. The options for comprehensive therapy are discussed in depth; indications such as venous leg ulcers and chronic venous insufficiency, as well as diabetic foot ulceration are also reviewed in this article. A summary of recent topical oxygen therapy evidence is presented, as well as the myths surrounding oxygen therapy. This guide is aimed at providing support for clinicians wishing to incorporate oxygen into their practice.

 

Advanced, or ‘smart’, technology continues to be utilized in all facets of healthcare, up to and including

for delivery of oxygen to the body. And while the use of smart technology is said to make life increasingly more convenient from both a personal and professional standpoint, it does not relieve wound care providers of having to understand the many nuances associated with caring for patients living with hard-to- heal wounds. From the mechanism of action and the administration of oxygen therapy, to the available research that offers proven pros and cons to oxygen’s use, providers must be comprehensively well versed with this modality regardless of how much today’s technology might be able to ‘think’ for us humans. What’s more, topical oxygen presents a myriad of challenges despite how sophisticated today’s technology is. This continues to place emphasis on the basic facts and best practices surrounding this important life-sustaining element.

 

Oxygen’s Important Role

 

Oxygen is crucial in all phases of the wound healing cascade of events. Cellular and biological processes depend on oxygen, especially during the repair process. These include cell proliferation, angiogenesis, collagen deposition, resistance to infection, and protein synthesis needed to restore tissue integrity and function.¹ Tissue oxygenation can trigger healing responses as well. Oxygen keeps cells nourished, oxidizes food during cellular respiration, is involved in the production of cell energy, and is an overall essential element to wound healing.² Hypoxia, a lower level of oxygen than normal, is caused when there’s an impaired delivery of oxygen or an impaired cellular oxygen uptake.² In the human body, normal blood oxygen level is categorized in the 94 – 98% range, while levels below 90% are considered dangerous and require intervention.³

 

Negative Effects of Decreased Oxygen

 

Limiting oxygen to the cells could have negative consequences, such as impaired healing and respiratory issues. Consider chronic obstructive pulmonary disease (COPD), which compromises lung function due to damage to the airways that renders breathing difficult. As COPD and breathing difficulties advance, a lack of oxygen to vital organs could lead to hypoxia. Symptoms include shortness of breath, frequent respiratory infection, fatigue, lower-extremity swelling, and reduced muscle strength.

 

Another condition that restricts the flow of oxygen and can impact wound healing is obstructive sleep apnea (OSA), a serious disorder that causes breathing to stop repeatedly during sleep when the body should be receiving extra oxygen. If left untreated, OSA can lead to hypertension, development of diabetes, heart conditions, and strokes, among other maladies. The importance of recognizing diminished oxygen levels has led clinicians to utilizing the delivery of oxygen as a treatment. COPD patients, depending on severity, can be prescribed supplemental oxygen, while patients with OSA can be treated with positive airway pressure devices that prevent breathing interruption.

Another form of oxygen as a treatment is hyperbaric oxygen therapy (HBOT), the roots of which actually date back to the 1600s. In the late 1930s, the military began using hyperbaric chambers to treat deep-sea divers who experienced decompression sickness. In 1967, the Undersea Medical Society, now known as the Undersea and Hyperbaric Medical Society (UHMS), was founded and later reviewed available evidence supporting the use of HBOT for a number of conditions. A listing of approved indications for HBOT by the U.S. Food & Drug Administration includes⁴

Approved Indications for HBOT:

• Air and gas bubbles in blood vessels
• Anemia (severe anemia when blood transfusions cannot be used)
• Burns (severe and large burns treated at a specialized burn center)
• Carbon monoxide poisoning
• Crush injury
• Decompression sickness
• Gas gangrene
• Hearing loss (complete hearing loss that occurs suddenly and without any known cause)

• Infection of the skin and bone (severe)
• Radiation injury
• Skin graft flap at risk of tissue death

• Vision loss (when sudden and painless in one eye due to blockage of blood flow)

• Wounds (non-healing, diabetic foot ulcers)

It is reported that there are more than 8 million chronic wounds that are more likely to be stuck in the inflammatory phase.⁵ The longer that it takes to manage these wounds effectively will increase likelihood of complications – time is tissue.

Options for Comprehensive Treatment

 

An arsenal of modalities is available that can impact cellular dysfunction in chronic wounds. These modalities could include electrical stimulation, high frequency ultrasound, low frequency contact and non-contact ultrasound, low level laser, shockwave therapy, pulse lavage, negative pressure wound therapy, diathermy, deep oscillation devices, and others that can be conducted in conjunction with sharp debridement, compression, and complete decongestive therapy (CDT). The goal with these modalities mainly includes the ability to ‘jump start’ chronic wounds into the progressive healing cascade and removing nonviable tissue to alter the wound environment.

Altering the chronic wound environment can move the wound along the healing path. Chronic wounds have an alkalic pH level of 7.15- 8.9, while wounds that make progress have a much lower pH level.⁶ If we are successful in decreasing the pH level by one numeric point, this increases the oxygenation level at the wound dramatically.⁶ Necrotic tissue is a medium for bacteria to proliferate and produce inflammatory mediators that inhibit healing. Without adequate local tissue oxygenation, the respiratory burst is impaired and the result is increased susceptibility to infection.⁷

Clinicians should also aim to assess arterial perfusion in lower-extremity wounds to establish adequate delivery of oxygen-rich blood to tissue. The delivery of oxygen is dependent on adequate blood flow at the capillary level. Without adequate perfusion, tissue death is eminent as the environment could become ischemic. Acute hypoxia is needed for cellular signaling, but chronic hypoxia will maintain the wound in an inflammatory phase. Treatment through revascularization can reestablish adequate levels of oxygen delivery to tissue.

Another important and often missed component in wound care is recognizing the negative effects of edema. Edema impairs the healing process because it delays the delivery of oxygen and nutrients to tissue. The endothelial glycocalyx plays an important role in fluid management, but increases endothelial cell permeability and leukocyte infiltration when injured. There’s also an increase in inflammatory cytokines, matrix metalloproteinases, reactive oxygen and nitrogen species, iron deposition, and tissue metabolites.⁸ When interstitial space increases due to endothelial glycocalyx damage or with an edematous condition, the distance from the capillaries to the cells requiring oxygen increases, therefore delaying oxygen transport. This increase in diffusion distance robs the wound of oxygen, which ultimately impairs the healing cascade of events. Patients with chronic venous leg ulcers (VLUs) and edematous lower extremities suffer from frequent infections, skin changes, and poor outcomes.

 

Chronic Edema and VLUs

 

Studies have validated the fact that patients with chronic edema have a difficult time healing. Rafetto et al. describe that the incidence of VLUs is 70 – 80% of all clinical ulcers, with recurrence rates of 50 – 70% at 6 months.⁸ VLUs pose a significant problem to our population, but new findings indicate that the numbers will continue to increase. The standard of care for VLUs consists of compression. With the recent changes in the Starling principle, it is understood that the lymphatic system is responsible for removing fluid and resolving edema. If a patient has a healthy lymphatic system, edema management will not pose a problem. However, if a patient’s lymphatic system fatigues, fails, or is damaged, any long- standing VLU edema will lead to a condition known as phlebolymphedema. A condition that indicates venous damage, phlebolymphedema when present with ulcers will lead to difficult healing  due  to  the  presence  of  stagnant protein-rich fluid and due to the longstanding fluid volume within the lower extremities. Essentially, the lymphatic system is working overtime and eventually fails. Margolis et al. discuss a prognostic model for VLUs, indicating that a wound that is < 10 cm2 and less than 12 months old at the first visit has a 29% chance of not healing by 24th week of care, while a wound > 10cm2 and > 12 months old has a 78% chance of not healing.⁹ This could be our answer as to why VLU patients with prolonged unresolved edema could have a poor chance of healing. If patients with VLUs have a lymphatic system that fails due to prolonged edema, compression will not suffice as the standard of care. The treatment at this point, along with compression, should be aimed at moving lymph to another quadrant with a normal lymphatic system. A 2022 article indicates that all edema is related to lymphatic dysfunction, whether transient or permanent, thereby creating a lymphedema continuum.¹⁰ Untreated lymphatic dysfunction will also lead to an increase in diffusion distance, thus decreasing the amount of oxygen delivered to the skin and/ or wound.

 

The Impact of CVI

 

In their 2020 study, Dean et al. established that lower-extremity lymphedema is predominantly caused by chronic venous insufficiency (CVI) and not the commonly encountered cancer.¹¹ This also underscores that when the cause of edema is not addressed properly, patients will encounter frequent infections, chronic wounds, and other complications while not allowing oxygen to diffuse adequately. Tests such as transcutaneous oximetry (PtcO2) can assess the peri-wound oxygen tension of wounds. Fife et al. determined oxygen tension < 40mm Hg to be defined as tissue hypoxia.¹²

 

Patients with edema, inflammation, and/ or infection could have initial Ptc02 readings < 30 mm Hg, due to the increased diffusion distance. When  adding  supplemental  oxygen  under normobaric conditions, if the PtcO2 is > 100mm Hg, there could be an edematous condition at fault, as opposed to an arterial condition, decreasing the delivery of O2. Noting the important role of oxygen throughout the healing process, focusing on adequate arterial perfusion and decreasing the diffusion distance of edematous legs can be of value to bringing wounds out of the inflammatory phase and into the proliferative phase. Additionally, wound bed oxygenation can increase by revascularization, debridement of necrotic tissue, address infection, and address edema.

 

A study published in 2003 found that the percent change in wound area at 4 weeks in those who healed was 82%, whereas the percent change in wound area was 25% in those who failed to heal.¹³ The percent change in foot ulcer area after 4 weeks of observation is a robust predictor of healing at 12 weeks. This study concluded that this can serve as a clinical decision point in care for diabetic foot ulcers to identify patients who may not respond to standard care requiring additional treatments. If limited or no progress is made at 4 weeks, it is recommended to reassess the wound for arterial perfusion, infection, and other factors that delay healing and potentially consider the use of advanced modalities.

 

If ischemia impairs the delivery of oxygen, a vascular referral is of importance, whereas edematous lower extremities require appropriate compression to decrease the larger diffusion distance to improve oxygenation.

 

The Emergence of Topical Oxygen Therapy

 

Topical   oxygen   therapy   (TOT) is  another  valuable  option  that  has been available for some time, but early research was lacking. As such, TOT was often labeled as ‘topical hyperbaric oxygen therapy’, which is incorrect based on its function.

More recently, there has been a great deal of available research on the effectiveness of TOT and its ability to help heal chronic wounds. TOT is not likely to replace HBOT, but should continue to produce optimal evidence-based results. What follows is a list of top challenges that exist related to the use of TOT.

 

Top 10 Challenges of Oxygen Therapy

 

The use of TOT at Home Doesn’t Alter Treatment at an Outpatient Wound Clinic

During the past 3 years, I’ve had the opportunity to use long wave infrared thermography and Near Infrared Spectroscopy on chronic hard to heal wounds. Medical thermography has over 800 published articles and this allows me to not only look for physiological anomalies in the nonvisible light spectrum but also to assess tissue oxygenation. These objective findings assist providers with their clinical assessments, while requesting further objective tests, validates treatment interventions and utilized in preventative measures not only for pressure injury but also for patients with diabetes. As we consider chronic wounds to have a decrease in oxygenation in the wound bed, I am also noting a decrease in thermal energy when imaging chronic wounds, classifying them in a hypoperfusion state. Thermographically, it is evident that technology can assist us with determining which wounds may not progress due to a lack of oxygen, whether the lack of oxygen is due to arterial disease of a problem with increased diffusion distance, as in an edematous extremity. In addition, dehiscence of incisions may occur when there’s increased diffusion distance, therefore minimizing the amount of oxygen needed to maintain surgical incision health.

Patients can utilize TOT at home and continue wound care treatments at an outpatient clinic and/ or with home health, without altering the plan of care. Providers can continue treatment, such as debridement and other modalities, just as if they were performing HBOT treatment. The only exception would be negative pressure wound therapy and/ or occlusive dressings, as oxygenation might not reach the wound bed due to the occlusive barrier. To be mindful of successful interventions, chronic wounds could require additional modalities, as long as the basic tenets of wound care have been implemented and not overlooked.

Recent TOT Evidence

There is growing evidence of the benefits of TOT. A sampling of studies includes:

Benefits of TOT

• Evidence of TOT promoting collagen formation and VEGF expression promoting angiogenesis26
• Use of a special probe to measure the superficial pO2 at the center of the wound (2mm depth) after exposure to topical oxygen27
• A comparison of a variety of chronic wounds being treated with HBOT versus TOT for 14 weeks and assessing healing outcomes19
• A study that examined VLUs being treated with TWO2 versus compression28

• A report that TOT can generate sustained increased in wound pO2 supporting angiogenesis and increased VEGF29
• A DFU study noting that at 12 weeks with TWO2 with a mean baseline wound area of 1 cm2, there was a healing rate of 82.4%, with a median of 56 days to heal; versus the control group with a mean baseline wound area of 1.4 cm2, there was a healing rate of 45.5%, with 93 median days to heal in the standard of care group30

• A study of VLUs with > 2 years onset, with no improvement over the previous year, demonstrating improved healing rates and median time to heal when using TWO231

• A multinational, multicenter, randomized, double- blinded, sham-controlled trial supporting cyclical pressurized TOT for the treatment of DFUs32

 

TOT Being Misunderstood

As indicated by a recent consensus statement on guidelines for the use of TOT in the treatment of hard-to-heal wounds²⁵, there’s a growing body of evidence suggesting that topical oxygen is valuable in healing DFUs.

Indications

As with any product, following manufacturer’s indications to ensure proper use is imperative. Indications for TOT includes the use for chronic, hard-to-heal wounds such as DFUs, VLUs, pressure ulcers (stage 3 – 4), and post- surgical and burn wounds. TCOT and/ or CDO list indications to treat such as skin ulcerations resulting from diabetes, venous stasis, post- surgical infections, gangrenous lesions, pressure ulcers, infected residual limbs, skin grafts, burns, and frostbite. Research lists wound types that are indicated and/ or have demonstrated successful outcomes for TOT,²¹ including diabetic ulcers, vascular ulcers, post-surgical infections, pressure injuries, amputations and infected stumps, skin grafts, ischemic tissues, burns, and frostbite. The utilization of various products and modalities as intended could alter the healing trajectory of chronically stalled hard-to-heal wounds.

Understanding TOT Contraindications

Contraindications for topical oxygen include:

Contraindications

• Inadequate perfusion to support wound healing
• Acute thrombophlebitis
• Ulcers due to Raynaud’s disease
• Presence of necrotic tissue if debridement is not Necrotic wounds with eschar or slough
• Wounds with fistulas or deep sinus tracts with unknown depth

• Wound dressings that are occlusive, including the use of petrolatum products

 

Also consider including untreated osteomyelitis, and malignant wounds.

TOT Safety & Precautions

Although there are benefits for using oxygen in the wound management field, the hazards and side effects of oxygen must be considered. Oxygen should be administered cautiously, as with any medication.

Generally, oxygen supports combustion, so smoking should not be permitted near the source of oxygen and it should be kept away from any heat source. Ensure that any electrical equipment involved is in safe working condition. Unlike precautions and possible complications with HBOT, TOT presents no risk for oxygen toxicity, ear barotrauma, pneumothorax, temporary change in vision, or a decrease in glucose levels. Devices that are worn continuously are recommended to be disconnected during a shower or bath. A recent systematic review and meta-analysis study on the efficacy and safety of TOT for DFUs concluded that TOT is effective and safe for chronic DFUs.²³ Another 2022 study describes TOT to be considered safe with no known risks to the patient above moist wound therapy alone with no reported serious adverse events or reactions in the literature.^21,24

Failing to Recognize and Address Importance of Oxygen

Oxygen levels affect the quality of new blood vessel growth, collagen formation, and the signaling of growth factors. Chronic wounds are found to have low oxygen levels. Adequate circulation should be determined with objective testing in lower-extremity wounds to ensure there’s oxygenation and nutrients reaching tissue. The importance of oxygen is also recognized in the numerous biological processes occurring throughout the healing cascade, such as cell proliferation, angiogenesis, protein synthesis, and resistance to infection, which are required for restoration of tissue function and integrity.^21,22

Uncertainty About TOT Changing Wound Environment

It is known that chronic wound beds have higher-than-normal pH levels. Dissemond et al. acknowledge that pH values influence wound healing and that insight into this allows for more individualized therapy.¹⁴ Percival et al. mention how pH has been shown to affect matrix metalloproteinase activity (MMP), tissue inhibitors of MMP, fibroblast activity, keratinocyte proliferation, microbial proliferation, and immunological responses in a wound.¹⁵

The pH of chronic wounds has been described to be between 7.15 and 8.9 (7 being neutral, above that as alkaline and below as acidic). For perspective, a pH of 4 is 10 times as acidic as a pH of 5, representing a 10-fold in H+ concentrations.¹⁶ The same study describes how pH level decreased as the wound progresses.¹⁷ Since there’s a higher number of MMP and necrotic tissue in the wound bed, there’s also an increased metabolic load resulting in tissue hypoxia.¹⁸

The pH also influences oxygen release to the tissue. By lowering the pH, there’s an increase of oxygen diffusion. Tissue oxygen tension (pO2) > 40mmHg increases the likelihood of healing. Gordillo demonstrated that tissues must have a pO2 of at least 40 mmHg to promote the production of VEGF, collagen, and restore angiogenesis.¹⁹ Fries et al. utilized a special probe at a depth of 2mm in the center of a wound, to determine if TOT raises pO2 levels. Another study utilized an oxygen aerosol delivery system, which could continue to answer questions on oxygenation penetration.²⁰

Understanding Available TOT

There are various types of topical oxygen therapy (TOT) delivery systems, including intermittent TOT, continuous TOT (TCOT), and continuous diffusion of oxygen (CDO), to deliver oxygen to the tissue. There are differences, however, in how oxygen is supplied to the wound bed and the equipment. TOT uses a high-flow oxygen concentrator connected to a disposable boot or bag, supplying oxygen to the area for 90 minutes, five days per week. The pressure on one device that’s available cannot be controlled, while the other device can control the pressure from 0 – 50 mmHg to help oxygen diffusion to the wound bed. The concentrator is connected to a power source and it’s capable of being used at multiple settings, including the patient’s home. The patient will be immobile during therapy. While oxygen could desiccate a wound bed, a humidifier is utilized to maintain the moisture level inside this boot or bag. Oxygen transfer requires the wound to be moist. One product utilizes non- contact cyclical compression to aid in edema management and the use of humidification, to maintain a moist wound barrier to aid in oxygen diffusion while preventing desiccation.

TCOT uses oxygen generators to continuously provide oxygen from the air to the wound 24 hours per day, 7 days per week. Tubing can be placed within a wound dressing. This continuous system requires a minimum relative humidity level and the level of humidity must be met for normal operation. CDO is a lightweight, handheld device using an oxygen generator providing continuous delivery of oxygen to the wound bed. It delivers oxygen via a cannula that is placed under a moist wound dressing indicated for 24 hours, 7 days per week therapy time. There are two types of CDO systems available: CDO with oxygen distribution system. These systems will produce oxygen even at lower levels of humidity.

Realizing TOT is Not HBOT

Topical oxygen is not and should not be classified in the same category as HBOT, nor ‘soft’ or ‘mild’ chambers. Although HBOT and TOT interventions deliver oxygen to the wound bed, HBOT mechanism of action is to deposit an increase of oxygen to the wound bed, HBOT mechanism of action is to deposit an increase of oxygen to the wound through the plasma as the patient breathes 100% oxygen. On the contrary, TOT is diffusing oxygen across the wound bed and can be utilized in various settings, including the patient’s home, making it convenient when there are barriers such as lack of transportation, rising gasoline prices, the pandemic, lack of resources, and no access to advanced modalities.

Topical oxygen pressures are slightly higher than normobaric pressure, equivalent up to 1.1 atmosphere absolute (ATA). HBOT pressures will be higher than normobaric pressures consisting of >1.4 ATA with treatments typically ranging from 2-3.0 ATA. There’s data indicating the effectiveness of TOT, especially for treating DFUs. But if the goal is to increase the tissue pO2 to a hyperoxygenated level systemically, HBOT will be the choice.

References

1. Castilla DM, Liu Z-J, Velazquez Oxygen: implications for wound healing. Adv Wound Care (New Rochelle). 2012;1(6):225-30.
2. MacIntyre Tissue hypoxia: implications for the respiratory clinician. Respir Care. 2014;59(10):1590-6.
3. Aviles F, Whitten-Byles D. Oxygen & wound healing: going beyond hyperbaric therapy. TWC. 2018;12(11):14-21.
4. Hyperbaric oxygen therapy: get the FDA. 2021. Accessed online: www.fda.gov/ consumers/consumer-updates/hyperbaric-oxygen-therapy-get-facts
5. Nussbaum SR, Carter MJ, Fife CE, et al. An economic evaluation of the impact, cost, and medicare policy implications of chronic nonhealing Value Health. 2018;21:27-32.
6. Gethin, (2007). The significance of surface pH in chronic wounds. Wounds UK. 3.
7. Cole Wound care update: the role of topical oxygen therapy in the treatment of wounds. Lower Extremity Review. 2020; 12(5):35-8.
8. RaffettoJD, Ligi D, ManiscalcoR, KhalilRA,Mannello, F. Why venous leg ulcers have difficulty healing: overview on pathophysiology, clinical consequences, and treatment. J Clin 2020;10(1):29.
9. Margolis DJ, Allen-Taylor L, HoffstadO, BerlinJA. The accuracy of venous leg ulcer prognostic models in a wound care Wound RepairRegen. 2004;12(2):163-8.
10. HettrickH, Aviles Jr. F. All edema is lymphedema: progressing lymphedema and wound management to an integrated model of Wound ManagPrev. 2022;68(1):8-15.
11. DeanSM, ValentiE, HockK, LefflerJ, CompstonA, AbrahamWT. The clinical characteristics of lower extremity lymphedema in 440 patients. J VascSurgVenous LymphatDisord. 2020;8(5):851-9.
12. FifeCE, SmartDR, SheffieldPJ, HopfHW, HawkinsG, Clarke Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based on evidence.Undersea HyperbMed. 2009;36(1),43-53.
13. Sheehan P, Jones P, Giurini JM, Caselli A, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Plastic and Reconstructive Surgery. 2006 Jun;117(7 Suppl):239S-244S. DOI: 1097/01.prs.0000222891.74489.33. PMID: 16799391.
14. Dissemond, , Witthoff, M., Brauns, T. C., Haberer, D., &Goos, M. (2003). pH-Wertdes Milieus chronischerWunden. UntersuchungenimRahmeneinermodernenWundtherapie [pH values in chronic wounds. Evaluation during modern wound therapy]. Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandteGebiete, 54(10), 959–965.

15. Percival, L., McCarty, S., Hunt, J. A., & Woods, E. J. (2014). The effects of pH on wound healing, biofilms, and antimicrobial efficacy. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society, 22(2), 174–186.
16. Tsukada K, Tokunaga K, Iwama T, Mishima Y (1992) The pH changes of pressure ulcers related to the healing process of wounds. Wounds 4(1): 16–20.

17. Solomon E, Schmidt R, Adragna P (1990) Human Anatomy and 2nd International edn. Saunders, USA.
18. Hunt TK, Beckert S (2005) Therapeutical and practical aspects of oxygen in wound In: Lee B (ed) The Wound Management Manual. McGraw-Hill Medical, New York.
19. Gordillo GM, Roy S, Khanna S, et Topical oxygen therapy induces vascular endothelial growth factor expression and improves closure of clinically presented chronic wounds. Clin Exp PharmacolPhysiol2008;35:957–964.
20. Petri M, Stoffels I, Jose J, et Photoacoustic imaging of real-time oxygen changes in chronic leg ulcers after topical application of a haemoglobin spray: a pilot study. J Wound Care. 2016; 25(2):87–91.

21. Oropallo A, Andersen Topical Oxygen. [Updated 2021 Sep 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
22. Oxygen: Implications for Wound Healing Diego M. Castilla,1 Zhao-Jun Liu,1,2 and Omaida C. Velazquez1,2, ADVANCES IN WOUND CARE, VOLUME 1, NUMBER 6 j 225-230 Copyright ª 2012 by Mary Ann Liebert, DOI: 10.1089/wound.2011.031.
23. Sun, K., Li, R., Yang, X. L., & Yuan, L. (2022). Efficacy and safety of topical oxygen therapy for diabetic foot ulcers: An updated systematic review and meta-analysis. International wound journal, 10.1111/iwj.13830. Advance online publication.
24. Kalliainen, K., Gordillo, G. M., Schlanger, R., & Sen, C. K. (2003). Topical oxygen as an adjunct to wound healing: a clinical case series. Pathophysiology : the official journal of the International Society for Pathophysiology, 9(2), 81–87.

25. Serena, E., Andersen, C., Cole, W., Garoufalis, M., Frykberg, R., &Simman, R. (2022). Guidelines for the use of topical oxygen therapy in the treatment of hard-to-heal wounds based on a Delphi consensus. Journal of wound care, 31(Sup3), S20–S24.
26. Scott, G., & Reeves, (2005). 051 Topical Oxygen Alters Angiogenesis Related Growth Factor Expression in Chronic Diabetic Foot Ulcers. Wound Repair and Regeneration, 13(2), A4-A27.

27. Fries RB, Wallace WA, Roy S, et al. Dermal excisional wound healing in pigs following treatment with topically applied pure oxygen. Mutat Res. 2005; 579(1-2):172-81. Epub 2005 Aug 18. PMID: 16105672.
28. Tawfick W, Sultan 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;38:125–132.
29. Gordillo GM, Sen Evidence-based recommendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds 2009;8:105–111.

30. Blackman E, Moore C, Hyatt J, Railton R, Frye Topical wound oxygen therapy in the treatment of severe diabetic foot ulcers: a prospective controlled study. Ostomy Wound Manage 2010; 56:24–31.

31. Tawfick WA, Sultan 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;47:30–37.

32. Frykberg, G., Franks, P. J., Edmonds, M., Brantley, J. N., Téot, L., Wild, T., Garoufalis, M. G., Lee, A. M., Thompson,
33. A., Reach, G., Dove, C. R., Lachgar, K., Grotemeyer, D., Renton, S. C., & TWO2 Study Group (2020). 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, 43(3), 616–624.

Guidance Documents

Reprinted from

      VOLUME 46 | SUPPLEMENT 1

12. Retinopathy, Neuropathy, and Foot Care:

Standards of Care in Diabetes 2023

Nuha A. ElSayed, Grazia Aleppo, Vanita R. Aroda,

Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer Billy S. Collins, Christopher H. Gibbons, John M. Giurini,

Marisa E. Hilliard, Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry,

Priya Prahalad, Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Jennifer K. Sun, and Robert A. Gabbay, on hehalf of the American Diabetes Association

Diabetes Care 2023;46(Suppl. 1):S203-S215 | https://doi.org/10.2337/dc23-S012

ISSN 0149-5992

12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes-2023

Diabetes Care 2023;46(Suppl. 1):5203-5215 I https://doi.org/10.2337/dc23-5012

The American Diabetes Association (ADA) “Standards of Care in Diabetes” in­ cludes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guide­ lines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for up­ dating the Standards of Care annually, or more frequently as warranted. For a de­ tailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

For prevention and management of diabetes complications in children and adoles­ cents, please refer to Section 14, “Children and Adolescents.”

DIABETIC R’ETINOPATHY

Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes, with prevalence strongly related to both the duration of diabetes and the level of glycemic control (1). Diabetic retinopathy is the most frequent cause of new cases of blindness among adults aged 20-74 years in developed countries. Glaucoma, cataracts, and other eye disorders occur earlier and more frequently in people with diabetes.

In addition to diabetes duration, factors that increase the risk of, or are associ­ ated with, retinopathy include chronic hyperglycemia (2,3), nephropathy (4), hyper­ tension (5), and dyslipidemia (6). Intensive diabetes management with the goal of achieving near-normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset and progression of diabetic retinopathy, reduce the need for future ocular surgical procedures, and potentially improve patient-reported visual function (2,7-10). A meta-analysis of data from cardiovascular outcomes studies showed no association between glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatment and retinopathy per se, except through the association between retinopathy and average AlC reduction at the 3-month and 1-year follow­ up. Long-term impact of improved glycemic control on retinopathy was not studied

Nuha A. EISayed, Grazia Aleppo,

Vanita R. Aroda, Raveendhara R. Bannuru, Florence M. Brown, Dennis Bruemmer, Billy 5. Collins, Christopher H. Gibbons, John M. Giurini, Marisa E. Hilliard,

Diana Isaacs, Eric L. Johnson, Scott Kahan, Kamlesh Khunti, Jose Leon, Sarah K. Lyons, Mary Lou Perry, Priya Prahalad,

Richard E. Pratley, Jane Jeffrie Seley, Robert C. Stanton, Jennifer K. Sun, and Robert A. Gabbay, on behalf of the American Diabetes Association

Disclosure information for each author is available at https://dai.org/10.2337/dc23-SDIS.

Suggested citation: EISayed NA, Aleppo G, Aroda VR, et al., American Diabetes Association. 12. Retinopathy, neuropathy, and foot care: Standards of Care in Diabetes-2023. Diabetes Care 2023; 46(Suppl. 1}:5203-5215

© 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www. diabetesjournals.org/journals/pages/license.

in these trials. Retinopathy status should be assessed when intensifying glucose­ lowering therapies such as those using GLP-1 RAs, since rapid reductions in AlC can be associated with initial worsening of retinopathy (11).

Screening

The preventive effects of therapy and the fact that individuals with prolifera­ tive diabetic retinopathy (PDR) or macu­ lar edema may be asymptomatic provide strong support for screening to detect diabetic retinopathy. Prompt diagnosis allows triage of patients and timely in­ tervention that may prevent vision loss in individuals who are asymptomatic despite advanced diabetic eye disease.

Diabetic retinopathy screening should be performed using validated approaches and methodologies. Youth with type 1 or type 2 diabetes are also at risk for compli­ cations and need to be screened for dia­ betic retinopathy (12) (see Section 14, “Children and Adolescents“). If diabetic retinopathy is evident on screening, prompt referral to an ophthalmologist is recom­ mended. Subsequent examinations for individuals with type 1 or type 2 diabe­ tes are generally repeated annually for individuals with minimal to no retinop­ athy. Exams every 1-2 years may be cost-effective after one or more normal eye exams. In a population with well­ controlled type 2 diabetes, there was little risk of development of significant retinopathy within a 3-year interval af­ ter a normal examination (13), and less frequent intervals have been found in simulated modeling to be potentially ef­ fective in screening for diabetic retinop­ athy in individuals without diabetic retinopathy (14). However, it is impor­ tant to adjust screening intervals based on the presence of specific risk factors for retinopathy onset and worsening retinopathy. More frequent examina­ tions by the ophthalmologist will be re­ quired if retinopathy is progressing or risk factors such as uncontrolled hyperglyce­ mia, advanced baseline retinopathy, or diabetic macular edema are present.

Retinal photography with remote read­ ing by experts has great potential to pro­ vide screening services in areas where qualified eye care professionals are not readily available (15-17). High-quality fun­ dus photographs can detect most clinically significant diabetic retinopathy. Interpreta­ tion of the images should be performed by a trained eye care professional. Retinal

photography may also enhance efficiency and reduce costs when the expertise of ophthalmologists can be used for more complex examinations and for therapy (15,18,19). In-person exams are still nec­ essary when the retinal photos are of unacceptable quality and for follow-up if abnormalities are detected. Retinal pho­ tos are not a substitute for dilated com­ prehensive eye exams, which should be performed at least initially and at yearly intervals thereafter or more frequently as recommended by an eye care profes­ sional. Artificial intelligence systems that detect more than mild diabetic retinopa­ thy and diabetic macular edema, autho­ rized for use by the U.S. Food and Drug Administration (FDA), represent an alter­ native to traditional screening approaches

(20). However, the benefits and optimal utilization of this type of screening have yet to be fully determined. Results of all screening eye examinations should be documented and transmitted to the refer­ ring health care professional.

Type 1 Diabetes

Because retinopathy is estimated to take at least 5 years to develop after the on­ set of hyperglycemia, people with type 1 diabetes should have an initial dilated and comprehensive eye exami­ nation within 5 years after the diagnosis of diabetes (21).

Type 2 Diabetes

People with type 2 diabetes who may have had years of undiagnosed diabetes and have a significant risk of prevalent diabetic retinopathy at the time of diag­ nosis should have an initial dilated and comprehensive eye examination at the time of diagnosis.

Pregnancy

Individuals who develop gestational dia­ betes mellitus do not require eye ex­ aminations during pregnancy since they do not appear to be at increased risk of developing diabetic retinopathy during pregnancy (22). However, individuals of childbearing potential with preexisting type 1 or type 2 diabetes who are plan­ ning pregnancy or who have become pregnant should be counseled on the baseline prevalence and risk of devel­ opment and/or progression of diabetic retinopathy. In a systematic review and meta-analysis of 18 observational studies of pregnant individuals with preexisting

type 1 or type 2 diabetes, the prevalence of any diabetic retinopathy and PDR in early pregnancy was 52.3% and 6.1%, re­ spectively. The pooled progression rate per 100 pregnancies for new diabetic reti­ nopathy development was 15.0 (95% Cl

9.9-20.8), worsened nonproliferative

diabetic retinopathy was 31.0 (95% Cl 23.2-39.2), pooled sight-threatening pro­ gression rate from nonproliferative dia­ betic retinopathy to PDR was 6.3 (95% Cl 3.3-10.0), and worsened PDR was 37.0

(95% Cl 21.2-54.0), demonstrating that close follow-up should be maintained during pregnancy to prevent vision loss

(23). In addition, rapid implementation of intensive glycemic management in the setting of retinopathy is associ­ ated with early worsening of retinop­ athy (24).

A systematic review and meta-analysis and a controlled prospective study dem­ onstrate that pregnancy in individuals with type 1 diabetes may aggravate reti­ nopathy and threaten vision, especially when glycemic control is poor or retinop­ athy severity is advanced at the time of conception (23,24). Laser photocoagu­ lation surgery can minimize the risk of vision loss during pregnancy for individ­ uals with high-risk PDR or center-involved diabetic macular edema (24). Anti-vascular endothelial growth factor (anti-VEGF) med­ ications should not be used in pregnant individuals with diabetes because of the­ oretical risks to the vasculature of the developing fetus.

Treatment

Two of the main motivations for screen­ ing for diabetic retinopathy are to pre­ vent loss of vision and to intervene with treatment when vision loss can be pre­ vented or reversed.

Photocoagulation Surgery

Two large trials, the Diabetic Retinopa­ thy Study (DRS) in individuals with PDR and the Early Treatment Diabetic Reti­ nopathy Study (ETDRS) in individuals with macular edema, provide the strongest support for the therapeutic benefits of photocoagulation surgery. The DRS (25) showed in 1978 that panretinal photo­ coagulation surgery reduced the risk of severe vision loss from PDR from 15.9% in untreated eyes to 6.4% in treated eyes with the greatest benefit ratio in those with more advanced baseline disease (disc neovascularization or vitre­ ous hemorrhage). In 1985, the ETDRS also verified the benefits of panretinal photocoagulation for high-risk PDR and in older-onset individuals with severe

nonproliferative diabetic retinopathy or less-than-high-risk PDR. Panretinal laser photocoagulation is still commonly used to manage complications of dia­ betic retinopathy that involve retinal neovascularization and its complications. A more gentle, macular focal/grid laser photocoagulation technique was shown in the ETDRS to be effective in treating eyes with clinically significant macular edema from diabetes (26), but this is now largely considered to be second-line treatment for diabetic macular edema.

Anti-Vascular Endothelial Growth Factor Treatment

Data from the DRCR Retina Network

(formerly the Diabetic Retinopathy Clini­ cal Research Network) and others dem­ onstrate that intravitreal injections of anti–VEGF agents are effective at re­ gressing proliferative disease and lead to noninferior or superior visual acuity outcomes compared with panretinal la­ ser over 2 years of follow-up (27,28). In addition, it was observed that individuals treated with ranibizumab tended to have less peripheral visual field loss, fewer vitrectomy surgeries for secondary com­ plications from their proliferative dis­ ease, and a lower risk of developing diabetic macular edema. However, a potential drawback in using anti-VEGF therapy to manage proliferative disease is that patients were required to have a greater number of visits and received a greater number of treatments than is typically required for management with panretinal laser, which may not be opti­ mal for some individuals. The FDA has approved aflibercept and ranibizumab for the treatment of eyes with diabetic retinopathy. Other emerging therapies for retinopathy that may use sustained intravitreal delivery of pharmacologic agents are currently under investigation. Anti-VEGF treatment of eyes with non­ proliferative diabetic retinopathy has been demonstrated to reduce subse­ quent development of retinal neovascu­ larization and diabetic macular edema but has not been shown to improve visual outcomes over 2 years of therapy and therefore is not routinely recom­ mended for this indication (29).

While the ETDRS (26) established the

benefit of focal laser photocoagulation surgery in eyes with clinically significant macular edema (defined as retinal edema

located at or threatening the macular center), current data from well-designed clinical trials demonstrate that intravi­ treal anti-VEGF agents provide a more effective treatment plan for center­ involved diabetic macular edema than monotherapy with laser (30,31). Most patients require near-monthly adminis­ tration of intravitreal therapy with anti­ VEGF agents during the first 12 months of treatment, with fewer injections needed in subsequent years to maintain remission from central-involved diabetic macular edema. There are currently three anti­ VEGF agents commonly used to treat eyes with central-involved diabetic macular edema-bevacizumab, ranibizumab, and atlibercept (1)-and a comparative effec­ tiveness study demonstrated that atliber­ cept provides vision outcomes superior to those of bevacizumab when eyes have moderate visual impairment (vision of 20/50 or worse) from diabetic macular edema (32). For eyes that have good vision (20/25 or better) despite diabetic macular edema, close monitoring with initiation of anti-VEGF therapy if vision worsens provides similar 2-year vision outcomes compared with immediate initi­ ation of anti-VEGF therapy (33).

Eyes that have persistent diabetic macu­ lar edema despite anti-VEGF treatment may benefit from macular laser photo­ coagulation or intravitreal therapy with corticosteroids. Both of these therapies are also reasonable first-line approaches for individuals who are not candidates for anti-VEGF treatment due to systemic considerations such as pregnancy.

Adjunctive Therapy

Lowering blood pressure has been shown to decrease retinopathy progression, although tight targets (systolic blood pressure <120 mmHg) do not impart additional benefit (8). In individuals with dyslipidemia, retinopathy progression may be slowed by the addition of feno­ fibrate, particularly with very mild non­ proliferative diabetic retinopathy at baseline (34,35).

NEUROPATHY

Screening

Diabetic neuropathies are a heteroge­ neous group of disorders with diverse clinical manifestations. The early rec­ ognition and appropriate management of neuropathy in people with diabetes is important. Points to be aware of in­ clude the following:

1. Diabetic neuropathy is a diagnosis of exclusion. Nondiabetic neuropa­ thies may be present in people with diabetes and may be treatable.
2. Up to 50% of diabetic peripheral neu­ ropathy may be asymptomatic. If not recognized and if preventive foot care is not implemented, people with dia­ betes are at risk for injuries as well as diabetic foot ulcers and amputations.
3. Recognition and treatment of au-

symptoms, reduce sequelae, and im­ prove quality of life.

Specific treatment to reverse the un­ derlying nerve damage is currently not available. Glycemic control can effec­ tively prevent diabetic peripheral neu­ ropathy (DPN) and cardiac autonomic neuropathy (CAN) in type 1 diabetes (36,37) and may modestly slow their progression in type 2 diabetes (38), but it does not reverse neuronal loss. Treat­ ments of other modifiable risk factors (including lipids and blood pressure) can aid in prevention of DPN progression in type 2 diabetes and may reduce disease progression in type 1 diabetes (39-41). Therapeutic strategies (pharmacologic and nonpharmacologic) for the relief of painful DPN and symptoms of autonomic neurop­ athy can potentially reduce pain (42) and improve quality of life.

Diagnosis

Diabetic Peripheral Neuropathy

Individuals with a type 1 diabetes dura­ tion 2′.5 years and all individuals with type 2 diabetes should be assessed an­ nually for DPN using the medical history and simple clinical tests (42). Symptoms vary according to the class of sensory fi­ bers involved. The most common early symptoms are induced by the involve­ ment of small fibers and include pain and dysesthesia (unpleasant sensations of burning and tingling). The involve­ ment of large fibers may cause numb­ ness and loss of protective sensation (LOPS). LOPS indicates the presence of distal sensorimotor polyneuropathy and is a risk factor for diabetic foot ulceration. The following clinical tests may be used to assess small- and large-fiber func­ tion and protective sensation:

1. Small-fiber function: pinprick and temperature sensation.
2. Large-fiber function: lower-extremity

reflexes, vibration perception, and 10-g monofilament.

1. Protective sensation: 10-g mono­ filament.

These tests not only screen for the presence of dysfunction but also predict future risk of complications. Electrophysi­ ological testing or referral to a neurolo-

tonomic neuropathy may improve gist is rarely needed, except in situations

where the clinical features are atypical or the diagnosis is unclear.

In all people with diabetes and DPN, causes of neuropathy other than diabetes should be considered, including toxins (e.g., alcohol), neurotoxic medica­ tions (e.g., chemotherapy), vitamin B12 deficiency, hypothyroidism, renal disease, malignancies (e.g., multiple myeloma, bronchogenic carcinoma), infections (e.g., HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis (43). See the American Diabetes Association position statement “Diabetic Neuropathy” for more details (42).

Diabetic Autonomic Neuropathy

Individuals who have had type 1 diabe­ tes for 2:5 years and all individuals with type 2 diabetes should be assessed an­ nually for autonomic neuropathy (42). The symptoms and signs of autonomic neuropathy should be elicited carefully during the history and physical examina­ tion. Major clinical manifestations of diabetic autonomic neuropathy include resting tachycardia, orthostatic hypoten­ sion, gastroparesis, constipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating. Screening for symp­ toms of autonomic neuropathy includes asking about symptoms of orthostatic in­ tolerance (dizziness, lightheadedness, or weakness with standing), syncope, exer­ cise intolerance, constipation, diarrhea, urinary retention, urinary incontinence, or changes in sweat function. Further testing can be considered if symptoms are present and will depend on the end organ involved but might include cardio­ vascular autonomic testing, sweat testing, urodynamic studies, gastric emptying, or endoscopy/colonoscopy. Impaired coun­ terregulatory responses to hypoglycemia in type 1 and type 2 diabetes can lead to hypoglycemia unawareness but are not directly linked to autonomic neuropathy.

Cardiovascular Autonomic Neuropathy. CAN is associated with mortality independently of other cardiovascular risk factors (44,45). In its early stages, CAN may be completely asymptomatic and detected only by decreased heart rate variability with deep breathing. Advanced disease may be associated with resting tachycardia (>100 bpm) and orthostatic hypoten­ sion (a fall in systolic or diastolic blood

pressure by >20 mmHg or >10 mmHg, respectively, upon standing without an appropriate increase in heart rate). CAN treatment is generally focused on allevi­ ating symptoms.

Gastrointestinal Neuropathies. Gastrointes­ tinal neuropathies may involve any por­ tion of the gastrointestinal tract, with manifestations including esophageal dysmotility, gastroparesis, constipation, diarrhea, and fecal incontinence. Gastro­ paresis should be suspected in individu­ als with erratic glycemic control or with upper gastrointestinal symptoms with­ out another identified cause. Exclusion of reversible/iatrogenic causes such as medi­ cations or organic causes of gastric outlet obstruction or peptic ulcer disease (with esophagogastroduodenoscopy or a barium study of the stomach) is needed before considering a diagnosis of or specialized testing for gastroparesis. The diagnostic gold standard for gastroparesis is the measurement of gastric emptying with scintigraphy of digestible solids at 15-min intervals for 4 h after food intake. The use of ¹³C octanoic acid breath test is an ap­ proved alternative.

Genitourinary Disturbances. Diabetic auto­ nomic neuropathy may also cause geni­ tourinary disturbances, including sexual dysfunction and bladder dysfunction. In men, diabetic autonomic neuropathy may cause erectile dysfunction and/or retrograde ejaculation (42). Female sex­ ual dysfunction occurs more frequently in those with diabetes and presents as decreased sexual desire, increased pain during intercourse, decreased sexual arousal, and inadequate lubrication (46). Lower urinary tract symptoms manifest as urinary incontinence and bladder dys­ function (nocturia, frequent urination, urination urgency, and weak urinary stream). Evaluation of bladder func­ tion should be performed for individuals with diabetes who have recurrent uri­ nary tract infections, pyelonephritis, in­ continence, or a palpable bladder.

Treatment

Glycemic Control

Near-normal glycemic control, imple­ mented early in the course of diabetes, has been shown to effectively delay or prevent the development of DPN and CAN in people with type 1 diabetes (47-50). Although the evidence for the benefit of near-normal glycemic control is not as strong that for type 2 diabetes, some studies have demonstrated a mod­ est slowing of progression without rever­ sal of neuronal loss (38,51). Specific glucose-lowering strategies may have dif­ ferent effects. In a post hoc analysis, par­ ticipants, particularly men, in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial treated with insulin sensitizers had a lower inci­ dence of distal symmetric polyneuropathy over 4 years than those treated with insu­ lin/sulfonylurea (52). Additionally, recent evidence from the Action to Control Car­ diovascular Risk in Diabetes (ACCORD) trial showed clear benefit of intensive glucose and blood pressure control on the preven­ tion of CAN in type 2 diabetes (53).

Lipid Control

Dyslipidemia is a key factor in the development of neuropathy in people with type 2 diabetes and may contrib­ ute to neuropathy risk in people with type 1 diabetes (54,55). Although the ev­ idence for a relationship between lipids

and neuropathy development has be­ come increasingly clear in type 2 diabe­ tes, the optimal therapeutic intervention has not been identified. Positive effects of physical activity, weight loss, and bar­ iatric surgery have been reported in indi­ viduals with DPN, but use of conventional lipid-lowering pharmacotherapy (such as statins or fenofibrates) does not appear to be effective in treating or preventing DPN development (56).

Blood Pressure Control

There are multiple reasons for blood pressure control in people with diabetes, but neuropathy progression (especially in type 2 diabetes) has now been added to this list. Although data from many studies have supported the role of hy­ pertension in risk of neuropathy devel­ opment, a recent meta-analysis of data from 14 countries in the International Prevalence and Treatment of Diabetes and Depression (INTERPRET-DD) study re­ vealed hypertension as an independent risk of DPN development with an odds ratio of 1.58 (57). In the ACCORD trial, intensive blood pressure intervention decreased CAN risk by 25% (53).

Neuropathic Pain

Neuropathic pain can be severe and can impact quality of life, limit mobility, and contribute to depression and social dys­ function (58). No compelling evidence exists in support of glycemic control or lifestyle management as therapies for neuropathic pain in diabetes or predia­ betes, which leaves only pharmaceutical interventions (59). A recent guideline by the American Academy of Neurology rec­ ommends that the initial treatment of pain should also focus on the concurrent treatment of both sleep and mood dis­ orders because of increased frequency of these problems in individuals with DPN (60).

A number of pharmacologic therapies exist for treatment of pain in diabetes. The American Academy of Neurology update suggested that gabapentinoids, serotonin-norepinephrine reuptake inhibi­ tors (SNRls), sodium channel blockers, tricyclic antidepressants (TCAs), and SNRI/ opioid dual-mechanism agents could all be considered in the treatment of pain in DPN (60). These American Academy of Neurology recommendations offer a sup­ plement to a recent American Diabetes Association pain monograph, although

some areas of disagreement exist, particu­ larly around SNRl/opioid dual-mechanism agents (61). A recent head-to-head trial suggested therapeutic equivalency for TCAs, SNRls, and gabapentinoids in the treatment of pain in DPN (62). The trial also supported the role of combination therapy over monotherapy for the treat­ ment of pain in DPN.

Gabapentinoids. Gabapentinoids include

several calcium channel a2-o subunit li­ gands. Eight high-quality studies and seven medium-quality studies support the role of pregabalin in treatment of pain in DPN. One high-quality study and many small studies support the role of gabapentin in the treatment of pain in DPN. Two medium-quality studies suggest that micro­ gabalin has a small effect on pain in DPN

(60). Adverse effects may be more severe in older individuals (63) and may be at­ tenuated by lower starting doses and more gradual titration.

SNRls. SNRls include duloxetine, venla­

faxine, and desvenlafaxine, all selective SNRls. Two high-quality studies and five medium-quality studies support the role of duloxetine in the treatment of pain in DPN. A high-quality study supports the role of venlafaxine in the treatment of pain in DPN. Only one medium-quality study sup­ ports a possible role for desvenlafaxine for treatment of pain in DPN (60). Adverse events may be more severe in older peo­ ple but may be attenuated with lower doses and slower titration of duloxetine. Tapentadol and Tramadol. Tapentadol and tramadol are centrally acting opioid anal­ gesics that exert their analgesic effects through both µ-opioid receptor agonism and norepinephrine and serotonin reuptake inhibition. SNRl/opioid agents are probably effective in the treatment of pain in DPN. However, the use of any opioids for man­ agement of chronic neuropathic pain carries the risk of addiction and should be avoided. Tricyclic Antidepressants. Tricyclic anti­ depressants have been studied for treat­ ment of pain, and most of the relevant data was acquired from trials of ami­ triptyline and include two high-quality studies and two medium-quality stud­ ies supporting the treatment of pain in DPN (60,62). Anticholinergic side effects may be dose limiting and restrict use in individuals 2′.65 years of age.

Sodium Channel Blockers. Sodium channel blockers include lamotrigine, lacosamide, oxcarbazepine, and valproic acid. Five medium-quality studies support the role

of sodium channel blockers in treating pain in DPN (60).

Capsaicin. Capsaicin has received FDA ap­ proval for treatment of pain in DPN using an 8% patch, with one high-quality study reported. One medium-quality study of 0.075% capsaicin cream has been re­ ported. In patients with contraindica­ tions to oral pharmacotherapy or who prefer topical treatments, the use of topical capsaicin can be considered.

Carbamazepine and a-Lipoic Acid. Carba­

mazepine and a-lipoic acid, although not approved for the treatment of painful DPN, may be effective and considered for the treatment of painful DPN (41,54,56).

Orthostatic Hypotension

Treating orthostatic hypotension is chal­ lenging. The therapeutic goal is to mini­ mize postural symptoms rather than to restore normotension. Most patients re­ quire both nonpharmacologic measures (e.g., ensuring adequate salt intake, avoid­ ing medications that aggravate hypoten­ sion, or using compressive garments over the legs and abdomen) and pharmaco­ logic measures. Physical activity and ex­ ercise should be encouraged to avoid deconditioning, which is known to ex­ acerbate orthostatic intolerance, and volume repletion with fluids and salt is critical. There have been clinical studies that assessed the impact of an approach incorporating the aforementioned non­ pharmacologic measures. Additionally, supine blood pressure tends to be much higher in these individuals, often requir­ ing treatment of blood pressure at bed­ time with shorter-acting drugs that also affect baroreceptor activity such as guan­ facine or clonidine, shorter-acting calcium blockers (e.g., isradipine), or shorter­ acting [3-blockers such as atenolol or metoprolol tartrate. Alternatives can in­ clude enalapril if an individual is unable to tolerate preferred agents (64-66). Midodrine and droxidopa are approved by the FDA for the treatment of ortho­ static hypotension.

Gastroparesis

Treatment for diabetic gastroparesis may be very challenging. A low-fiber, low-fat eating plan provided in small frequent meals with a greater proportion of liquid calories may be useful (67-69). In addi­ tion, foods with small particle size may improve key symptoms (70). With­ drawing drugs with adverse effects on

gastrointestinal motility, including opioids, anticholinergics, tricyclic antidepressants, GLP-1 RAs, and pramlintide, may also improve intestinal motility (67,71). How­ ever, the risk of removal of GLP-1 RAs should be balanced against their potential benefits. In cases of severe gastroparesis, pharmacologic interventions are needed. Only metoclopramide, a prokinetic agent, is approved by the FDA for the treatment of gastroparesis. However, the level of evidence regarding the benefits of meto­ clopramide for the management of gas­ troparesis is weak, and given the risk for serious adverse effects (extrapyramidal signs such as acute dystonic reactions, drug-induced parkinsonism, akathisia, and tardive dyskinesia), its use in the treat­ ment of gastroparesis beyond 12 weeks is no longer recommended by the FDA. It should be reserved for severe cases that are unresponsive to other thera­ pies (71). Other treatment options in­ clude domperidone (available outside the U.S.) and erythromycin, which is only effective for short-term use due to tachy­ phylaxis (72,73). Gastric electrical stimula­ tion using a surgically implantable device has received approval from the FDA, although its efficacy is variable and use is limited to individuals with severe symp­ toms that are refractory to other treat­ ments (74).

Erectile Dysfunction

In addition to treatment of hypogonadism if present, treatments for erectile dys­ function may include phosphodiester­ ase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses. As with DPN treatments, these interventions do not change the underlying pathol­ ogy and natural history of the disease process but may improve a person’s qual­ ity of life.

FOOT CARE

Foot ulcerations and amputations are common complications associated with diabetes. These may be the consequences of several factors, including peripheral neuropathy, peripheral arterial disease (PAD), and foot deformities. They rep­ resent major causes of morbidity and mortality in people with diabetes. Early recognition of at-risk feet, preulcerative lesions, and prompt treatment of ulcer­ ations and other lower-extremity com­ plications can delay or prevent adverse outcomes.

Early recognition requires an under­

standing of those factors that put peo­ ple with diabetes at increased risk for ulcerations and amputations. Factors that are associated with the at-risk foot include the following:

1. • Poor glycemic control
   • Peripheral neuropathy/LOPS
   • PAD
   • Foot deformities (bunions, hammer- toes, Charcot joint, etc.)
   • Preulcerative corns or calluses
   • Prior ulceration
   • Prior amputation
   • Smoking
   • Retinopathy
   • Nephropathy (particularly individuals on dialysis or posttransplant)

Identifying the at-risk foot begins with a detailed history documenting diabetes control, smoking history, exercise toler­ ance, history of claudication or rest pain, and prior ulcerations or amputations. A thorough examination of the feet should be performed annually in all people with diabetes and more frequently in at-risk individuals (75). The examination should include assessment of skin integrity, as­ sessment for LOPS using the 10-g mono­ filament along with at least one other neurological assessment tool, pulse ex­ amination of the dorsalis pedis and pos­ terior tibial arteries, and assessment for foot deformities such as bunions, ham­ mertoes, and prominent metatarsals, which increase plantar foot pressures and increase risk for ulcerations. At-risk individuals should be assessed at each visit and should be referred to foot care specialists for ongoing preventive care and surveillance. The physical examina­ tion can stratify patients into different categories and determine the frequency of these visits (76) (Table 12.1).

Evaluation for Loss of Protective Sensation

The presence of peripheral sensory neu­ ropathy is the single most common com­ ponent cause for foot ulceration. In a multicenter trial, peripheral neuropathy was found to be a component cause in 78% of people with diabetes with ulcer­ ations and that the triad of peripheral sensory neuropathy, minor trauma, and foot deformity was present in >63% of participants (77). All people with dia­ betes should undergo a comprehensive foot examination at least annually, or

more frequently for those in higher-risk categories (75,76).

LOPS is vital to risk assessment. One of the most useful tests to determine LOPS is the 10-g monofilament test. Studies have shown that clinical exami­ nation and the 10-g monofilament test are the two most sensitive tests in iden­ tifying the foot at risk for ulceration

(78). The monofilament test should be performed with at least one other neu­ rologic assessment tool (e.g., pinprick, temperature perception, ankle reflexes, or vibratory perception with a 128-Hz tuning fork or similar device). Absent monofilament sensation and one other abnormal test confirms the presence of LOPS. Further neurological testing, such as nerve conduction, electromyography, nerve biopsy, or intraepidermal nerve fi­ ber density biopsies, are rarely indicated for the diagnosis of peripheral sensory neuropathy (42).

Evaluation for Peripheral Arterial Disease

Initial screening for PAD should include a history of leg fatigue, claudication, and rest pain relieved with dependency. Physical examination for PAD should include assessment of lower-extremity pulses, capillary refill time, rubor on dependency, pallor on elevation, and ve­ nous filling time (75,79). Any patient ex­ hibiting signs and symptoms of PAD should be referred for noninvasive arte­ rial studies in the form of Doppler ultra­ sound with pulse volume recordings. While ankle-brachia! indices will be calculated, they should be interpreted carefully, as they are known to be inac­ curate in people with diabetes due to

noncompressible vessels. Toe systolic blood pressure tends to be more accurate. Toe systolic blood pressures <30 mmHg are suggestive of PAD and an inability to heal foot ulcerations (80). Individuals with abnormal pulse volume recording tracings and toe pressures <30 mmHg with foot ulcers should be referred for immediate vascular evaluation. Due to the high prevalence of PAD in people with dia­ betes, it has been recommended by the Society for Vascular Surgery and the American Pediatric Medical Associa­ tion in their 2016 guidelines that all people with diabetes >50 years of age should undergo screening via noninva­ sive arterial studies (79,81). If nor­ mal, these should be repeated every 5 years (79).

Patient Education

All people with diabetes (and their families), particularly those with the aforementioned high-risk conditions, should receive general foot care edu­ cation, including appropriate manage­ ment strategies (82-84). This education should be provided to all newly diag­ nosed people with diabetes as part of an annual comprehensive examination and to individuals with high-risk conditions at every visit. Recent studies have shown that while education improves knowl­ edge of diabetic foot problems and self­ care of the foot, it does not improve behaviors associated with active participa­ tion in their overall diabetes care and to achieve personal health goals (85). Evi­ dence also suggests that while patient and family education are important, the knowledge is quickly forgotten and needs to be reinforced regularly (86).

Table 12.1-lnternational Working Group on the Diabetic Foot risk stratification system and corresponding foot screening frequency Category Ulcer risk Characteristics Examination frequency* 0 Very low No LOPS and No PAD Annually
1	Low	LOPS or PAD	Every 6-12 months
2	Moderate	LOPS + PAD, or LOPS + foot deformity, or PAD + foot deformity	Every 3-6 months
3 High LOPS or PAD and one or more of the following: Every 1-3 months History of foot ulcer Amputation (minor or major) End-stage renal disease Adapted with permission from Schaper et al. (76). LOPS, loss of protective sensation; PAD, peripheral artery disease. *Examination frequency suggestions are based on expert opinion and patient-centered requirements.

Individuals considered at risk should understand the implications of foot de­ formities, LOPS, and PAD; the proper care of the foot, including nail and skin care; and the importance of foot inspec­ tions on a daily basis. Individuals with LOPS should be educated on appropriate ways to examine their feet (palpation or visual inspection with an unbreakable mirror) for daily surveillance of early foot problems. Patients should also be educated on the importance of refer­ rals to foot care specialists. A recent study showed that people with diabetes and foot disease lacked awareness of their risk status and why they were be­ ing referred to a multidisciplinary team of foot care specialists. Further, they ex­ hibited a variable degree of interest in learning further about foot complica­ tions (87).

Patients’ understanding of these issues

and their physical ability to conduct proper foot suNeillance and care should be as­ sessed. Those with visual difficulties, physi­ cal constraints preventing movement, or cognitive problems that impair their ability to assess the condition of the foot and to institute appropriate responses will need other people, such as family members, to assist with their care.

The selection of appropriate footwear and footwear behaviors at home should also be discussed (e.g., no walking barefoot, avoiding open-toed shoes). Therapeutic footwear with custom-made orthotic devices have been shown to re­ duce peak plantar pressures (84). Most studies use reduction in peak plantar pressures as an outcome as opposed to ulcer prevention. Certain design features of the orthoses, such as rocker soles and metatarsal accommodations, can reduce peak plantar pressures more significantly than insoles alone. A systematic review, however, showed there was no signifi­ cant reduction in ulcer incidence after

18 months compared with standard insoles and extra-depth shoes. Fur­ ther, it was also noted that evidence to prevent first ulcerations was non­ existent (88).

Treatment

Treatment recommendations for people with diabetes will be determined by their risk category. No-risk or low-risk individuals can often be managed with

education and self-care. People in the moderate- to high-risk category should be referred to foot care specialists for further evaluation and regular surveil­ lance as outlined in Table 12.1. This in­ cludes individuals with LOPS, PAD, and/ or structural foot deformities, such as Charcot foot, bunions, or hammertoes. Individuals with any open ulceration or unexplained swelling, erythema, or in­ creased skin temperature should be re­ ferred urgently to a foot care specialist or multidisciplinary team.

Initial treatment recommendations should include daily foot inspection, use of moisturizers for dry, scaly skin, and avoidance of self-care of ingrown nails and calluses. Well-fitted athletic or walking shoes with customized pressure­ relieving orthoses should be part of ini­ tial recommendations for people with increased plantar pressures (as demon­ strated by plantar calluses). Individuals with deformities such as bunions or hammertoes may require specialized footwear such as extra-depth shoes. Those with even more significant de­ formities, as in Charcot joint disease, may require custom-made footwear.

Special consideration should be given to individuals with neuropathy who pre­ sent with a warm, swollen, red foot with or without a history of trauma and without an open ulceration. These indi­ viduals require a thorough workup for possible Charcot neuroarthropathy (89). Early diagnosis and treatment of this condition is of paramount importance in preventing deformities and instability that can lead to ulceration and amputa­ tion. These individuals require total non­ weight-bearing and urgent referral to a foot care specialist for further manage­ ment. Foot and ankle X-rays should be performed in all individuals presenting with the above clinical findings.

There have been a number of devel­

opments in the treatment of ulcerations over the years (90). These include negative-pressure therapy, growth fac­ tors, bioengineered tissue, acellular ma­ trix tissue, stem cell therapy, hyperbaric oxygen therapy, and, most recently, topi­ cal oxygen therapy (91-93). While there is literature to support many modalities currently used to treat diabetic foot wounds, robust randomized controlled trials (RCTs) are often lacking. How­ ever, it is agreed that the initial treat­ ment and evaluation of ulcerations

include the following five basic prin­ ciples of ulcer treatment:

• Offloading of plantar ulcerations
• Debridementofnecrotic,nonviable tissue
• Revascularization of ischemic wounds when necessary
• Management of infection: soft tissue or bone
• Use of physiologic, topical dressings

However, despite following the above principles, some ulcerations will become chronic and fail to heal. In those situa­ tions, advanced wound therapy can play a role. When to employ advanced wound therapy has been the subject of much discussion, as the therapy is often quite expensive. It has been determined that if a wound fails to show a reduc­ tion of 50% or more after 4 weeks of appropriate wound management (i.e., the five basic principles above), consid­ eration should be given to the use of advanced wound therapy (94). Treat­ ment of these chronic wounds is best managed in a multidisciplinary setting.

Evidence to support advanced wound

therapy is challenging to produce and to assess. Randomization of trial partici­ pants is difficult, as there are many variables that can affect wound heal­ ing. In addition, many RCTs exclude certain cohorts of people, e.g., individu­ als with chronic renal disease or those on dialysis. Finally, blinding of participants and clinicians is not always possible. Meta-analyses and systematic reviews of obseNational studies are used to deter­ mine the clinical effectiveness of these modalities. Such studies can augment for­ mal RCTs by including a greater variety of participants in various clinical settings who are typically excluded from the more rigidly structured clinical trials.

Advanced wound therapy can be cat­

egorized into nine broad categories (90) (Table 12.2). Topical growth factors, acel­ lular matrix tissues, and bioengineered cellular therapies are commonly em­ ployed in offices and wound care cen­ ters to expedite healing of chronic, more superficial ulcerations. Numerous clinical reports and retrospective studies have demonstrated the clinical effectiveness of each of these modalities. Over the years, there has been increased evidence to support the use of these modalities.

Nonetheless, use of those products or agents with robust RCTs or system­ atic reviews should generally be pre­ ferred over those without level 1 evidence (Table 12.2).

Negative-pressure wound therapy was

first introduced in the early to mid- 1990s. It has become especially useful in wound preparation for skin grafts and flaps and assists in the closure of deep, large wounds (95,96). A variety of types exist in the marketplace and range from electrically powered to mechanically

powered in different sizes depending upon the specific wound requirements.

Electrical stimulation, pulsed radio­ frequency energy, and extracorporeal shockwave therapy are biophysical mo­ dalities that are believed to upregulate growth factors or cytokines to stimulate wound healing, while low-frequency non­ contact ultrasound is used to debride wounds. However, most of the studies advocating the use of these modalities have been retrospective observational or poor-quality RCTs.

Hyperbaric oxygen therapy is the de­ livery of oxygen through a chamber, ei­ ther individual or multiperson, with the intention of increasing tissue oxygena­ tion to increase tissue perfusion and neovascularization, combat resistant bac­ teria, and stimulate wound healing. While there had been great interest in this modality being able to expedite healing of chronic diabetic foot ulcers (DFUs), there has only been one positive RCT published in the last decade that re­ ported increased healing rates at 9 and 12 months compared with control subjects (97). More recent studies with significant design deficiencies and par­ ticipant dropouts have failed to provide corroborating evidence that hyperbaric oxygen therapy should be widely used for managing nonhealing DFUs (98,99). While there may be some benefit in prevention of amputation in selected chronic neuroischemic ulcers, recent stud­ ies have shown no benefit in healing DFUs in the absence of ischemia and/ or infection (93,100).

Topical oxygen therapy has been studied rather vigorously in recent years, with several high-quality RCTs and at least five systematic reviews and meta­ analyses all supporting its efficacy in healing chronic DFUs at 12 weeks (19,20,30-34,91,92,101-105). Three

types of topical oxygen devices are available, including continuous-delivery, low-constant-pressure, and cyclical­ pressure modalities. Importantly, topical oxygen therapy devices provide for home-based therapy rather than the need for daily visits to specialized cen­ ters. Very high participation with very few reported adverse events combined with improved healing rates makes this therapy another attractive option for ad­ vanced wound care.

If DFUs fail to heal despite appropriate wound care, adjunctive advanced thera­ pies should be instituted and are best managed in a multidisciplinary manner. Once healed, all individuals should be enrolled in a formal comprehensive prevention program focused on reducing the incidence of recurrent ulcerations and subsequent amputations (75,106,107).

References

1. Solomon SD, Chew E, Duh EJ, et al. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care 2017;40:412- 418

1. Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, et al. The effect of intensive treatment of diabetes on the development and progression of long­ term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986
2. Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in type II diabetes over 6 years from diagnosis. Diabetologia 2001;44:156-163
3. Estacio RO, McFarling E, Biggerstaff S, Jeffers BW, Johnson D, Schrier RW. Overt albuminuria predicts diabetic retinopathy in Hispanics with NIDDM. Am J Kidney Dis 1998;31:947-953
4. Yau JWY, Rogers SL, Kawasaki R, et al.; Meta­ Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35: 556-564
5. Eid S, Sas KM, Abcouwer SF, et al. New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia 2019;62:1539-1549
6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853
7. Chew EV, Ambrosius WT, Davis MD, et al.; ACCORD Study Group; ACCORD Eye Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233-244
8. Writing Team for the DCCT/EDIC Research Group; Gubitosi-Klug RA, Sun W, Cleary PA, et al. Effects of prior intensive insulin therapy and risk factors on patient-reported visual function outcomes in the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. JAMA Ophthalmol 2016;134:137-145
9. Aiello LP, Sun W, Das A, et al.; DCCT/EDIC Research Group. Intensive diabetes therapy and ocular surgery in type 1 diabetes. N Engl J Med 2015;372:1722-1733
10. Bethel MA, Diaz R, Castellana N, Bhattacharya I, Gerstein HC, Lakshmanan MC. HbA1c change and diabetic retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: a meta-analysis and meta-regression. Diabetes Care 2021;44:290-296
11. Dabelea D, Stafford JM, Mayer-Davis EJ, D’Agostino R, Dolan L, Imperatore G, et al. Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood. JAMA 2017;317:825-835
12. Agardh E, Tababat-Khani P. Adopting 3-year screening intervals for sight-threatening retinal vascular lesions in type 2 diabetic subjects without retinopathy. Diabetes Care 2011;34:1318-1319
13. Nathan DM, Bebu I, Hainsworth D, et al.; DCCT/EDIC Research Group. Frequency of evidence­ based screening for retinopathy in type 1 diabetes. N Engl J Med 2017;376:1507-1516
14. Silva PS, Horton MB, Clary D, et al. Identification of diabetic retinopathy and ungradable image rate with ultrawide field imaging in a national teleophthalmology program. Ophthalmology 2016; 123:1360-1367
15. Bragge P, Gruen RL, Chau M, Forbes A, Taylor HR. Screening for presence or absence of diabetic

retinopathy: a meta-analysis. Arch Ophthalmol 2011;129:435-444

1. Walton OB 4th, Garoon RB, Weng CY, et al. Evaluation of automated teleretinal screening program for diabetic retinopathy. JAMA Ophthalmol 2016;134:204-209
2. Daskivich LP, Vasquez C, Martinez C Jr, Tseng CH, Mangione CM. Implementation and evaluation of a large-scale teleretinal diabetic retinopathy screening program in the Los Angeles County Department of Health Services. JAMA Intern Med 2017;177:642-649
3. Sim DA, Mitry D, Alexander P, et al. The evolution of teleophthalmology programs in the United Kingdom: beyond diabetic retinopathy screening. J Diabetes Sci Technol 2016;10:308-317
4. Abramoff MD, Lavin PT, Birch M, Shah N, Folk JC. Pivotal trial of an autonomous Al-based diagnostic system for detection of diabetic retinopathy in primary care offices. NPJ Digit Med 2018;1:1-8
5. Hooper P, Boucher MC, Cruess A, Dawson KG, Delpero W, Greve M, et al. Canadian Ophthalmological Society evidence-based clinical practice guidelines for the management of diabetic retinopathy. Can J Ophthalmol 2012; 47(2 Suppl):S1-S54
6. Gunderson EP, Lewis CE, Tsai AL, et al. A 20-year prospective study of childbearing and incidence of diabetes in young women, controlling for glycemia before conception: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Diabetes 2007;56:2990-2996
7. Widyaputri F, Rogers SL, Kandasamy R, Shub A, Symons RCA, Lim LL. Global estimates of diabetic retinopathy prevalence and progression in pregnant women with preexisting diabetes: a systematic review and meta-analysis. JAMA Ophthalmol 2022;140:486-494
8. Diabetes Control and Complications Trial Research Group. Effect of pregnancy on micro­ vascular complications in the diabetes control and complications trial. Diabetes Care 2000;23: 1084-1091
9. The Diabetic Retinopathy Study Research Group. Preliminary report on effects of photo­ coagulation therapy. Am J Ophthalmol 1976;81: 383-396
10. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-1806
11. Gross JG, Glassman AR, Jampol LM, et al.; Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photo­ coagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA 2015;314:2137-2146
12. Sivaprasad S, Prevost AT, Vasconcelos JC, et al.; CLARITY Study Group. Clinical efficacy of intravitreal aflibercept versus panretinal photo­ coagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial. Lancet 2017;389:2193-2203
13. Maturi RK, Glassman AR, Josic K, et al.; DRCR Retina Network. Effect of intravitreous anti-vascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of

diabetic retinopathy: the Protocol W randomized clinical trial. JAMA Ophthalmol 2021;139:701-712

1. Elman MJ, Bressler NM, Qin H, et al.; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609-614
2. Mitchell P, Bandello F, Schmidt-Erfurth U,

et al.; RESTORE study group.The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615-625

1. Wells JA, Glassman AR, Ayala AR, et al.;

Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015; 372:1193-1203

1. Baker CW, Glassman AR, Beaulieu WT, et al.; DRCR Retina Network. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA 2019;321:1880-1894
2. Chew EV, Davis MD, Danis RP, et al.; Action to Control Cardiovascular Risk in Diabetes Eye Study Research Group. The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) eye study. Ophthalmology 2014;121:2443-2451
3. Shi R, Zhao L, Wang F, et al. Effects of lipid­ lowering agents on diabetic retinopathy: a Meta­ analysis and systematic review. Int J Ophthalmol 2018;11:287-295
4. Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep 2014;14:528
5. Martin CL, Albers JW; DCCT/EDIC Research Group. Neuropathy and related findings in the diabetes control and complications trial/ epidemiology of diabetes interventions and complications study. Diabetes Care 2014;37:31-38
6. lsmail-Beigi F, Craven T, Banerji MA, et al.;

ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010;376:419-430

1. Bashir M, Elhadd T, Dabbous Z, et al. Optimal glycaemic and blood pressure but not lipid targets are related to a lower prevalence of diabetic microvascular complications. Diabetes Metab Syndr 2021;15:102241
2. Look AHEAD Research Group. Effects of a

long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study. Diabetologia 2017;60:980-988

1. Callaghan BC, Reynolds EL, Banerjee M, et al. Dietary weight loss in people with severe obesity stabilizes neuropathy and improves symptomatology. Obesity (Silver Spring) 2021;29: 2108-2118
2. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care 2017;40:136-154

1. Freeman R. Not all neuropathy in diabetes is of diabetic etiology: differential diagnosis of diabetic neuropathy. Curr Diab Rep 2009;9:423-431
2. Pop-Busui R, Evans GW, Gerstein HC, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010;33:1578-1584
3. Pop-Busui R, Cleary PA, Braffett BH, et al.; DCCT/EDIC Research Group. Association between cardiovascular autonomic neuropathy and left ventricular dysfunction: DCCT/EDIC study (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications). J Am Coll Cardiel 2013;61:447-454
4. Smith AG, Lessard M, Reyna S, Doudova M, Singleton JR. The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. J Diabetes Complications 2014;28:511-516
5. Diabetes Control and Complications Trial (DCCT) Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol 1995;38:869-880
6. CDC Study Group. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998; 41:416-423
7. Albers JW, Herman WH, Pop-Busui R, et al.; Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Diabetes Care 2010; 33:1090-1096

SO. Pop-Busui R, Low PA, Waberski BH, et al.; DCCT/EDIC Research Group. Effects of prior intensive insulin therapy on cardiac autonomic nervous system function in type 1 diabetes mellitus: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study (DCCT/EDIC). Circulation 2009;119:2886-2893

1. Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev 2012;6:CD007543
2. Pop-Busui R, Lu J, Brooks MM, et al.; BARI 2D Study Group. Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascular­ ization Investigation 2 Diabetes (BARI 2D) cohort. Diabetes Care 2013;36:3208-3215
3. Tang Y, Shah H, Bueno Junior CR, et al. Intensive risk factor management and cardio­ vascular autonomic neuropathy in type 2 diabetes: the ACCORD trial. Diabetes Care 2021;44:164-173
4. Callaghan BC, Xia R, Banerjee M, et al.; Health ABC Study. Metabolic syndrome components are associated with symptomatic polyneuropathy independent of glycemic status. Diabetes Care 2016;39:801-807
5. Andersen ST, Witte DR, Dalsgaard EM, et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes

followed for 13 years: ADDITION-Denmark. Diabetes Care 2018;41:1068-1075

1. Afshinnia F, Reynolds EL, Rajendiran TM, et al. Serum lipidomic determinants of human diabetic neuropathy in type 2 diabetes. Ann Clin Transl Neural 2022;9:1392-1404
2. Lu Y, Xing P, Cai X, et al. Prevalence and risk factors for diabetic peripheral neuropathy in type 2 diabetic patients from 14 countries: estimates of the INTERPRET-DD study. Front Public Health 2020;8:534372
3. Sadosky A, Schaefer C, Mann R, et al. Burden of illness associated with painful diabetic peripheral neuropathy among adults seeking treatment in the US: results from a retrospective chart review and cross-sectional survey. Diabetes Metab Syndr Obes 2013;6:79-92
4. Waldfogel JM, Nesbit SA, Dy SM, et al. Pharmacotherapy for diabetic peripheral neuro­ pathy pain and quality of life: a systematic review. Neurology 2017;88:1958-1967
5. Price R, Smith D, Franklin G, et al. Oral and topical treatment of painful diabetic polyneuropathy: practice guideline update summary: report of the AAN Guideline Subcommittee. Neurology 2022;98:31-43
6. Pop-Busui R, Ang L, Boulton AJM, et al. Diagnosis and Treatment of Painful Diabetic Peripheral Neuropathy. Arlington, VA, American Diabetes Association, 2022
7. Tesfaye S, Sloan G, Petrie J, et al.; OPTION-OM trial group. Comparison of amitriptyline supple­ mented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-OM): a multicentre, double-blind, randomised crossover trial. Lancet 2022;400:68Q-690
8. Dworkin RH, Jensen MP, Gammaitoni AR, Olaleye DO, Galer BS. Symptom profiles differ in patients with neuropathic versus non-neuropathic pain. J Pain 2007;8:118-126
9. Briasoulis A, Silver A, Yano Y, Bakris GL. Orthostatic hypotension associated with baro­ receptor dysfunction: treatment approaches. J Clin Hypertens (Greenwich) 2014;16:141-148
10. Figueroa JJ, Basford JR, Low PA. Preventing and treating orthostatic hypotension: as easy as A, B, C. Cleve Clin J Med 2010;77:298-306
11. Jordan J, Fanciulli A, Tank J, et al. Manage­ ment of supine hypertension in patients with neurogenic orthostatic hypotension: scientific statement of the American Autonomic Society, European Federation of Autonomic Societies, and the European Society of Hypertension. J Hypertens 2019;37:1541-1546
12. Camilleri M, Parkman HP, Shafi MA, Abell TL; American College of Gastroenterology. Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013;108:18-37
13. Parrish CR, Pastors JG. Nutritional manage­ ment of gastroparesis in people with diabetes. Diabetes Spectr 2007;20:231-234
14. Parkman HP, Yates KP, Hasler WL, et al.; NIDDK Gastroparesis Clinical Research Consortium. Dietary intake and nutritional deficiencies in patients with diabetic or idiopathic gastroparesis. Gastroenterology 2011;141:486-498, 498.el-498.e7
15. Olausson EA, Sti:irsrud S, Grundin H, lsaksson M, Attvall S, Simren M. A small particle size diet reduces upper gastrointestinal symptoms in patients with diabetic gastroparesis: a randomized

controlled trial. Am J Gastroenterol 2014;109: 375-385

1. Umpierrez GE (Ed.) Therapy for Diabetes Mellitus and Related Disorders. 6th ed. Arlington, VA, American Diabetes Association; 2014
2. Sugumar A, Singh A, Pasricha PJ. A sys­ tematic review of the efficacy of domperidone for the treatment of diabetic gastroparesis. Clin Gastroenterol Hepatol 2008;6:726-733
3. Maganti K, Onyemere K, Jones MP. Oral erythromycin and symptomatic relief of gastro­ paresis: a systematic review. Am J Gastroenterol 2003;98:259-263
4. McCallum RW, Snape W, Brody F, Wo J, Parkman HP, Nowak T. Gastric electrical stimulation with Enterra therapy improves symptoms from diabetic gastroparesis in a prospective study. Clin Gastroenterol Hepatol 2010;8:947-954; quiz e116
5. Boulton AJM, Armstrong DG, Albert SF, et al.; American Diabetes Association; American Association of Clinical Endocrinologists. Compre­ hensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 2008;31: 1679-1685
6. Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ; IWGDF Editorial Board. Practical guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev 2020;36(Suppl. 1):e3266
7. Reiber GE, Vileikyte L, Boyko EJ, et al. Causal pathways for incident lower-extremity ulcers in patients with diabetes from two settings. Diabetes Care 1999;22:157-162
8. Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 2000;23:606-611
9. Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Pediatric Medical Association and the Society for Vascular Medicine. J Vase Surg 2016;63(Suppl.): 3S-21S
10. Conte MS, Bradbury AW, Kolh P, White JV, Dick F, Fitridge R, et al. Global vascular guidelines on the management of chronic limb-threatening ischemia. Eur J Vase Endovasc Surg 2019;58(1S): Sl-S109.e33
11. American Diabetes Association. Peripheral arterial disease in people with diabetes. Diabetes Care 2003;26:3333-3341
12. Reaney M, Gladwin T, Churchill S. Information about foot care provided to people with diabetes with or without their partners: Impact on recommended foot care behavior. Appl Psychol Health Well-Being 2022;14:465-482
13. Heng ML, Kwan YH, llya N, et al. A collaborative approach in patient education for diabetes foot and wound care: A pragmatic randomised controlled trial. Int Wound J 2020; 17:1678-1686
14. Bus SA, Lavery LA, Monteiro-Soares M, et al.; International Working Group on the Diabetic Foot. Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev 2020;36(Suppl. 1):e3269

1. Goodall RJ, Ellauzi J, Tan MKH, Onida S, Davies AH, Shalhoub J. A systematic review of the impact of foot care education on self efficacy and self care in patients with diabetes. Eur J Vase Endovasc Surg 2020;60:282-292
2. Yuncken J, Williams CM, Stolwyk RJ, Haines TP. People with diabetes do not learn and recall their diabetes foot education: a cohort study. Endocrine 2018;62:250-258
3. Walton DV, Edmonds ME, Bates M, Vas PRJ, Petrova NL, Manu CA. People living with diabetes are unaware of their foot risk status or why they are referred to a multidisciplinary foot team. J Wound Care 2021;30:598-603
4. Bus SA, van Deursen RW, Armstrong DG, Lewis JE, Caravaggi CF; International Working Group on the Diabetic Foot. Footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in patients with diabetes: a systematic review. Diabetes Metab Res Rev 2016;32(Suppl. 1):99-118
5. Rogers LC, Frykberg RG, Armstrong DG, et al. The Charcot foot in diabetes. Diabetes Care 2011; 34:2123-2129
6. Frykberg RG, Banks J. Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle) 2015;4:560-582
7. Carter MJ, Frykberg RG, Oropallo A, Sen CK, Armstrong DG, Nair HKR, et al. Efficacy of topical wound oxygen therapy in healing chronic diabetic foot ulcers: systematic review and meta-analysis. Adv Wound Care (New Rochelle). 21 June 2022 [Epub ahead of print]. DOI: 10.1089/wound.2022. 0041
8. Frykberg RG, Franks PJ, Edmonds M, et al.; 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;43:616-624

1. Boulton AJM, Armstrong DG, Li:indahl M, et al. New Evidence-Based Therapies far Complex Diabetic Foot Wounds. Arlington, VA, American Diabetes Association, 2022
2. Sheehan P, Jones P, Caselli A, Giurini JM, Veves A. Percent change in wound area of diabetic foot ulcers over a 4-week period is a robust predictor of complete healing in a 12-week prospective trial. Diabetes Care 2003;26:1879- 1882
3. Blume PA, Walters J, Payne W, Ayala J, Lantis J. Comparison of negative pressure wound therapy using vacuum-assisted closure with advanced moist wound therapy in the treatment of diabetic foot ulcers: a multicenter randomized controlled trial. Diabetes Care 2008;31:631-636
4. Argenta LC, Morykwas MJ, Marks MW, DeFranzo AJ, Molnar JA, David LR. Vacuum­ assisted closure: state of clinic art. Plast Reconstr Surg 2006;117(Suppl. ):1275-1425
5. Li:indahl M, Katzman P, Nilsson A, Hammarlund

C. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Diabetes Care 2010;33:998-1003

1. Santema KTB, Stoekenbroek RM, Koelemay MJW, et al.; DAMO2CLES Study Group. Hyperbaric oxygen therapy in the treatment of ischemic lower- extremity ulcers in patients with diabetes: results of the DAMO₂CLESmulticenter randomized clinical trial. Diabetes Care 2018;41:112-119
2. Fedorko L, Bowen JM, Jones W, et al. Hyperbaric oxygen therapy does not reduce indications for amputation in patients with diabetes with nonhealing ulcers of the lower limb: a prospective, double-blind, randomized controlled clinical trial. Diabetes Care 2016;39: 392-399
3. Lalieu RC, Brouwer RJ, Ubbink DT, Hoencamp R, Bol Raap R, van Hulst RA. Hyperbaric oxygen therapy for nonischemic diabetic ulcers: a sys­ tematic review. Wound Repair Regen 2020;28: 266-275
4. Niederauer MQ, Michalek JE, Liu Q, Papas KK, Lavery LA, Armstrong DG. Continuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre study. J Wound Care 2018;27(Suppl. 9):530- 545
5. Serena TE, Bullock NM, Cole W, Lantis J, Li L, Moore S, et al. Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled clinical trial. J Wound Care 2021;30(Suppl. 5):57-514
6. Sun XK, Li R, Yang XL, Yuan L. Efficacy and safety of topical oxygen therapy for diabetic foot ulcers: an updated systematic review and meta­ analysis. Int Wound J. 5 May 2022 [Epub ahead of print]. DOI: 10.1111/iwj.13830
7. Frykberg RG.Topical wound oxygen therapy

in the treatment of chronic diabetic foot ulcers. Medicina (Kaunas) 2021;57:917

1. Sethi A, Khambhayta Y, Vas P. Topical oxygen therapy for healing diabetic foot ulcers: a systematic review and meta-analysis of randomised control trials. Health Sci Rep 2022;3:100028
2. van Netten JJ, Price PE, Lavery LA, et al.; International Working Group on the Diabetic Foot. Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review. Diabetes Metab Res Rev 2016;32(Suppl. 1):84-98
3. Frykberg RG, Vileikyte L, Boulton AJM,

Armstrong DG. The at-risk diabetic foot: time to focus on prevention. Diabetes Care 2022;45: e144-e145

 

Clinical Research

Efficacy of Topical Wound Oxygen Therapy in Healing Chronic Diabetic Foot Ulcers: Systematic Review and Meta-Analysis

Marissa J. Carter,^1,* Robert G. Frykberg,² Alisha Oropallo,³ Chandan K. Sen,⁴ David G. Armstrong,⁵

Harikrishna K.R. Nair,⁶ and Thomas E. Serena⁷

¹Strategic Solutions, Inc., Bozeman, Montana, USA.

²Diabetic Foot Consultants, Midwestern University, Glendale, Arizona, USA.

³Department of Vascular Surgery, Donald and Barbara Zucker School of Medicine, Hofstra/Northwell Health, Hempstead, New York, USA.

⁴Indiana Center for Regenerative Medicine and Engineering, School of Medicine, Indiana University, Indianapolis, Indiana, USA.

⁵Department of Surgery, Keck School of Medicine of University of Southern California, Los Angeles, California, USA. ⁶Wounds Malaysia, Wound Care Unit, Department of Internal Medicine, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia. ⁷SerenaGroup Research Foundation, Cambridge, Massachusetts, USA.

Objective: To conduct a systematic review and meta-analysis of recently published randomized controlled trials (RCTs) that employed the use of topical oxygen therapy (TOT) as an adjunct therapy in the treatment of Wagner 1 and 2 diabetic foot ulcers.

Approach: Following a literature search of eligible studies from 2010 on- ward, four RCTs were included. Studies were analyzed for patient and wound characteristics, outcomes, risk of bias, and quality of the evidence assessed using the Grading of Recommendations Assessment, Development, and Evalua- tion (GRADE) methodology. A random-effects meta-analysis for complete wound healing was carried out due to statistical heterogeneity of included studies.

Results: Risk of bias judgment (RoB2 analysis) resulted in one low-risk trial and three trials with some risk. One study was determined to be the origin of the statistical heterogeneity. Pooled results showed statistical significance with a risk ratio (RR) of 1.59 (95% confidence interval [CI]: 1.07–2.37; p = 0.021). Sensitivity analysis, based on imputed values for missing outcomes, demonstrated that both the RR and 95% CIs changed little. The GRADE ratings for each do- main were as follows: (a) risk of bias: moderate (3); (b) imprecision: mod- erate (2), high (1); (c) inconsistency: low (2), high (1); (d) indirectness:

moderate (2), high (1); and (e) publication bias: moderate (1), high (2). Overall, the evidence was moderate.

Innovation: Our study shows that TOT is a viable diabetic foot ulcer therapy. Conclusions: These data support the use of TOT for the treatment of chronic Wagner 1 or 2 diabetic foot ulcers in the absence of infection and ischemia.

Keywords: diabetic foot ulcer, topical oxygen therapy, systematic review, meta-analysis

Open camera or QR reader and scan code to access this article and other resources online.

Marissa J. Carter, PhD, MA

Submitted for publication March 8, 2022.

Accepted in revised form May 13, 2022.

*Correspondence: Strategic Solutions, Inc., 37 Voyager Lane, Bozeman, MT 59718, USA

(e-mail: [email protected]).

ª Marissa J. Carter et al., 2022; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License [CC-BY-NC] (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.

j

ADVANCES IN WOUND CARE, VOLUME 00, NUMBER 00                                                                                                                                                                   1

2022 by Mary Ann Liebert, Inc.                                                                                        DOI: 10.1089/wound.2022.0041

INTRODUCTION

Diabetes-related foot ulcers (DFUs), affect- ing up to one third of patients with diabetes during the course of their disease, have long been con- sidered major precursors to lower extremity am- putation, whether of neuropathic, ischemic, or neuroischemic etiology.^1,2 A recent systematic re- view reported a worldwide prevalence of DFU of 6.3%, with the highest prevalence being 13% in North America.³ Another report found the global burden of diabetes-related lower extremity com- plications to be high, with a crude estimate of DFUs affecting 18.6 million persons.⁴ The costs of treat- ing chronic DFUs are commensurate with the frequent complexity of the problem itself. A 2014 U.S.-based administrative database study found that such costs can range from $9 to $13 billion, and the excess health care costs of DFU approximately double the cost of treating diabetes itself.⁵

The rapid growth of the global population with diabetes will lead to a greater number of pa- tients suffering from DFUs and a concomitant increase in global amputation rates. Current pro- tocols for managing acute or chronic DFUs focus on thorough systematic assessment, debridement, ef- fective offloading, wound bed preparation, and re- vascularization, as necessary.^6–8 Unfortunately, many DFUs are refractory to optimal standard of care (SOC) as defined by healing less than 50% in 4 weeks. These patients require reassessment of vascular, nutritional, and infection status; exami- nation of the effectiveness of debridement and off- loading regimens; and reevaluation of renal status, diabetic control, residual small artery disease (not amenable to intervention), or other significant metabolic abnormalities that may adversely affect wound healing. These patients are likely to benefit from advanced wound healing therapies, such as topical oxygen therapy (TOT).^7,9,10

When TOT was introduced to clinical practice over 50 years ago, practitioners initially viewed it as a controversial therapy, due to the sparse evi- dence supporting its use. Technological advances in delivery systems and recent clinical trials sug- gest that TOT is a viable advanced treatment mo- dality for DFUs.^10–15

There are several types of TOT devices on the market, including continuous diffusion of oxy- gen (CDO) delivery systems, devices delivering low constant pressure O₂ (at 22 mmHg), and a system that delivers cyclically pressurized oxygen (from 10 to 50 mb above atmospheric pressure).^10,16 CDO devices, delivering a low constant flow of pure oxygen at 3–15 mL/h, are designed for continu- ous ambulatory use through proprietary wound

dressings, whereas the latter two devices de- liver oxygen within a flexible, disposable extremity chamber used in the home.

Early clinical studies on TOT lacked scientific rigor. For example, a poorly designed, unblinded, and inadequately powered trial published in 1988 compared 12 hospitalized patients with chronic DFUs who received 14 days of topical ‘‘hyperbaric’’ oxygen therapy with 16 similar patients treated with standard care. The investigators reported no difference in healing outcomes after 2 weeks of treatment, and they concluded that TOT pro- vided no appreciable benefit in the treatment of DFUs.¹⁷

Despite this early report, several reviews, ob- servational human studies, and preclinical animal work suggested a positive wound healing benefit associated with TOT.^18–24 A very compelling ani- mal study was published by Fries et al. in 2017 that clearly demonstrated an upregulation of growth factors and significant increases in tissue level oxygen partial pressures after treatment with TOT compared with control wounds.¹⁹ Furthermore, these physiological attributes were corroborated by clinical as well as histological evidence of improved healing in the oxygen-treated wounds.

The last decade, however, has given rise to several more robust randomized controlled trials (RCTs) that demonstrate the efficacy of TOT in treatment of chronic DFUs compared with controls treated with SOC alone.^11–15 Additionally, several recent independent systematic reviews and meta- analyses validate the additional benefit of TOT in this regard.^25–27 These systematic reviews, how- ever, were fairly heterogeneous in the types of studies analyzed and did not include the most re- cent RCT published in 2021.¹³

Our aim in this systematic review and meta- analysis was to provide a rigorous assessment of recently reported RCTs comparing adjunctive TOT with control patients receiving SOC for the treat- ment of chronic DFUs. Distinct from the several other systematic reviews, we include only robust prospective RCTs with primary outcomes of com- plete healing at 12 weeks. Complete healing (or complete wound closure), as used in this analy- sis, is defined as complete reepithelialization with no further evidence of drainage nor visible granulation tissue. To avoid potential duplication of patient data, we have specifically excluded those publications with reported interim data. The data from studies evaluating CDO and cy- clically pressurized systems were included and pooled. There were too few studies to perform separate meta-analyses.

INNOVATION

TOT has had a checkered history as an adjunc- tive therapy in wound healing in part due to the development of the technology itself. Recent ad- vances have made the devices more robust and reliable with the potential to accelerate wound healing in chronic diabetic foot ulcers. By con- ducting a systematic review of all the relevant RCTs using the most conservative outcome of complete wound healing at a minimum of 12 weeks, we demonstrate that more robust devices do have the ability to improve wound healing in less severe chronic diabetic foot ulcers.

CLINICAL PROBLEM ADDRESSED

Chronic diabetic foot ulcers are an unfortunate but common complication of diabetes. While con- sistent SOC can heal many DFUs given enough time, a substantial proportion of these wound types are stuck in the inflammatory phase of wound healing and need an adjunctive treatment to ad- dress the issue(s) so that the wound can tran- sition to the proliferative phase. While a variety of treatments have demonstrated efficacy in this regard, many are expensive, and some are not available to all patients. Given that TOT is a pos- sible adjunctive therapy for DFUs, we decided to formally assess the RCTs conducted to date using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), including meta-analysis, to determine if this mode of therapy can be recommended.

MATERIALS AND METHODS

The study was performed according to the 2015 Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement²⁸ and was registered at PROSPERO (CRD42021259090).

Eligibility

Studies involving patients with chronic DFUs using TOT (intermittent or continuous application of oxygen) in addition to SOC (debridement, off- loading, and moist wound care) in any health care setting were eligible provided that they were RCTs. Data of studies with 20 patients or fewer or with- out primary outcomes of healing at 12 weeks were excluded from the assessment.

Literature search

The following databases were used in the search:

• PubMed
• MEDLINE/OVID

• Embase
• Cochrane Central Register of Controlled Trials
• Cochrane Database of Systematic Reviews
• Health Technology Assessment Database
• gov
• International Clinical Trials Registry Plat- form Search Portal.

The following search terms were used: Topical Oxygen OR Topical Wound Oxygen OR Continuous Diffusion of Oxygen OR Continuous Topical Oxy- gen OR Topical Hyperbaric Oxygen OR High- Pressure Cyclical Oxygen AND Clinical Trial OR Trial OR Placebo OR Random.

In addition, the full-text document (e.g., journal article or clinical study report) had to be available and published after January 1, 2010. Any language was permissible provided that English titles and abstracts were available and indicated potential relevance.

Figure 1 summarizes the literature search and study selection process. On October 20, 2021, 2 authors conducted the literature search, which yielded 51 clinical trials and 240 publications with 11 RCTs (14 publications) meeting search criteria (Table 1). All members of the study team discussed the search results and reached a consensus that four studies met the predefined inclusion criteria (Supplementary Tables S1 and S2).^11–13,15

Data extraction and risk of bias analysis

The primary outcome of interest was complete wound healing (skin reepithelialization without drainage or dressing requirements confirmed at two consecutive study visits 2 weeks or more apart) at 12 weeks with the following secondary out- comes collected if available: wound-related pain, readmission to the hospital, health-related quality of life, dependence on outside help or need for care, adherence to prescribed therapy, and adverse events (AEs), including amputation and mortality. SOC in treatment of DFUs includes debride- ment as necessary (typically sharp debridement), offloading of plantar ulcers, appropriate dressings to maintain a moist wound care bed, and infec- tion control. Reporting should include debridement type and frequency, as well as details of dressings and offloading. Although findings were not tabu-

lated, we noted if details were missing.

Two reviewers independently extracted key study metrics and outcomes, and a third member checked congruity of the data. A consensus among the team members was reached that only complete wound healing was a useful outcome, as not all studies provided other wound healing outcomes.

Figure 1. PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis.

The risk of bias analysis used the RoB2 approach developed by the Cochrane group.²⁹ The same re- viewers who extracted the data carried out the risk of bias analysis independently. The senior sys- tematic reviewer/statistician adjudicated differ- ences in assessment for each domain for each study and reviewed the overall results.

Meta-analysis

Meta-analysis  was  conducted  for  complete

significant. Heterogeneity was explored by sys- tematically omitting one of the included studies. The effect measure used was relative risk, and the analysis was conducted using MedCalc and SPSS (v 28.0).

Table 1. Literature search data

Parameter                                                    Clinical Trials               Publications

Unique results from search terms                            51                              240

wound healing at 12 weeks using all eligible stud-

ies, as only one study was low risk. A fixed-effects

Those involving gaseous, topically applied oxygen

30                              101

 

model (inverse variance method; Mantel–Haenszel) was used when heterogeneity was judged nonsig- nificant, including the I² and Cochran’s Q metrics. A random-effects model (DerSimonian and Laird method) was used when heterogeneity was judged

RCTs meeting criteria                                             11                               14

Completed with full-text publication                          4                                10^a

^aTwo clinical trials had multiple publications. Only one reference from each study contained the primary outcomes used in the meta-analysis. Refer to Supplementary Tables S1 and S2.

RCT, randomized controlled trial.

The primary sensitivity analysis was carried out using a modified jump-to-reference ( J2R) ap- proach,³⁰ in which subjects lost to follow-up or withdrawals due to other reasons for the complete wound healing outcome in the TOT group were assumed to have had the same proportional out- comes as the control/sham/SOC only group. Since outcomes for subjects withdrawn from the studies depend on the reason why the subjects were with- drawn, for serious adverse events (SAEs) or AEs in which the event was serious enough that a subject was withdrawn from the study, the event would likely have affected the wound healing trajectory in an adverse manner. For nonserious AEs or most other reasons for withdrawals, the wound healing trajectory would likely have been similar to the healing rate of the uncensored control/sham/SOC only group.

Thus, the algorithm for a secondary sensitivity analysis was implemented first for the control/ sham/SOC only group as: (a) index wounds of subjects who had an SAE/AE that forced with- drawal or caused a voluntary withdrawal by the subject were scored as not healed; death was scored as not healed. If insufficient data were reported to enable a determination, then the algorithm as- sumed that this category was 0; (b) all other index

wounds were scored as healed/not healed according to the J2R method, which uses complete case re- sults. The adjusted healing rate thus obtained was then used as the J2R value for the TOT group. When calculating the number of subjects in a sen- sitivity analysis, if fractions were involved, num- bers of subjects were rounded up or down to integers depending on whether the fraction was

>0.5 or not.

Grading of Recommendations Assessment, Development, and Evaluation

Three team members evaluated independently the body of evidence using the GRADE methodol- ogy.³¹ Consensus among all authors determined recommendations.

RESULTS

Study details

Three of the four studies had larger and similar numbers of enrolled participants (N = 130–146), whereas the Frykberg RCT¹⁵ was smaller (N = 73) (Table 2). The mean wound age was comparable among all studies, although the Driver study¹¹ enrolled smaller area wounds on average (Table 2). All RCTs had a study length of 12 weeks.

Table 2. Characteristics of included studies

 

Study	Year	RCT Study Design	No. of Subjects Randomized	Study Duration, Weeks	Setting	Intention-to-Treat Analysis	Wound Characteristics	Right-Censored Outcomes
Driver	2017	•  Subject blinded	130	12	22 Wound clinics	•  Active: 65b	•  Class: UT 1A	•  Active: 12
et al.11		•  Assessor blinded •  2 Groups	•  Activea: 66 •  Shama: 64		(United States and Canada)	•  Sham: 63b	•  Mean wound age: Active: 17.7 weeks; Sham: 14.9	•  SOC: 17
							weeks
							•  Mean wound area: Active: 2.0 cm2; Sham: 2.3 cm2
Niederauer	2018	•  Subject blinded	146	12	34 Wound clinics	•  Active: 74	•  Class: UT 1A	•  Active: 22
et al.12		•  Assessor blinded	•  Active: 74		(United States)	•  Sham: 72	•  Mean wound age: Active:	•  SOC: 19
		•  2 Groups	•  Sham: 72				18.8 weeks; Sham: 20.5
							weeks
							•  Mean wound area: Active: 3.5 cm2; Sham: 3.9 cm2
Frykberg	2020	•  Subject blinded	73	12	17 Diabetic	•  Active: 36	•  Class: UT 1A–D, 2A–D	•  Active: 3
et al.15		•  Assessor blinded	•  Active: 36		foot centers	•  Sham: 37	•  Mean wound age: Active:	•  SOC: 4
		•  2 Groups	•  Sham: 37		(United States,		22.9 weeks; Sham: 24.9
					United Kingdom,		weeks
					France, Germany, and Luxembourg)		•  Mean wound area: Active: 3.0 cm2; Sham: 3.2 cm2
Serena	2021	•  No blinding	145	12	19 Wound clinics	•  Active: 81	•  Class: Wagner 1 or 2	•  Active: 15
et al.13		•  2 Groups	•  Active: 81		(United States)	•  SOC: 64	•  Mean wound age: Active:	•  SOC: 12
			•  SOC: 64				24.5 weeks; SOC: 23.8
							weeks
							•  Mean wound area: Active: 2.9 cm2; SOC: 3.5 cm2

^aActive group defined as the group allocated to the intervention; sham group defined as the group allocated to SOC alone using a sham device.

^bSubjects randomized and also received allocated treatment. SOC, standard of care; UT, University of Texas.

Table 3. Complete wound healing outcomes and safety analysis of included studies

 

Study	Year	Outcome Dataa	Safety Results	Healing Confirmation Visit
Driver et al.11	2017	•  Activeb: 35/65 (54%) •  Shamb: 31/63 (49%) •  p = 0.42	•  SAEs: Active: 12; Sham: 13 B All unrelated/unlikely related to device •  AEs: Active: 53 Sham: 55	2 Weeks after initial healing date

 

 Niederauer et al.¹²           2018          • Active: 24/74 (32%)

• Sham: 12/72 (17%)
• p = 027

Frykberg et al.¹⁵               2020          • Active: 15/36 (41%)

• Sham: 5/37 (14%)
• p = 007

Serena et al.¹³                2021          • Active: 36/81 (44%)

• SOC: 18/64 (28%)
• p = 04

^aBased on proportions of wounds healed at 12 weeks.

B 1 Probably related to SOC

B 3 Possibly related to device

• Infections: Active: 3; Sham: 10
• AEs: Active: 11; Sham: 13

B Related to study wound: Active: 6; Sham: 10

 

• SAEs: Active: 10; Sham: 10
• AEs: Active: 8; Sham: 8
• Index limb amputations: Active: 2; Sham: 3
• AEs: Active: 41; SOC: 32
• Severe/life-threatening AEs: Active: 7; SOC: 8
• Possibly/probably related to product: Active: 1; SOC: 12 AEs

 

Follow-up telephone call/12-week durability visit

2 Weeks after initial healing date

2-Week confirmation visit (T.E. Serena, pers. comm.)

^bActive group defined as the group allocated to the intervention; sham group defined as the group allocated to SOC alone using a sham device. AE, adverse event; SAE, serious adverse event.

The difference between intervention and SOC groups in terms of complete wound healing ranged from 5% to 27% (all rates had higher healing rates compared with the SOC group), but only the Driver trial reported statistically nonsignificant results (Table 3). AEs were similar in both groups for all studies, although the absolute rates varied con- siderably.

Risk of bias analysis

There were eight disagreements between the two reviewers regarding judgment of the five do- mains for the four studies, half of which were for the Driver study.¹¹ There was also a disagreement about the overall judgment for the Driver trial.¹¹ After adjudication, this resulted in one low-risk trial and three trials with some risk (Table 4).

Meta-analysis

Since only one study was low risk, meta-analysis proceeded with all eligible studies. A random-effects model was chosen because there was substan- tial heterogeneity (I²: 55.7%; p = 0.081). The simple explanation for the origin of the heterogeneity was the Driver study,¹¹ as its removal resulted in no heterogeneity.

The pooled results showed statistical signifi- cance with a risk ratio (RR) of 1.59 (95% confi- dence interval [CI]: 1.07–2.37; p = 0.021) (Fig. 2 and

Table 5). A funnel plot suggested that the magni- tude of the intervention response varied consider- ably with the degree of precision (Fig. 3).

Sensitivity analysis using imputed values for missing outcomes, which was based on random- effects models, demonstrated that despite some fairly high levels of missing outcomes in three studies, neither the pooled estimate or 95% CIs changed substantially (Table 6) ( p = 0.039).

Grading of Recommendations Assessment, Development, and Evaluation

The ratings for each domain were as follows: (a) risk of bias: moderate (3); (b) imprecision: moderate (2), high (1); (c) inconsistency: low (2), high (1); (d) indirectness: moderate (2), high (1); and (e) publi- cation bias: moderate (1), high (2). All agreed that the overall evidence was moderate. Based on our meta-analysis and GRADE review, the study panel agreed that TOT can be recommended for the in- dication of chronic DFUs that have not responded to an initial trial of effective offloading and sharp debridement in the absence of infection and ischemia.

DISCUSSION

Our systematic review of RCT evidence for TOT indicates that it is a viable treatment for Wagner 1

Table 4. Final summary table risk of bias judgment for complete wound healing outcome at 12 weeks

 

Study	Domain 1	Domain 2	Domain 3	Domain 4	Domain 5	Overall
Driver et al.11	Low risk	Low risk	Some concerns	Low risk	Low risk	Some concerns
Frykberg et al.15	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Niederauer et al.12	Some concerns	Low risk	Some concerns	Low risk	Low risk	Some concerns
Serena et al.13	Low risk	Some concerns	Some concerns	Low risk	Low risk	Some concerns

 

 

Figure 2. Forest plot for the random-effects model including all studies.

Figure 3. Funnel plot of the magnitude of the intervention response in- cluding all studies.

and 2 DFUs. The meta-analysis supports efficacy in the defined populations under study; that is, chronic nonischemic DFUs of at least 4 weeks duration and not adequately responding to SOC alone. Our recommendation corroborates and is consistent with the other aforementioned system- atic reviews that also support TOT for the treat- ment of chronic DFUs.^25–27 Additional studies are needed to clarify the indications for use and effi- cacy in other wound types.

The meta-analysis demonstrated that, even in the presence of statistical heterogeneity addressed using random-effects models, results were statis- tically significant and remained so when apply- ing reasonable sensitivity analysis. While other systematic reviews have already reported positive findings,^25–27 our study was the first to analyze only RCTs, including the most recent trial,¹³ and we applied the most rigorous form of risk of bias analysis, GRADE, and meta-analysis.

It is interesting to note that if the Driver study¹¹ is removed from meta-analysis, there is no het- erogeneity, and a fixed-effects model is possible with extremely statistically significant results. One possible reason for the failure to achieve sta-

tistical significance in the Driver study¹¹ could be premature failure of the active device, Epiflo™ (Neogenix, formerly Ogenix, Beachwood, OH). This older continuous topical oxygen (CTO) device uses an electrochemical generator to produce oxygen at a flow rate of 3 mL/h. While the device has a blinking red light that indicates when the power is on, it does not contain an alarm or indicator to notify the patient or provider that the generator is not functioning properly. If the device fails, the patient and clinician may believe that the device is working properly, even though it is no longer gen- erating oxygen. In addition, CTO devices may not function in regions with low humidity levels.³²

These weaknesses may explain the poorer re- sults in the CTO clinical trials compared with the other systems. While the trial was generally well designed, the control group achieved nearly a 50% closure rate at 12 weeks compared with 54% in the active group. This would ostensibly indicate that those ulcers enrolled would have been as likely to heal with SOC as with active therapy. Further- more, the authors acknowledged that they specifi- cally excluded patients with typical comorbidities

 

Risk   Weight, in the meta-analysis (p = 0.039)   Study TOT SOC Ratio 95% CI % Risk Weight,

Table 5. Results of the random-effects model including all studies

Table 6. Sensitivity analysis of the complete wound healing outcome using a random-effects model

 

Driver et al.11	35/65	31/63	1.09	0.78–1.53	35.2	Study	TOT	SOC	Ratio	95% CI	%
Niederauer et al.12	24/74	12/72	1.95	1.06–3.59	22.2	Driver et al.11	41/65	38/63	1.05	0.80–1.37	33.9
Frykberg et al.15	15/36	5/37	3.08	1.25–7.60	13.7	Niederauer et al.12	26/74	13/72	1.95	1.09–3.48	23.3
Serena et al.13	36/81	18/64	1.58	1.00–2.51	28.8	Frykberg et al.15	15/36	5/37	3.08	1.25–7.60	14.8
Total	110/256	66/236	1.59	1.07–2.37	100.0	Serena et al.13	38/81	19/64	1.58	1.02–2.46	28.0

Total                            120/256       75/236       1.59        1.02–2.48        100.0

CI, confidence interval; TOT, topical oxygen therapy.                                                                                                                                                                     

 

KEY FINDINGS •   TOT has been recognized as a potential adjunctive therapy for the treatment of diabetic foot ulcers. •   A random-effects meta-analysis of four RCTs showed that TOT improved wound healing at 12 weeks over SOC alone (RR: 1.59; 95% CI: 1.07–2.37; p = 0.021). •   Investigation of statistical heterogeneity indicated that older TOT tech- nology might be the reason for earlier poor results. •   The overall GRADE level of evidence for TOT was moderate.

seen in patients with DFU (ischemia, renal insufficiency, etc.) and patients with deeper ulcers that would be consid- ered more difficult to heal.¹¹

The current SARS-Cov-2 pandemic has resulted considerable disruption to wound care especially for patients par- ticularly for treatments that involve wound care clinics and hospitals.³³ Con- sequently, treatments that can be con- ducted in the patient’s home care setting may have some advantage,³⁴ including

TOT for treatment of DFUs. It remains unknown whether the economics of using TOT are favorable since no studies have been published on the sub- ject. Although any advanced therapy will be more costly initially, long-term benefits are almost uni- formly supportive of such therapies since they heal wounds faster and avoid hospitalizations and am- putations. Indeed, a recent publication supports this premise.³⁵

There are some limitations to this meta- analysis. First, complete wound healing was the only common endpoint available for this review and meta-analysis. The U.S. Food and Drug Ad- ministration favors this endpoint³⁶; however, the analysis was unable to assess patient-centered outcomes, such as quality of life or wound-associated pain, or clinical endpoints of interest, such as pre- vention of infection or amputation. Second, there is invariably some heterogeneity in applying SOC for DFU treatment even in RCTs in which there is considerable training and assessment at each participating site; examples include types of dressings, debridement frequencies, and types of permissible offloading. Within a trial, heterogene- ity is usually minimal due to randomization pro- cedures, but between trials, differences can be a factor in determining what the overall SOC healing rate is over the length of the study.

However, what really matters is the difference between the treatment groups in regard to healing rates rather than absolute values. SOC can also be insufficiently detailed in the study publication, which is a reporting issue; for example, only two of the trials described debridement, and offloading details were missing in one trial. This can lead to uncertainty in regard to study assessment, partic- ularly for assessors not familiar with the trials. Third, our recommendations are limited to Wagner grade 1 or 2 DFUs: none of the clinical trials in- cluded more severe ulcers. Similarly, the trials primarily treated chronic uninfected ulcers with adequate perfusion. Therefore, the conclusions do not extend to infected or ischemic ulcers. Last, our recommendations are based on only four RCTs; more well-conducted trials would be likely to strengthen or amend our conclusions.

In conclusion, this systemic review and meta- analysis supports the use of TOT as an adjunctive therapy in the treatment of Wagner 1 and 2 DFUs that have not responded to preliminary treatment with optimal SOC alone.

AUTHORS’ CONTRIBUTIONS

Marissa Carter: Data curation (lead), formal analysis (lead), investigation (supporting), meth- odology (lead), supervision (equal), visualization (supporting), writing—original draft (supporting), and writing–review and editing (equal). Robert Frykberg: Data curation (supporting), formal analysis (supporting), investigation (lead), meth- odology (supporting), writing—original draft (sup- porting), and writing—review and editing (equal). Alisha Oropallo: Data curation (supporting), for- mal analysis (supporting), investigation (supporting), methodology (supporting), writing—original draft (supporting), and writing—review and editing (equal). Chandan Sen: Investigation (supporting), methodology (supporting), and writing—review and editing (equal).

David Armstrong: Data curation (supporting), investigation (supporting), and writing—review and editing (equal). Harikrishna Nair: Writing— original draft (supporting) and writing—review and editing (equal). Thomas Serena: Conceptuali- zation (lead), funding acquisition (lead), supervision (equal), visualization (supporting), writing—original draft (supporting), and writing—review and editing (equal). Marissa Carter takes full responsibility for the work, the study design, had access to data, and made the decision to submit and publish the article.

 

ACKNOWLEDGMENTS AND FUNDING SOURCES

The authors acknowledge the valuable input of Prof. Michael Edmonds (Kings College Hospital, London, United Kingdom) and the editorial assis- tance of Kristen Eckert, Strategic Solutions, Inc. The study was funded by SerenaGroup Research Foundation (Cambridge, MA); the study sponsor’s role was to organize the study and maintain flow of work, not to influence how decisions were taken.

 

AUTHOR DISCLOSURE AND GHOSTWRITING

M.J.C.: Has received an honorarium from EO2 Concepts. R.G.F.: Has received research support and consulting fees from Advanced Oxygen Ther- apy, Inc. A.O.: Has received research support from EO2 Concepts. C.K.S.: No conflicts of interest. D.G.A.: No conflicts of interest. H.K.R.N.: No con- flicts of interest. T.E.S.: Has received research support from Inotec and EO2 Concepts. The con- tent of this article was expressly written by the authors listed. No ghostwriters were used to write this article.

 

ABOUT THE AUTHORS

Marissa J. Carter, PhD, is president of Stra- tegic Solutions and is a clinical trial designer and biostatistician with considerable experience in wound care. Robert G. Frykberg, DPM, recently retired from his longstanding position as Chief of Podiatry at the Phoenix VA Medical Center but

continues to hold the academic rank of Professor, University of Arizona College of Medicine-Phoenix. Alisha Oropallo, MD, is a vascular surgeon and wound care physician, and the medical director of the Comprehensive Wound Healing Center and Hyperbarics at Northwell Health. Chandan K. Sen, PhD, is a J. Stanley Battersby Chair and Professor of Surgery, Director of the Indiana Cen- ter for Regenerative Medicine and Engineering (ICRME), and Editor-in-Chief of Advances in Wound Care.

David G. Armstrong, DPM, is an interna- tionally recognized leader in the field of podiatric surgery, diabetic foot, limb preservation, tissue repair, and wound healing. Harikrishna K.R. Nair, MD, is well-known expert in the field of wound healing and is head of the Wound Care Unit, Department of Internal Medicine, Kuala Lumpur Hospital, Malaysia. Thomas E. Serena, MD, is founder and Medical Director of The SerenaGroup, a family of wound, hyperbaric and research com- panies, and a recognized leader in medical wound research and clinical trials.

SUPPLEMENTARY MATERIAL

Supplementary Table S1 Supplementary Table S2

REFERENCES

1. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation: basis for Diabetes Care 1990;13:513–521.
2. Armstrong DG, Boulton AJM, Bus Diabetic foot ulcers and their recurrence. N Engl J Med 2017;376:2367–2375.
3. Zhang P, Lu J, Jing Y, et al. Global epidemi- ology of diabetic foot ulceration: a systematic review and meta-analysis. Ann Med 2017;49: 106–116.
4. Zhang Y, Lazzarini PA, McPhail SM, et al. Global disability burdens of diabetes-related lower- extremity complications in 1990 and Dia- betes Care 2020;43:964–974.
5. Rice JB, Desai U, Cummings AK, et al. Burden of diabetic foot ulcers for medicare and private in- Diabetes Care 2014;37:651–658.

5. Schaper NC, van Netten JJ, Apelqvist J, et al. Practical Guidelines on the prevention and man- agement of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev 2020;36(Suppl 1):e3266.
6. Hingorani A, LaMuraglia GM, Henke P, et al. The management of diabetic foot: a clinical prac- tice guideline by the Society for Vascular Surgery in collaboration with the American Po- diatric Medical Association and the Society for Vascular Medicine. J Vasc Surg 2016;63(2 Suppl): 3S–21S.
7. American Diabetes 11. Microvascular complications and foot care: standards of medi- cal care in diabetes–2021. Diabetes Care 2021; 44(Suppl 1):S151–S167.

8. Frykberg RG, Banks Challenges in the treatment of chronic wounds. Adv Wound Care (New Ro- chelle) 2015;4:560–582.
9. Frykberg Topical wound oxygen therapy in the treatment of chronic diabetic foot ulcers. Medi- cina (Kaunas) 2021;57:917.
10. Driver VR, Reyzelman A, Kawalec J, et al. A prospective, randomized, blinded, controlled trial comparing transdermal continuous oxygen deliv- ery to moist wound therapy for the treatment of diabetic foot ulcers. Ostomy Wound Manage 2017; 63:12–28.

12. Niederauer MQ, Michalek JE, Liu Q, et al. Con- tinuous diffusion of oxygen improves diabetic foot ulcer healing when compared with a placebo control: a randomised, double-blind, multicentre J Wound Care 2018;27(Suppl 9):S30–S45.
13. Serena TE, Bullock MN, Cole W, et Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled clinical trial. J Wound Care 2021;30(Suppl 5): S1–S8.
14. Yu J, Lu S, McLaren AM, et Topical oxygen therapy results in complete wound healing in di- abetic foot ulcers. Wound Repair Regen 2016;24: 1066–1072.
15. Frykberg RG, Franks PJ, Edmonds M, et al. 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;43: 616–624.
16. Gottrup F, Dissemond J, Baines C, et Use of oxygen therapies in wound healing. J Wound Care 2017;26(Suppl 5):S1–S43.
17. Leslie CA, Sapico FL, Ginunas VJ, et Rando- mized controlled trial of topical hyperbaric oxy- gen for treatment of diabetic foot ulcers. Diabetes Care 1988;11:111–115.
18. Blackman E, Moore C, Hyatt J, et al. Topical wound oxygen therapy in the treatment of se- vere diabetic foot ulcers: a prospective controlled Ostomy Wound Manage 2010;56:24–31.
19. Fries RB, Wallace WA, Roy S, et Dermal ex- cisional wound healing in pigs following treat- ment with topically applied pure oxygen. Mutat Res 2005;579:172–181.
20. Gordillo GM, Roy S, Khanna S, et Topical ox- ygen therapy induces vascular endothelial growth factor expression and improves closure of clini- cally presented chronic wounds. Clin Exp Phar- macol Physiol 2008;35:957–964.

21. Kalliainen LK, Gordillo GM, Schlanger R, et Topical oxygen as an adjunct to wound healing: a clinical case series. Pathophysiology 2003;9: 81–87.
22. Gordillo GM, Sen Evidence-based recom- mendations for the use of topical oxygen therapy in the treatment of lower extremity wounds. Int J Low Extrem Wounds 2009;8:105–111.
23. Hirsh F, Berlin SJ, Holtz Transdermal oxygen delivery to diabetic wounds: a report of 6 cases. Adv Skin Wound Care 2009;22:20–24.
24. Sen CK, Khanna S, Gordillo G, et Oxygen, ox- idants, and antioxidants in wound healing: an emerging paradigm. Ann N Y Acad Sci 2002;957: 239–249.
25. Nataraj M, Maiya AG, Karkada G, et al. Applica- tion of topical oxygen therapy in healing dynamics of diabetic foot ulcers—a systematic review. Rev Diabet Stud 2019;15:74–82.
26. Thanigaimani S, Singh T, Golledge J. Topical ox- ygen therapy for diabetes-related foot ulcers: a systematic review and meta-analysis. Diabet Med 2021;38:e14585.
27. Connaghan F, Avsar P, Patton D, et Impact of topical oxygen therapy on diabetic foot ulcer healing rates: a systematic review. J Wound Care 2021;30:823–829.
28. Moher D, Shamseer L, Clarke M, et Preferred reporting items for systematic review and meta- analysis protocols (PRISMA-P) 2015 statement. Syst Rev 2015;4:1.
29. Sterne JAC, Savovic´ J, Page MJ, et RoB 2: a revised tool for assessing risk of bias in rando- mised trials. BMJ 2019;366:l4898.
30. Cro S, Morris TP, Kenward MG, et al. Sensitivity analysis for clinical trials with missing continuous outcome data using controlled multiple imputa- tion: a practical Stat Med 2020;39:2815– 2842.
31. Siemieniuk R, Guyatt G. What is GRADE? BMJ Best Practice. https://bestpractice.bmj.com/info/ us/toolkit/learn-ebm/what-is-grade/ (last accessed February 2, 2022).

32. Neyerlin KC, Gasteiger HA, Mittelsteadt CK, et al. Effect of relative humidity on oxygen reduction kinetics in a J Electrochem Soc 2005;152:A1073.
33. Driver VR, Couch KS, Eckert KA, et The impact of the SARS-CoV-2 pandemic on the management of chronic limb-threatening ischemia and wound care. Wound Repair Regen 2022;30:7–23.
34. Kaufman H, Gurevich M, Tamir E, et Topical oxygen therapy used to improve wound healing in a large retrospective study of wounds of mixed aetiology. Wounds Int 2021;12:63–68.
35. Yellin JI, Gaebler JA, Zhou FF, et al. Reduced hospitalizations and amputations in patients with diabetic foot ulcers treated with cyclical pressurized topical wound oxygen therapy: real-world Adv Wound Care (New Rochelle) 2021. [Epub ahead of print]; DOI: 10.1089/wound.2021.0118.
36. S. Food and Drug Administration. Guidance for Industry: Chronic Cutaneous Ulcer and Burn Wounds–Developing Products for Treatment, 2006. www.fda.gov/downloads/drugs/guidancecompliance regulatoryinformation/guidances/ucm071324.pdf (last accessed February 2, 2022).