research on diabetic foot care

History of Oxygen Therapy for the Treatment of DFUs

New, evidence-based therapies for dfus, looking ahead: therapeutic approaches in the research and development pipeline, keeping the ulcer healed: patients’ views on digital technology in the prevention of ulcer recurrence, conclusions, article information, abbreviations, new evidence-based therapies for complex diabetic foot wounds.

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Andrew J.M. Boulton, David G. Armstrong, Magnus Löndahl, Robert G. Frykberg, Frances L. Game, Michael E. Edmonds, Dennis P. Orgill, Kimberly Kramer, Geoffrey C. Gurtner, Michael Januszyk, Loretta Vileikyte; New Evidence-Based Therapies for Complex Diabetic Foot Wounds. ADA Clinical Compendia 22 February 2022; 2022 (2): 1–23. https://doi.org/10.2337/db2022-02

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After the outstanding success of two previous American Diabetes Association (ADA) compendia on the diabetic foot— Diagnosis and Management of Diabetic Foot Complications ( 1 ) and Diagnosis and Management of Diabetic Foot Infections ( 2 )—the Association asked us to proceed with a third volume.

At the time of writing, the International Diabetes Federation had just published the 10th edition of its IDF Diabetes Atlas ( 3 ), which, in many ways, makes for depressing reading. The past 2 years have seen a 16% increase in the global prevalence of diabetes, with one in 10, or >537 million, adults now having the disease. However, depressing though these data are, they do not take into account the impact the current global coronavirus disease 2019 (COVID-19) pandemic will likely have on the worldwide prevalence of diabetes and its complications. Our pessimism regarding this possible impact is supported by a recent study from the United Kingdom which, using A1C as a surrogate, estimated the effect of the pandemic on diabetes diagnosis and management ( 4 ). An 80% reduction in A1C testing was reported in April 2020; in the first 6 months of the pandemic, an estimated 1.4 million A1C tests were missed for routine monitoring of glycemic control, and >5 million more tests were missed for the diagnosis of diabetes. Thus, we fear a tsunami of diabetes and its late complications in the next decade.

Sadly, despite recent progress in prevention, diagnosis, and management, these recent developments will likely result in an increased incidence of diabetic foot ulcers (DFUs). Thus, the need for good, evidence-based, efficacious treatments for chronic DFUs is more important than ever.

Previously, we reported on a renaissance in diabetic foot care, with new evidence-based treatments ( 1 , 2 ). A number of new therapies are now available, with efficacy supported by well-designed, randomized controlled trials (RCTs).

Although there is a long history of the use of oxygen therapies for chronic DFUs, hyperbaric oxygen therapy (HBOT), which is most commonly used in the United States, has little evidence to support its use, and almost all RCTs of this treatment have been negative ( 5 ). However, recent trials of topical oxygen therapy (TOT) for DFUs have been encouraging ( 6 , 7 ). Thus, we asked our expert writing group first to review the history of oxygen therapies in the diabetic foot and then to discuss the increasing evidence that TOT can accelerate the healing of chronic DFUs.

Other new, evidence-based therapies for DFUs include autologous leucocyte, platelet, and fibrin multilayered patches for hard-to-heal ulcers and sucrose octasulfate dressings for hard-to-heal neuroischemic ulcers ( 8 , 9 ). This treatise includes reviews of both of these new therapies by members of our author group (F.L.G. and M.E.E.) who participated in the clinical trials of the respective agents. Additionally, the use of negative pressure wound therapy (NPWT), which is also supported by evidence from RCTs, is reviewed. The final two sections of this compendium explore putative new, evidence-based therapies for DFUs that are in the pipeline and, most importantly, how we might engage digital technology and other aids to facilitate the prevention of DFU recurrence.

Oxygen is essential for energy production and tissue survival in humans. However, it is not only a prerequisite for aerobic cell metabolism. Reactive oxygen species such as hydrogen peroxide and superoxide are crucial in the oxidative killing of bacteria. They also serve as cellular messengers to stimulate key processes in wound healing, including cell motility, cytokine action, and angiogenesis. Inflammatory reactions and reparative processes, including cell proliferation and collagen synthesis following tissue injuries such as DFUs, increase oxygen requirements. If the need for oxygen is beyond the body’s delivery capacity to the affected area, the healing process will be compromised, increasing the risk of severe infections and gangrene. Although the role of oxygen in ulcer healing is not yet completely understood, many experimental and clinical studies have shown DFU healing to be impaired in hypoxic conditions.

In diabetes, macrovascular and microvascular disease contribute to impaired blood circulation in the lower extremities. It is mandatory to evaluate peripheral circulation early in the course of DFU treatment, as an open or endovascular procedure might restore the vascular and oxygen-delivering capacity to a level conducive to ulcer healing. Macrovascular disease tends to occur at a younger age and engages more distal vessels in people with diabetes. Microvascular dysfunction is an even more treacherous companion to diabetes, as it progresses over a long time and engages all organ systems. The consequences of the capillary basement membrane thickening with endothelial hypertrophy, increased permeability, and decreased responsiveness to environmental and physical changes are frequently present in people with DFUs. These changes result in diminished blood flow, decreased oxygen tension, tissue edema, and subsequent capillary rarefaction. Because the rate of oxygen delivery is inversely proportional to the square of the distance and directly proportional to the partial pressure of oxygen (Po 2 ) at the initial point at the capillary, these consequences lead to reduced oxygen delivery capacity and increased risk of clinically significant ischemia.

Accordingly, as a rational consequence of the observation that the lack of oxygen decreases ulcer healing, applying oxygen either topically or systemically has a long history, and several methods have been implemented to increase DFU healing by modifying oxygen concentration.

In 1775, Joseph Priestley tested his discovered dephlogisticated air (later called oxygen by Lavoisier) on himself and wrote, “The feeling of it in my lungs was not sensibly different from that of common air, but I fancied that my breast felt peculiarly light and easy for some time afterwards” ( 10 , 11 ). The first investigations on the efficacy of oxygen in treating disease occurred from 1798 to 1800 at the Pneumatic Institution in Bristol, U.K., and it is possible that this is where the first oxygen inhalation treatment for a DFU was given. Apart from that, many of the techniques used in modern oxygen therapy, including corrugated noncrushable breathing tubes, mouthpieces, and the mass production of gases, originate from this early work ( 12 ). These early rational years were followed by dark ages when intermittent oxygen treatment became a panacea and was brought to the market by charlatans and profiteers. This era climaxed in 1869, when an article in The Lancet advocated oxygenated bread and water ( 13 ). The early 1890s were a new dawning for oxygen therapy, during which continuous inhaling was successfully introduced in people with pneumonia ( 14 ). The origin of rational systemic medical oxygen use can be dated to early 1917, when John Scott Haldane published an article titled “The Therapeutic Administration of Oxygen” ( 15 ).

Oxygen was added to the armamentarium of DFUs some 50 years later. Anecdotal stories of reduced infection and hastened healing resulting from daily flooding of DFUs with oxygen in hospitalized patients might be considered the origin of TOT (A. Nilsson, personal communication). TOT, the administration of oxygen applied topically over injured tissue by either continuous or pressurized delivery, was introduced in the mid-20th century ( 16 ). A bag, boot, or extremity chamber is placed around the DFU, sealed tightly to prevent leakage, and attached to an oxygen delivery device or tank. In TOT, oxygen is given with either constant or cyclical pressure. If not continuous, a typical session lasts 90 minutes, and the therapy is given three to five times per week. In animal models, TOT has been shown to increase wound tissue Po 2 levels tenfold, accompanied by increased vascular endothelial growth factor (VEGF) levels, signs of improved angiogenesis, and better collagen quality. Until recently, clinical evidence supporting TOT in the healing of DFUs has been scarce, but in recent years, several positive, well-designed trials of TOT have been published and are discussed in detail below.

Parallel to the introduction of TOT, Brummelkamp et al. ( 17 ) reported beneficial effects of HBOT for infected ischemic leg ulcers, and in 1979, Hart and Strauss ( 18 ) published the first DFU study. HBOT is a short-term, high-dose oxygen inhalation and diffusion therapy that is delivered systemically through airways and blood and achieved by having the patient breathe concentrated oxygen at a pressure >1 absolute atmosphere (ATA). The treatment is given in hyperbaric chambers. Patients with DFUs are usually treated once daily for 80–90 minutes at 2.0–2.5 ATA (the pressure 10–15 m below sea surface), on 5 days per week for 6–8 weeks.

The rationale for HBOT is to restore abnormal tissue oxygen tension by applying basic physical gas laws. Compared to normobaric air-breathing, the volume of dissolved oxygen in plasma and tissue during an HBOT session increases 20-fold, allowing survival without erythrocytes. In cell and animal models, HBOT has been shown to improve leukocyte function, enhance neovascularization, reduce edema, downregulate inflammation, and enhance granulation tissue formation. Altogether, 210 patients with hard-to-heal ulcers without the need for or possibility of vascular intervention at the time of randomization have been included in RCTs reporting long-term follow-up of at least 1 year ( 19 – 21 ). Of the patients receiving HBOT, 63% healed compared to 20% of those in control groups. Two RCTs that included patients with severe peripheral artery disease (PAD) and allowed for early vascular intervention have been published. In 68 hospitalized patients with severe infection or PAD, Faglia et al. ( 22 ) demonstrated a statistically significant reduction in major amputation of 9 versus 33% in favor of HBOT, although this trial later came under criticism. More recently, Santema et al. ( 23 ) showed a nonsignificant 45% reduction in major amputations of 12 versus 22% during the first year after HBOT. However, this study exemplified one of the main problems with HBOT studies in that it was underpowered, with pre-terminated enrollment when only 53% of the preplanned 226 participants had been randomized.

Robust evidence is lacking for the selection of a treatment regimen leading to optimal therapeutic benefit (i.e., hyperbaric pressure level, duration of treatment sessions, number of HBOT sessions, and—not least—timing of HBOT). Transcutaneous oxygen pressure (TcPo 2 ), in contrast to ankle-brachial index (ABI) or toe-brachial index (TBI), seems to be helpful to predict treatment outcome, with the increment during hyperbaric conditions being the best predictor. Furthermore, the cost of HBOT, especially in the United States, has resulted in questioning of its usefulness. Finally, there have been a number of negative studies on HBOT in DFUs in the past two decades, although these, too, received much criticism ( 5 ).

In the 21st century, new methods to increase ulcer oxygenation have focused on dressings and local treatments such as a topical spray containing purified porcine hemoglobin to facilitate oxygen transport from the surface to the bottom of the wound bed. The clinical efficacy of these methods remains to be proven. Future possible noteworthy methods include an alginate gel containing oxygen-storing droplets and a gel containing microspheres with hydrogen peroxide.

History repeats itself. Mirroring the use of oxygen a century earlier, HBOT was, during parts of the 20th century, promoted as a cure for almost any disease, often without supporting evidence beyond single case reports. These issues have affected the reputation of the therapy. Hypoxia impairs the healing of DFUs. Both TOT and HBOT can remedy tissue hypoxia, and several RCTs have shown their potential for improving DFU healing. However, rigorously designed, adequately powered, and well-executed RCTs are needed to accurately validate the potential benefits of these and other oxygen concentration–increasing therapies in the plausible future DFU armamentarium.

History of Oxygen Therapy for the Treatment of DFUs

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