Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2023 update).

AIMS: Offloading mechanical tissue stress is arguably the most important of multiple interventions needed to heal diabetes-related foot ulcers. This is the 2023 International Working Group on the Diabetic Foot (IWGDF) evidence-based guideline on offloading interventions to promote healing of foot ulcers in persons with diabetes. It serves as an update of the 2019 IWGDF guideline. MATERIALS AND METHODS: We followed the GRADE approach by devising clinical questions and important outcomes in the PICO (Patient-Intervention-Control-Outcome) format, undertaking a systematic review and meta-analyses, developing summary of judgement tables and writing recommendations and rationales for each question. Each recommendation is based on the evidence found in the systematic review, expert opinion where evidence was not available, and a careful weighing of GRADE summary of judgement items including desirable and undesirable effects, certainty of evidence, patient values, resources required, cost effectiveness, equity, feasibility, and acceptability. RESULTS: For healing a neuropathic plantar forefoot or midfoot ulcer in a person with diabetes, use a non-removable knee-high offloading device as the first-choice offloading intervention. If contraindications or patient intolerance to non-removable offloading exist, consider using a removable knee-high or ankle-high offloading device as the second-choice offloading intervention. If no offloading devices are available, consider using appropriately fitting footwear combined with felted foam as the third-choice offloading intervention. If such a non-surgical offloading treatment fails to heal a plantar forefoot ulcer, consider an Achilles tendon lengthening, metatarsal head resection, joint arthroplasty, or metatarsal osteotomy. For healing a neuropathic plantar or apex lesser digit ulcer secondary to flexibile toe deformity, use digital flexor tendon tenotomy. For healing rearfoot, non-plantar or ulcers complicated with infection or ischaemia, further recommendations have been outlined. All recommendations have been summarised in an offloading clinical pathway to help facilitate the implementation of this guideline into clinical practice. CONCLUSION: These offloading guideline recommendations should help healthcare professionals provide the best care and outcomes for persons with diabetes-related foot ulcers and reduce the person's risk of infection, hospitalisation and amputation.

Prevalence and characteristics of pain in patients with lower-extremity ulcers-A cross-sectional study.

The study aimed to investigate the prevalence and characteristics of pain in different ulcer types and to identify factors associated with pain experience in patients with lower-extremity ulcers. A cross-sectional single-centre study was performed, including 130 newly referred outpatients with lower-extremity ulcers. Pain intensity was measured with a visual analog scale (VAS) and pain characteristics with the short form mcgill pain questionnaire-2 (SF-MPQ-2). The mean pain intensity was 29.5 (SD 31.8) at rest and 35.5 (SD 34.1) during movement (0-100 VAS). 61.5% of the patients experienced pain (VAS > 0) at rest and 70.8% during movement. Moderate to severe pain at rest was seen in 39.2% and in 43.8% of patients during movement. The mean total score on SF-MPQ-2 (range 0-220) was 35.9 (SD 32.6). Most of the patients described pain as intermittent (mean 11.8 SD 13.9). Analgesics were prescribed for 78% of the patients. Ulcer type (i.e., arterial, immunological, pressure and venous) and age were associated with pain severity, and women had a significantly lower well-being score than men. Prevalence of pain in patients with lower-extremity ulcers was high across different ulcer aetiologies. Pain intensity and quality must be assessed to obtain adequate pain management.

Effect of Stabilized Hypochlorous Acid on Re-epithelialization and Bacterial Bioburden in Acute Wounds: A Randomized Controlled Trial in Healthy Volunteers.

The aim of this randomized controlled trial was to evaluate the wound-healing effect and antimicrobial properties of a novel stabilized hypochlorous acid solution on acute wounds, using a suction blister wound model. One suction blister was raised and de-roofed on each forearm in 20 healthy volunteers. Stabilized hypochlorous acid/control (sterile 0.9% NaCl) solutions were assigned to either wound by randomization. Wounds were irrigated and treated on days 0, 2 and 4. Re-epithelialization was assessed blindly by digital planimetry, and bacterial growth was assessed as the number of colony-forming units cultured from surface swabs. Hypochlorous acid solution increased the degree of re-epithelialization on day 4 by 14% compared with the control solution (95% confidence interval (CI) 6.8-20%, p = 0.00051) and was not inferior (p < 0.0001) to the control solution on day 10 (0.3%, 95% CI -1.3-1.9%). Median bacterial counts were lower with stabilized hypochlorous acid compared with control and were further reduced after irrigation and treatment of both groups on day 4, but remained lower in the stabilized hypochlorous acid group compared with the control group. This study demonstrates immediate and durable antimicrobial action and a beneficial effect on acute wound healing after irrigation and treatment with a stabilized hypochlorous acid formulation.

Biomarkers of Skin Graft Healing in Venous Leg Ulcers.

There is a need for biomarkers that predict the success of transplantation of venous leg ulcers (with autologous split-thickness skin grafts). The primary objective of this exploratory study was to investigate the association between split-thickness skin graft healing in venous leg ulcers and candidate wound fluid biomarkers representing inflammatory cell and endogenous proteinase activities, and bioactivity. A secondary objective was to compare biomarker levels of the 17 venous leg ulcers with sterile split-thickness skin graft donor-site wounds in another 10 patients with venous leg ulcers. Wound fluids were collected for 24 h using a validated method. The concentration of preoperative matrix metalloproteinase-9 in wound fluid was higher in venous leg ulcers showing good healing (n = 10) than in venous leg ulcers showing poor healing (n = 7) 12 weeks after transplantation with meshed split-thickness skin grafts. The diagnostic value of matrix metalloproteinase-9 was good according to receiver-operating characteristic curve analysis. Matrix metalloproteinase activity in wound fluids from split-thickness skin graft donor-site wounds increased as a function of time and healing, but was still lower than matrix metalloproteinase activity in venous leg ulcer wound fluids, which showed increased levels of most biomarkers except for matrix metalloproteinase-9 and matrix metalloproteinase-2. In conclusion, wound fluid matrix metalloproteinase-9 concentration is a potential predictive biomarker of split-thickness skin graft healing in venous leg ulcers.

Cytokines and Venous Leg Ulcer Healing-A Systematic Review.

Venous leg ulcers (VLUs) are the most common type of leg ulcers with a significant socioeconomic burden due to slow healing. Cytokines may be involved in the pathogenesis of VLUs. In this systematic review, our objective was to investigate the association between cytokine levels, including growth factors, with the healing of VLUs. PubMed, Embase, Web of Science and Cochrane Library were searched from their inception to August 2021. We retrieved 28 articles investigating 38 different cytokines in 790 patients. Cytokines were most commonly investigated in wound fluid and less frequently in biopsies and serum. The studies were judged as having a moderate to high risk of bias, and the results were often inconsistent and sometimes conflicting. A meta-analysis was not performed due to clinical and methodological heterogeneities. We found weak evidence for elevated IL-1α, IL-6, IL-8, TNF-α and VEGF levels in non-healing VLUs, an elevation that declined with healing. TGF-ß1 levels tended to increase with VLU healing. Other cytokines warranting further investigations include EGF, FGF-2, GM-CSF, IL-1ß, IL-1Ra and PDGF-AA/PDGF-BB. We conclude that non-healing VLUs may be associated with an elevation of a palette of pro-inflammatory cytokines, possibly reflecting activated innate immunity in these wounds. There is a paucity of reliable longitudinal studies monitoring the dynamic changes in cytokine levels during wound healing.

Wounds in chronic leg oedema.

Wounds and chronic oedema are common disorders, but rarely studied together. The objective of this cross-sectional study was to investigate the point-prevalence and risk factors of wounds on the leg, in chronic leg oedema. Forty sites in nine countries were included. Of 7077 patients with chronic leg oedema, 12.70% had wounds. Independent risk factors were: peripheral arterial disease (odds ratio (OR) 4.87, 95% confidence intervals (CI) 3.63-6.52), cellulitis within the past 12 months (OR 2.69, 95% CI 2.25-3.21), secondary lymphoedema (OR 2.64, 95% CI 1.93-3.60), being male (OR 2.08, 95% CI 1.78-2.44), being over 85 years of age (OR 1.80, 95% CI 1.23-2.62), underweight (OR 1.79, 95% CI 1.14-2.79), bed bound (OR 1.79, 95% CI 1.01-3.16), chair bound (OR 1.52, 95% CI 1.18-1.97), diabetes (OR 1.47, 95% CI 1.23-1.77), and walking with aid (OR 1·41, 95% CI 1.17-1.69). 43.22% of those with wounds had clinically defined well-controlled oedema, associated with a significantly lower risk of wounds (OR 0.50, 95% CI 0.42-0.58, P < .001). Hard/fibrotic tissue (OR 1.71, 95% CI 1.19-2.48), and a positive Stemmers sign (OR 1.57, 95% CI 1.05-2.35) were associated with wounds. The study reinforces the importance of measures to control oedema, as controlled swelling was associated with a 50% lower risk of wounds.

A novel chronic wound biofilm model sustaining coexistence of Pseudomonas aeruginosa and Staphylococcus aureus suitable for testing of antibiofilm effect of antimicrobial solutions and wound dressings.

Chronic wounds are a large burden to patients and healthcare systems. Biofilm infections in chronic wounds are crucial factors leading to non-healing of wounds. It is important to study biofilm in wounds and to develop effective interventions against wound biofilm. This study presents a novel in vitro biofilm model mimicking infected chronic wounds. The novel layered chronic wound biofilm model uses woundlike media and includes both Pseudomonas aeruginosa and Staphylococcus aureus, which have been identified as the most important pathogens in wounds. The model sustains their coexistence for at least 96 h. Microscopy of the model revealed microbial growth in non-surface attached microcolonies as previously observed in vivo. The model was used to determine log10 -reduction for the use of an antimicrobial solution and antimicrobial dressings (containing silver or honey) showing moderate-to-low antibiofilm effect, which indicates better concordance with the observed clinical performance of this type of treatment than other widely used standard tests.

Pseudomonas aeruginosa transcriptome during human infection.

Laboratory experiments have uncovered many basic aspects of bacterial physiology and behavior. After the past century of mostly in vitro experiments, we now have detailed knowledge of bacterial behavior in standard laboratory conditions, but only a superficial understanding of bacterial functions and behaviors during human infection. It is well-known that the growth and behavior of bacteria are largely dictated by their environment, but how bacterial physiology differs in laboratory models compared with human infections is not known. To address this question, we compared the transcriptome of Pseudomonas aeruginosa during human infection to that of P. aeruginosa in a variety of laboratory conditions. Several pathways, including the bacterium's primary quorum sensing system, had significantly lower expression in human infections than in many laboratory conditions. On the other hand, multiple genes known to confer antibiotic resistance had substantially higher expression in human infection than in laboratory conditions, potentially explaining why antibiotic resistance assays in the clinical laboratory frequently underestimate resistance in patients. Using a standard machine learning technique known as support vector machines, we identified a set of genes whose expression reliably distinguished in vitro conditions from human infections. Finally, we used these support vector machines with binary classification to force P. aeruginosa mouse infection transcriptomes to be classified as human or in vitro. Determining what differentiates our current models from clinical infections is important to better understand bacterial infections and will be necessary to create model systems that more accurately capture the biology of infection.

Diabetic foot off loading and ulcer remission: Exploring surgical off-loading.

INTRODUCTION: Diabetic peripheral neuropathy leads to foot deformity, soft tissues damage, and gait imbalance, all of which can increase the mechanical stress imposed on the foot and give rise to Charcot neuroarthropathy. The current International Working Group of the Diabetic Foot International Guidelines on offloading focus on managing neuropathic foot ulcers related to pressure: only 2 of their 9 recommendations deal with surgical interventions. We assess the role of surgical techniques in off-loading to heal and possibly prevent diabetic foot ulceration. METHODS: We systematically analysed published data from January 2000 to November 2020 to assess methods of surgical offloading and associated outcomes for the surgical reconstruction. We tried to identify healing, remission-rates, return to ambulation, complications and limitations. RESULTS: Five discrete categories of surgical offloading are used in recalcitrant ulcers: 1. Lesser toe tenotomies; 2. Metatarsal head resection ± Achilles tendon release; 3. Hallux procedures; 4. Bony off-loading procedures in the form of exostectomy; and 5. Complex surgical foot reconstruction. Adjuvant modalities including surgically placed antibiotic delivery systems show promise, but further studies are required to clarify their role and effect on systemic antibiotic requirements. CONCLUSIONS AND IMPLICATIONS: Surgery is important to mechanically stabilise and harmonise the foot for long term off-loading and foot-protection. Surgery should not be reserved for recalcitrant cases only, but extended to ulcer prevention and remission. Further comparative studies will benefit surgical decision making to avoid recurrence and define time point when surgical off-loading could protect against irretrievable tissue loss/re-ulceration.

The zone model: A conceptual model for understanding the microenvironment of chronic wound infection.

In 2008, two articles in Wound Repair and Regeneration changed the clinical perspective on chronic wounds. They stated that chronic wounds that do not heal contain bacterial biofilms and that these biofilms may be one of the reasons for the nonhealing properties of the wounds. However, we still do not understand the exact role biofilms play in the halted healing process, and we are not able to successfully treat them. The reason for this could be that in vivo biofilms differ substantially from in vitro biofilms, and that most of the knowledge about biofilms originates from in vitro research. In this article, we introduce the zone model as a concept for understanding bacterial behavior and the impact of the microenvironment on both the host and the bacteria. Until now, identification of bacteria, gene expression, and postscript regulation have been looking at a bulk of bacteria and averaging the behavior of all the bacteria. As the zone model dictates that every single bacterium reacts to its own microenvironment, the model may facilitate the planning of future research with improved clinical relevance. The zone model integrates physiology and biology from single cells, microbial aggregates, local host response, surrounding tissue, and the systemic context of the whole host. Understanding the mechanisms behind the actions and reactions by a single bacterium when interacting with other neighboring bacteria cells, other microorganisms, and the host will help us overcome the detrimental effects of bacteria in chronic wounds. Furthermore, we propose use of the terminology "bacterial phenotype" when describing the actions and reactions of bacteria, and the term "biofilms" to describe the morphology of the bacterial community.

Staphylococcus aureus Augments Release of Matrix Metalloproteinase-8 from Human Polymorpho-nuclear Leukocytes.

is missing (Short communication).

Non-antibiotic antimicrobial interventions and antimicrobial stewardship in wound care.

Control of wound infection today relies largely on antibiotics, but the continual emergence of antibiotic-resistant microorganisms threatens a return to the pre-antibiotic era when physicians used antiseptics to prevent and manage infection. Some of those antiseptics are still used today, and others have become available. A diverse variety of non-antibiotic antimicrobial interventions are found on modern formularies. Unlike the mode of action of antibiotics, which affect specific cellular target sites of pathogens, many non-antibiotic antimicrobials affect multiple cellular target sites in a non-specific way. Although this reduces the likelihood of selecting for resistant strains of microorganisms, some have emerged and cross-resistance between antibiotics and antiseptics has been detected. With the prospect of a post-antibiotic era looming, ways to maintain and extend our antimicrobial armamentarium must be found. In this narrative review, current and emerging non-antibiotic antimicrobial strategies will be considered and the need for antimicrobial stewardship in wound care will be explained.

Acute foot attack in patients with diabetes requires urgent action.

This review summarises the present knowledge of acute foot attacks in patients with diabetes. Diagnosis and treatment of acute foot attacks in patients with diabetes are often delayed, which increases the risk of amputations. To prevent this, urgent action is necessary, as it is for acute myocardial infarction and stroke, to ensure that patients are seen by competent specialists in a multidisciplinary team within hours. By following evidence-based guidelines, such as the National Treatment Guideline for diabetic foot disease from the Danish Endocrine Society, and seeking immediate medical attention, the risk of amputation and complications can be significantly reduced.

A First-in-Human Randomized Clinical Study Investigating the Safety and Tolerability of Stabilized Hypochlorous Acid in Patients with Chronic Leg Ulcers.

Objective: Biofilm infections in chronic wounds are common and pose a significant clinical challenge. This challenge was addressed by developing the SoftOx Biofilm Eradicator (SBE) composed of hypochlorous acid (HOCl) and acetic acid with strong broad-spectrum antimicrobial activity. Approach: First-in-human study investigating the safety and tolerability as primary endpoints and wound size effect and antimicrobial efficacy as secondary endpoints of SBE treatment in chronic leg wound patients. The study was divided into two as follows: a randomized, double-blinded, Single Ascending Dose (SAD) phase (n = 16 SBE; n = 4 placebo), where patients were treated with SBE or saline (placebo) only once, followed by an open-label, Multiple Ascending Dose (MAD) phase (n = 8), where patients were treated with SBE once daily or twice daily over five days. Reporting is according to CONSORT guidelines. Results: SBE was safe and well-tolerated in chronic leg wound patients. There were no significant differences in pain during and after treatment with SBE or the placebo. The SBE treatment reduced bioburden in wounds compared to baseline, with 98% and 49% median reduction after SBE or placebo treatment, respectively. A dose-dependent trend in absolute wound size reduction was observed in the MAD groups with a median (min, max) change of -2.99 (-14.25, -1.5) cm2 in the once-daily and -10.48 (-17.95, -0.38) cm2 in the twice-daily group, respectively. Innovation and Conclusion: This study demonstrated the safe use of HOCl-based SBE in chronic leg wounds with promising trends of immediate antimicrobial action and beneficial effect on wound healing.

Novel sampling technique maintaining the two-dimensional organization of microbes during cultivation from chronic wounds: The Imprint method.

This study aimed to develop and validate "the Imprint method,", a technique for sampling microbes from chronic wounds while preserving their two-dimensional spatial organization. We used nylon filters to sample bacteria and compared with sampling using Eswabs in 12 patients. The Imprint method identified a mean of 0.93 unique species more than Eswab (4.3 ± 2.2 and 3.4 ± 1.4 unique species, respectively; mean ± SD; n = 30). Accuracy between the Eswab and the Imprint method was 93.2% and in cases of disagreement between methods, Imprint had a higher sensitivity in 6/8 of the most prevalent species. In vitro validation confirmed that the Imprint method could transfer bacterial colonies while replicating their two-dimensional organization and the area covered by bacteria on the plate sampled. Clinical testing demonstrated that the imprint method is a rapid and feasible technique that identified more unique bacterial species than Eswab with a good agreement between methods but that Imprint was better at detecting important pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. The Imprint method is a novel technique that cultures and records the two-dimensional organization of microbes, providing an alternative or supplement to conventional surface culture using Eswab.

Glucagon-like peptide-1 treatment reduces the risk of diabetes-type 2 related amputations: A cohort study in Denmark.

AIMS: To assess the impact of Glucagon-like peptide-1 (GLP-1) agonists on the risk of lower extremity amputations in patients with type 2 diabetes mellitus (DM2). METHODS: We conducted a cohort study on 309,116 patients with DM2 using Danish National Register and Diabetes Database. We tracked the GLP-1 agonists over time along with the medication dose. Time-varying models are used to assess the risk of amputation for patients with/without GLP-1 treatment. RESULTS: Patients on GLP-1 treatment experience a notable reduction in the risk of amputation compared to those without the treatment with a hazard ratio (HR) of 0.5, 95% CI [0.54-0.74], indicating a statistically significant difference (p <.005). This risk reduction was consistent across different age groups, but notably most pronounced among middle income patients. The findings were further validated by using time-varying Cox models, which considered the patient's comorbidity history. CONCLUSIONS: Our analysis reveals compelling evidence of a reduced risk of amputation among patients receiving GLP-1 therapy, an effect dominated by liraglutide, compared to those without the treatment, even after adjusting for various socio-economic factors. However, further investigation is required to identify and account for any other potential confounding variables that may impact the outcome.

Amputations in Denmark in patients with diabetes.

In Denmark, the incidence rate of lower extremity amputations (LEA) in patients with diabetes has decreased remarkably from 1980 to 2017, in contrast to USA, where it has increased in the last decade. In this review the development in Denmark is summarised. In fact, in 2017, the incidence rate of LEA in patient with diabetes was "only" two-4 four-fold larger than in persons without diabetes. Evidence-based guidelines, like the national treatment guideline from the Danish Endocrine Society, must be followed by health-care providers and patients to further decrease the incidence rate of LEA.

The Safety and Antimicrobial Properties of Stabilized Hypochlorous Acid in Acetic Acid Buffer for the Treatment of Acute Wounds-a Human Pilot Study and In Vitro Data.

Acute wounds may require cleansing to reduce the risk of infection. Stabilized hypochlorous acid in acetic buffer (HOCl + buffer) is a novel wound irrigation solution with antimicrobial properties. We performed a first-in-man, prospective, open-label pilot study to document preliminary safety and performance in the treatment of acute wounds. The study enrolled 12 subjects scheduled for a split-skin graft transplantation, where the donor site was used as a model of an acute wound. The treatment time was 75 s, given on 6 occasions. A total of 7 adverse events were regarded as related to the treatment; all registered as pain during the procedure for 2 subjects. One subject had a wound infection at the donor site. The mean colony-forming unit (CFU) decreased by 41% after the treatment, and the mean epithelialization was 96% on both days 14 (standard deviation [SD] 8%) and 21 (SD 10%). The study provides preliminary support for the safety, well-tolerance, and efficacy of HOCl + buffer for acute wounds. The pain was frequent although resolved quickly. Excellent wound healing and satisfying antimicrobial properties were observed. A subsequent in vitro biofilm study also indicated good antimicrobial activity against Pseudomonas aeruginosa with a 96% mean reduction of CFU, when used for a treatment duration of 15 min (P < .0001), and a 50% decrease for Staphylococcus aureus (P = .1010). Future larger studies are needed to evaluate the safety and performance of HOCl + buffer in acute wounds, including the promising antimicrobial effect by prolonged treatment on bacterial biofilms.

Bacterial invasion of the submicron osteocyte lacuna-canaliculi network (OLCN): a part of osteomyelitis disease biology.

Two chronic osteomyelitis patients, a diabetic foot osteomyelitis patient and a fracture-related infection patient, all with staphylococci-positive microbiology, were examined to confirm the clinical relevance of bacterial invasion of the submicron osteocyte lacuna-canaliculi network (OLCN) in bone tissue. Based on immunohistochemistry and light microscopy both Staphylococcus aureus and Staphylococcus epidermidis were identified within the OLCN of all four patients. The findings consolidate that bacterial OLCN invasion is a clinically relevant part of osteomyelitis disease biology, which from experimental porcine infections, seems to be time depending. The microscopy pictures of the four patients significantly add to visualize the phenomenon of bacterial OLCN invasion.