Wound Bed Preparation 2024: Delphi Consensus on Foot Ulcer Management in Resource-Limited Settings.

GENERAL PURPOSE: To review a practical and scientifically sound application of the wound bed preparation model for communities without ideal resources. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and registered nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Summarize issues related to wound assessment.2. Identify a class of drugs for the treatment of type II diabetes mellitus that has been shown to improve glycemia, nephroprotection, and cardiovascular outcomes.3. Synthesize strategies for wound management, including treatment in resource-limited settings.4. Specify the target time for edge advancement in chronic, healable wounds.

Chronic wound management in low-resource settings deserves special attention. Rural or underresourced settings (ie, those with limited basic needs/healthcare supplies and inconsistent availability of interprofessional team members) may not have the capacity to apply or duplicate best practices from urban or abundantly-resourced settings. The authors linked world expertise to develop a practical and scientifically sound application of the wound bed preparation model for communities without ideal resources. A group of 41 wound experts from 15 countries reached a consensus on wound bed preparation in resource-limited settings. Each statement of 10 key concepts (32 substatements) reached more than 88% consensus. The consensus statements and rationales can guide clinical practice and research for practitioners in low-resource settings. These concepts should prompt ongoing innovation to improve patient outcomes and healthcare system efficiency for all persons with foot ulcers, especially persons with diabetes.

Growth factors for treating chronic venous leg ulcers: A systematic review and meta-analysis.

Chronic venous leg ulcers (VLU) are wounds that commonly occur due to venous insufficiency. Many growth factors have been introduced over the past two decades to treat VLU. This systematic review and meta-analysis evaluates the impact of growth factor treatments of VLU in comparison to control for complete wound healing, percent reduction in wound area, time to wound healing, and adverse events. A systematic review and meta-analysis of randomised trials was conducted. MEDLINE and EMBASE were searched up to December 2020. Studies were included if they compared a growth factor versus placebo or standard care in patients with VLU. From 1645 articles, 13 trials were included (n = 991). There was a significant difference between any growth factor and placebo in complete wound healing (P = 0.04). Any growth factor compared to placebo significantly increased the likelihood of percent wound reduction by 48.80% (P = <0.00001). There was no difference in overall adverse event rate. Most comparisons have low certainty of evidence according to Grading of Recommendations, Assessment, Development, and Evaluation. This meta-analysis suggests that growth factors have a beneficial effect in complete wound healing of VLU. Growth factors may also increase percent reduction in wound area. The suggestion of benefit for growth factors identified in this review is not a strong one based on the low quality of evidence.

Biomarker directed chronic wound therapy - A new treatment paradigm.

AIM: To develop a treatment paradigm for chronic leg ulcers that incorporates new biomarkers of wound healing with currently available therapies. METHODS: Recently published data on GM-CSF and MMP-13 as biomarkers of venous leg ulcer (VLU) healing status with accuracies of 92% and 78% respectively, was reviewed along with the wound bed preparation (WBP) theoretical framework for treatment of chronic wounds. The broad categories of wound treatments that align with the WBP concepts were identified. These were then considered in a hierarchical order that initially improves the wound bed and subsequently incorporates more complex advanced wound therapies. Identification of the non-healing status of the wound is the driver to advance through the different treatments. RESULTS: A point of care test of wound healing status is the key to the systematic use of currently available therapies for chronic leg ulcers in a timely fashion. The different therapies address - debridement, moisture control, bacterial contamination, protease inhibition, formation of granulation tissue, application of growth factors, application of matrix constructs, and application of cellular components. Progression through this hierarchical order of therapies is directed by the leg ulcer remaining in a non-healing state with the previous therapies having been implemented. CONCLUSION: Combining a validated point of care test of wound healing with a systematic approach to wound therapies, has the potential to create a new paradigm of chronic leg ulcer treatment - biomarker directed wound therapy.

Evaluation of wound fluid biomarkers to determine healing in adults with venous leg ulcers: A prospective study.

Clinical practice guidelines recommend using repeated wound surface area measurements to determine if a chronic ulcer is healing. This results in delays in determining the healing status. This study aimed to evaluate whether any of a panel of biomarkers can determine the healing status of chronic venous leg ulcers. Forty-two patients with chronic venous leg ulcers had their wound measured and wound fluid collected at weekly time points for 13 weeks. Wound fluid was analyzed using multiplex enzyme-linked immunosorbent assay to determine the concentration of biomarkers in the wound fluid at each weekly time point. Healing status was determined by examining the change in wound size at the previous and subsequent weeks. Predictive accuracy with 95% confidence intervals (CI) is reported. Of 42 patients, 105 evaluable weekly time points were obtained, with 32 classified as healing, 27 as nonhealing, and 46 as indeterminate. Thirteen biomarkers significantly differed between healing and nonhealing wounds (p < 0.1) and were included in a multivariate logistic regression model. Granulocyte macrophage-colony stimulating factor (p < 0.001) and matrix metalloprotease-13 (p = 0.004) were the best predictors of wound healing. Receiver operating characteristic curves indicated 92% accuracy (95% CI: 85%,100%) for granulocyte macrophage-colony stimulating factor, and 78% accuracy (95% CI: 65%,90%) for matrix metalloprotease-13 in discriminating between healing and nonhealing wounds. This study found that two biomarkers from wound fluid can predict healing status in chronic venous leg ulcers. These findings may lead to the ability to determine the future trajectory of a wound and the ability to modify treatment accordingly.

Ultrasonography Detects Deep Tissue Injuries in the Subcutaneous Layers of the Buttocks Following Spinal Cord Injury.

Background: Ultrasonography may have potential as an effective diagnostic tool for deep tissue injury (DTI) in tissues overlying bony prominences that are vulnerable when under sustained loading in sitting. Methods: Three cases of DTI in the fat and muscle layers overlying the ischial tuberosity of the pelvis in 3 persons with spinal cord injury (SCI) with different medical histories and abnormal tissue signs are described. Conclusion: There is a need for prospective studies using a reliable standardized ultrasonography protocol to diagnose DTI and to follow its natural history to determine its association with the development of pressure injuries.

Adaptation of a MR imaging protocol into a real-time clinical biometric ultrasound protocol for persons with spinal cord injury at risk for deep tissue injury: A reliability study.

BACKGROUND: High strain in soft tissues that overly bony prominences are considered a risk factor for pressure ulcers (PUs) following spinal cord impairment (SCI) and have been computed using Finite Element methods (FEM). The aim of this study was to translate a MRI protocol into ultrasound (US) and determine between-operator reliability of expert sonographers measuring diameter of the inferior curvature of the ischial tuberosity (IT) and the thickness of the overlying soft tissue layers on able-bodied (AB) and SCI using real-time ultrasound. MATERIAL AND METHODS: Part 1: Fourteen AB participants with a mean age of 36.7 ± 12.09 years with 7 males and 7 females had their 3 soft tissue layers in loaded and unloaded sitting measured independently by 2 sonographers: tendon/muscle, skin/fat and total soft tissue and the diameter of the IT in its short and long axis. Part 2: Nineteen participants with SCI were screened, three were excluded due to abnormal skin signs, and eight participants (42%) were excluded for abnormal US signs with normal skin. Eight SCI participants with a mean age of 31.6 ± 13.6 years and all male with 4 paraplegics and 4 tetraplegics were measured by the same sonographers for skin, fat, tendon, muscle and total. Skin/fat and tendon/muscle were computed. RESULTS: AB between-operator reliability was good (ICC = 0.81-0.90) for 3 soft tissues layers in unloaded and loaded sitting and poor for both IT short and long axis (ICC = -0.028 and -0.01). SCI between-operator reliability was good in unloaded and loaded for total, muscle, fat, skin/fat, tendon/muscle (ICC = 0.75-0.97) and poor for tendon (ICC = 0.26 unloaded and ICC = -0.71 loaded) and skin (ICC = 0.37 unloaded and ICC = 0.10). CONCLUSION: A MRI protocol was successfully adapted for a reliable 3 soft tissue layer model and could be used in a 2-D FEM model designed to estimate soft tissue strain as a novel risk factor for the development of a PU.

Reliability and measurement error of digital planimetry for the measurement of chronic venous leg ulcers.

Area measurements of a chronic wound are the gold standard outcome measure to determine if a wound is on a healing or nonhealing trajectory. The use of digital planimetry can provide increased accuracy in measuring wound area however it is important to know the reliability and measurement error of these devices when used by multiple assessors. The aim of this study is to determine the within rater, between rater, and standard error of measurement of a digital planimetry device. Wound area in 42 patients was measured weekly for 12 weeks by two different raters, with each rater measuring the wound 10 times per visit. Intraclass correlation coefficients (ICC 1,k) and standard error of measurement were calculated for both within and between raters using 10 and the first three repeated measures to determine if using less measurements was as reliable. The true change in wound area was calculated by dividing stander error of measurements by mean wound areas. Within rater reliability for raters 1 and 2 were 0.995 and 0.992 for 10 measurements, and 0.996 and 0.992 for 3 measurements per time point. Between rater reliability was 0.979 for 10 measurements and 0.996 for 3 measurements per time point. The within rater standard error of measurement for raters 1 and 2 was 0.98 cm2 and 1.28 cm2 for 10 measurements and 0.895 cm2 and 1.29 cm2 for 3 measurements at each time point. The standard error of measurement for between raters was 2.07 cm2 for 10 measurements and 2.25 cm2 for 3 measurements per time point. The true change in wound size varied from 6.4% for within one rater to 15.7% for across different raters. This study found that both within and between rater reliability of the digital planimetry device was very high for three measurements per time point.

Hard to diagnose and potentially fatal: slow aortic erosion post spinal fusion.

BACKGROUND: Delayed aortic injuries are a rare, but well-recognized complication of spinal surgery. They are a result of slow erosion of osteosynthesis material into the aorta. Although this is a life-threatening complication, patients might present years later with nonspecific symptoms. OBJECTIVE: A complex case of slow aortic injury after thoracic spinal surgery is presented, which highlights the challenges involved in diagnosis and treatment. CASE REPORT: A 62-year-old man had a T6 vertebrectomy and T5-7 anterior spinal fusion for multiple myeloma 5 years earlier. Two years postoperatively, the patient developed intermittent hemoptysis that triggered several presentations to the emergency department and consecutive hospital admissions during a 3-year period. All investigations, including endoscopy, bronchoscopy, and repeated chest computed tomography (CT) scans, were unremarkable. Eventually, the patient presented with frank hemoptysis associated with severe left-sided chest pain. Urgent CT angiography revealed a pseudoaneurysm measuring 34 × 20 mm at the level of the vertebrectomy. The patient underwent emergency surgery and an endoluminal stent graft was successfully placed. The patient remains well after 6 months. CONCLUSIONS: The close proximity of the aorta and spine entertains the risk of aortic injury associated with vertebral osteosynthesis. Long-term complications of slow aortic erosion are extremely difficult to diagnose. The presented patient suffered from an undetected bronchio-aortic fistula with consecutive pseudoaneurysm formation and rupture. Awareness of slow aortic erosion is important for correct diagnostic pathways and subsequent early diagnosis to ensure a positive outcome for the patient.

Oral doxycycline for the treatment of chronic leg ulceration.

This pilot study investigated oral doxycycline as an adjunct to compression therapy for non-healing venous leg ulcers. Ten patients received doxycycline 20 mg twice daily (low-dose doxycycline) and ten patients received doxycycline 100 mg twice daily (high-dose doxycycline). Utilising a pre-test post-test study design, ulcer area was measured and wound fluid was collected before and after 4 weeks of treatment. In the high-dose doxycycline group, the reduction in median ulcer area was 48% (p = 0.1) and there was a significant reduction in wound fluid total matrix metalloprotease-1 (p = 0.02). These effects were not observed with low-dose doxycycline. There were no significant changes in wound fluid tumour necrosis factor-α or quantitative bacteriology following treatment with low-dose or high-dose doxycycline. There was no significant relationship between change in ulcer area and matrix metalloprotease-1, -8 or -9 activities in wound fluid at the end of treatment. Median wound fluid doxycycline concentrations after 4 weeks of treatment were 0.2 mg/L(0.45 lM) and 2.3 mg/L (5.18 lM) [DOSAGE ERROR CORRECTED] in the low-dose and high-dose groups, respectively, which are lower than that previously shown to inhibit matrix metalloproteases and tumour necrosis factor-α. Our study suggests that doxycycline 100 mg twice daily may improve the healing rate of recalcitrant leg ulcers, however the mechanism remains unclear.

Human pilot studies reveal the potential of a vitronectin: growth factor complex as a treatment for chronic wounds.

Several different advanced treatments have been used to improve healing in chronic wounds, but none have shown sustained success. The application of topical growth factors (GFs) has displayed some potential, but the varying results, high doses and high costs have limited their widespread adoption. Many treatments have ignored the evidence that wound healing is driven by interactions between extracellular matrix proteins and GFs, not just GFs alone. We report herein that a clinical Good Manufacturing Practice-grade vitronectin:growth factor (cVN:GF) complex is able to stimulate functions relevant to wound repair in vitro, such as enhanced cellular proliferation and migration. Furthermore, we assessed this complex as a topical wound healing agent in a single-arm pilot study using venous leg ulcers, as well as several 'difficult to heal' case studies. The cVN:GF complex was safe and re-epithelialisation was observed in all but 1 of the 30 patients in the pilot study. In addition, the case studies show that this complex may be applied to several ulcer aetiologies, such as venous leg ulcers, diabetic foot ulcers and pressure ulcers. These findings suggest that further evaluation is warranted to determine whether the cVN:GF complex may be an effective topical treatment for chronic wounds.

Characterization of tumor necrosis factor-α block haplotypes associated with susceptibility to chronic venous leg ulcers in Caucasian patients.

Polymorphisms in the central major histocompatibility complex (MHC) are associated with several immunopathologic and inflammatory diseases, including chronic venous leg ulcers (CVLU). Because of strong linkage disequilibrium, identification of loci affecting disease susceptibility must be based on comparisons between haplotypes. Here we examine the association of conserved tumor necrosis factor (TNF) block haplotypes with CVLU susceptibility. A total of 171 Caucasian patients with CVLU were compared with 173 age-/gender-matched controls, excluding individuals with type 1 diabetes or rheumatoid arthritis. A total of 194 healthy subjects formed a separate population-based control group. Samples were typed for 38 tumor necrosis factor (TNF) block single nucleotide polymorphisms (SNP), human leukocyte antigen (HLA)-B and HLA-DRB1 alleles. TNF haplotypes were derived using the PHASE algorithm and assigned numbers (FVx) defined previously. The patients and matched controls shared 16 TNF block haplotypes. The patients had increased carriage of FV16 and alleles of the 8.1 and 60.3 MHC ancestral haplotypes (AH). CVLU risk is modulated by alleles within FV16 (e.g., TNF-308A and BAT1intron10 C insertion) or near FV16 in the 8.1AH. CVLU risk may also be mediated by unidentified alleles (not in FV22) marked by HLA-B40 and HLA-DR13. FV16 appears to be the best MHC and TNF block marker of susceptibility. After disease onset, an individual's TNF block haplotype does not modulate CVLU severity.

High-frequency ultrasound measurement for assessing post-thrombotic syndrome and monitoring compression therapy in chronic venous disease.

BACKGROUND: The purpose of this study was to validate high-frequency ultrasound (HFU) measurement of dermal thickness for quantification of edema in patients with different severities of chronic venous disease. METHODS: HFU measurements of dermal thickness were made with a 17-MHz probe (Philips iU22 Ultrasound scanner, Bothell, Wash) or a 20-MHz medium-focus probe (DermaScan-C, Cortex Technology, Denmark), 7.5 cm above the medial malleolus. For validation, 20 patients with venous leg ulcers who were not receiving compression therapy, 20 patients with previous deep vein thrombosis (DVT) and symptoms of post-thrombotic syndrome (PTS) without ulceration, and 31 age-matched healthy controls were measured on a single occasion. To investigate the effect of compression on dermal thickness, the leg ulcer patients from the validation study were treated with compression therapy for 7 weeks and measured after 1, 3, 5, and 7 weeks. The association between dermal thickness and the clinical (C) component of the CEAP classification was examined in a cross-sectional analysis of 157 patients with a confirmed history of DVT >or=3 years ago. RESULTS: Dermal thickness in patients with venous leg ulcers before compression therapy (median, 2.56 mm; interquartile range [IQR], 2.31-2.82 mm) was significantly greater (P = .002) than that in patients with symptoms of PTS without ulceration (median, 2.16 mm; IQR, 1.90-2.36 mm). Dermal thickness in both groups was significantly greater (P < .0001) than the control group (median, 1.34 mm; IQR, 1.29-1.44 mm). Compression therapy caused a steady and significant decrease in dermal thickness during the first 5 weeks until normal control levels were achieved. Dermal thickness increased with increasing CEAP category. In 121 patients with a positive diagnosis of DVT >or=3 years ago from Radiology Department records, a hypothetical test cutoff of 1.985 mm for the prediction of severe PTS noted as C(4b), C(5), and C(6) (lipodermatosclerosis or leg ulceration) had a positive predictive value of 46.9% and a negative predictive value of 90.3%. CONCLUSION: HFU measurement of dermal thickness enables the monitoring of edema reduction by compression therapy. A prospective study is required to determine the temporal dynamics of dermal thickness changes after DVT and the relationship to the development of PTS. This test has the potential to be beneficial in the follow-up of patients after a DVT and provide clinical evidence for using graduated elastic compression stockings to control edema and prevent the development of more advanced skin changes.

Induction of MMP-1, MMP-3 and TIMP-1 in normal dermal fibroblasts by chronic venous leg ulcer wound fluid*.

In the wound bed of chronic venous leg ulcers, an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) may cause excessive proteolysis and impair wound granulation. Soluble mediators in the wound environment may be responsible for this imbalance. The in vitro effect of wound fluid from venous leg ulcers on dermal fibroblast production of MMP-1, MMP-3 and TIMP-1 was compared with the effect of acute wound fluid from two different sources: fluid from post-mastectomy axillary drains and fluid from skin graft donor sites. Significantly higher MMP-1 and MMP-3 levels were induced by chronic venous leg ulcer wound fluid compared with both types of acute wound fluid (P < 0.005). Chronic venous ulcer wound fluid reduced TIMP-1 protein levels significantly more than acute graft fluid (P < 0.05). Venous ulcer wound fluid significantly increased MMP-1 and MMP-3 production in dermal fibroblasts and reduced TIMP-1 production, confirming that mediators in the leg ulcer microenvironment can potentially induce excessive proteolysis in the ulcer dermis by altering the balance between MMPs and TIMPs. Inflammatory mediators including interleukin-1beta and tumour necrosis factor-alpha can induce these MMPs. Further work is required to confirm the factors responsible for the induction of a high MMP and low TIMP profile in fibroblasts by venous ulcer wound fluid.

Venous leg ulcers - the search for a prognostic indicator.

Disordered cell function within chronic wounds generates many parameters that can be measured to differentiate between healing and non healing status. Theoretically, these may form the basis of a wound assessment system to define disease severity and response to treatment. In a review of tissue, wound exudate and microbiology studies of venous leg ulcers, we identify many such parameters that are associated with healing status. These include cytokines, proteases and their inhibitors, senescence markers, oxidative stress markers and microbiological status defined by culture. Some of these, such as protease level in wound exudate, have been proposed as prognostic indicators of healing status and many more could be considered potential markers to incorporate into a wound assessment system. However, no published data are available that validate known wound components to accurately reflect wound progression on a single patient basis. Rather than further characterisation of the expression of known wound biomarkers, the development of an accurate and objective test for prediction of chronic wound outcome requires identification of an appropriate combination of novel molecules that vary coordinately with healing status.

Cytomegalovirus infection of a cutaneous ulcer in a patient with ANCA-positive vasculitis.

This case describes a patient in whom cytomegalovirus (CMV) infected a preexisting ulcer. The patient was immune-suppressed because of treatment for Wegener's granulomatosis. Specific antiviral therapy was delayed because of uncertainty as to the role of CMV, but the infection cleared and the ulcer improved promptly on institution of valganciclovir.

Prediction and monitoring the therapeutic response of chronic dermal wounds.

A significant proportion of chronic wounds fail to heal in response to treatment of underlying pathologies combined with good wound care practice. Current prognostic tests to identify these wounds rely on the use of algorithms based on clinically measurable parameters such as wound dimensions and wound duration. Venous leg ulcers may be stratified into healing/non healing at 24 weeks of compression therapy and diabetic foot ulcer treatment outcome assessed using a 3-parameter algorithm. Accurate and reproducible measurement of wound area is required for these algorithms to have clinical utility. Whilst a number of attempts have been made to develop computerised wound-assessment techniques, wound tracing by clinicians combined with planimetry remains the standard methodology. Once treatment has been initiated, it is important to continuously monitor the wound to assess efficacy of treatment. This can be achieved by measuring wound area change over the first weeks of treatment to identify whether re-assessment of treatment strategy is required. A number of algorithms for assessing rate of wound area change have been evaluated to determine a surrogate endpoint for healing. Retrospective analysis of large patient groups indicates that approximately 75% correct prediction of healing outcome can be achieved.

General practitioners' experiences of managing patients with chronic leg ulceration.

OBJECTIVE: To understand general practitioners' experiences of managing patients with chronic leg ulceration, thus informing future strategies to improve leg ulcer care in general practice, Australia. DESIGN: Qualitative study using phenomenology and in-depth interviewing. PARTICIPANTS AND SETTING: Maximum variation sample of 12 GPs working in the Perth and Hills Division of General Practice between September and December 2004. MAIN OUTCOME MEASURE: Themes in participants' experiences of leg ulcer care. FINDINGS: Participants regarded leg ulcer management as an integral part of general practice. They expressed a desire to maintain their involvement, yet relied on nursing assistance. They perceived that ulcer care was usually straightforward and successful. Approaches to management appeared to differ significantly from that outlined in current guidelines. Instead, participants valued accessibility of care for the patient, awareness of patient context and regular review. Occasional problems with non-healing ulcers were experienced, and, in these situations, specialist opinion was appreciated. CONCLUSION: This study highlights fundamental differences between GP and specialist conceptualisation of leg ulcer care. For GPs, it identifies key areas of ulcer management that could be improved. For specialists, it suggests that widespread implementation of traditional guidelines may not be appropriate or acceptable. New approaches to leg ulcer management in general practice are likely to need a combination of education, human resources and practical support.

Predicting commercial success for Australian medical inventions patented in the United States: a cross sectional survey of Australian inventors.

OBJECTIVES: To examine the commercial development of Australian medical patents and identify the determinants of their being used in innovations (new or improved products or production processes). DESIGN: Cross-sectional survey with a nested case-control study. PARTICIPANTS AND SETTING: 177 inventors listed as the first Australian on medical patents granted in the United States between 1 January 1984 and 30 December 1994, and surveyed in 1998-1999. MAIN OUTCOME MEASURE: A series of predictor variables (including characteristics of the patents; characteristics of the inventors; ideas, advice and funding during commercialisation; and the process of commercialisation) for whether or not a patent became an innovation. RESULTS: Half (89/177) of the medical patents became innovations, with 34% generating a total of A $287 million (13% over $1 million) in annual sales a median of 8 years after the patent had been granted. A patent was more likely to become an innovation if the inventor was employed by industry at the time of invention (odds ratio [OR], 3.2; 95% CI, 1.1-9.2), had invested their own finances (OR, 2.8; 95% CI, 1.0-7.4), and if the patent had been licensed (OR, 4.6; 95% CI 1.7-12.7), led to further patents (OR, 3.2; 95% CI, 1.0-10.4) and involved an industry partner in its commercial development (OR, 10.1; 95% CI, 3.6-27.7). It was less likely to become an innovation if finance came from a research funding agency (OR, 0.3; 95% CI, 0.1-0.8) and if interest from Australian industry was judged by inventors as "poor" (OR, 0.6; 95% CI, 0.4-0.9). CONCLUSIONS: Medical patents in the US listing Australian inventors are more likely to become innovations if they originate from industry rather than the public sector, and if inventors are willing to invest their own finances.