Compression therapy in peripheral artery disease: a literature review.

OBJECTIVE: Our objective is to examine the pathophysiology of oedema in the ischaemic and post-revascularised limb, compare compression stockings to pneumatic compression devices, and summarise compression regimens in patients with severe peripheral artery disease (PAD) without revascularisation, after revascularisation, and in mixed arterial and venous disease. METHOD: A scoping literature review of the aforementioned topics was carried out using PubMed. RESULTS: Compression therapy has been shown to increase blood flow and aid in wound healing through a variety of mechanisms. Several studies suggest that intermittent pneumatic compression (IPC) devices can be used to treat critical limb ischaemia in patients without surgical options. Additionally, compression stockings may have a role in preventing oedema after peripheral artery bypass surgery, thereby diminishing pain and reducing the risk of surgical wound dehiscence. CONCLUSION: Oedema may occur in the ischaemic limb after revascularisation surgery, as well as in combination with venous disease. Clinicians should not fear using compression therapy in PAD.

Oxidant Signaling Mediated by Nox2 in Neutrophils Promotes Regenerative Myelopoiesis and Tissue Recovery following Ischemic Damage.

Ischemic tissue damage activates hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM)-generating myeloid cells, and persistent HSPC activity may drive chronic inflammation and impair tissue recovery. Although increased reactive oxygen species in the BM regulate HSPC functions, their roles in myelopoiesis of activated HSPCs and subsequent tissue recovery during ischemic damage are not well understood. In this paper, we report that deletion of Nox2 NADPH oxidase in mice results in persistent elevations in BM HSPC activity and levels of inflammatory monocytes/macrophages in BM and ischemic tissue in a model of hindlimb ischemia. Ischemic tissue damage induces oxidants in BM such as elevations of hydrogen peroxide and oxidized phospholipids, which activate redox-sensitive Lyn kinase in a Nox2-dependent manner. Moreover, during tissue recovery after ischemic injury, this Nox2-ROS-Lyn kinase axis is induced by Nox2 in neutrophils that home to the BM, which inhibits HSPC activity and inflammatory monocyte generation and promotes tissue regeneration after ischemic damage. Thus, oxidant signaling in the BM mediated by Nox2 in neutrophils regulates myelopoiesis of HSPCs to promote regeneration of damaged tissue.

Wound healing outcomes: Using big data and a modified intent-to-treat method as a metric for reporting healing rates.

Chronic wounds are increasing in prevalence and are a costly problem for the US healthcare system and throughout the world. Typically outcomes studies in the field of wound care have been limited to small clinical trials, comparative effectiveness cohorts and attempts to extrapolate results from claims databases. As a result, outcomes in real world clinical settings may differ from these published studies. This study presents a modified intent-to-treat framework for measuring wound outcomes and measures the consistency of population based outcomes across two distinct settings. In this retrospective observational analysis, we describe the largest to date, cohort of patient wound outcomes derived from 626 hospital based clinics and one academic tertiary care clinic. We present the results of a modified intent-to-treat analysis of wound outcomes as well as demographic and descriptive data. After applying the exclusion criteria, the final analytic sample includes the outcomes from 667,291 wounds in the national sample and 1,788 wounds in the academic sample. We found a consistent modified intent to treat healing rate of 74.6% from the 626 clinics and 77.6% in the academic center. We recommend that a standard modified intent to treat healing rate be used to report wound outcomes to allow for consistency and comparability in measurement across providers, payers and healthcare systems.

Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community.

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.

Clinical interventions for venous leg ulcers: Proposals to improve the quality of clinical leg ulcer research.

The present status of clinical leg ulcer healing research was reviewed by 25 experts over 2 days on September 28 and 29, 2015. Multiple clinical effectiveness reviews were presented suggesting that published clinical wound healing research often does not meet present (2015) evidence based standards. Specific areas requiring remediation were highlighted and approaches to overcoming existing challenges were proposed. Participants using anonymous voting technology developed an action plan to resolve perceived deficiencies. Statements were accepted if 75% of participants agreed. Older patients with a high frequency of comorbid conditions posed particular difficulties in designing clinical research protocols and better diagnostic categorization is necessary A standardized model template for collecting information about diagnosis and evaluation of the effect of interventions on healing of all types of leg ulcers was considered a high priority. Such a model template could be modified depending on the specific etiology of the leg ulcers. Generally agreed on quantifiable standards to establish degree of morbidity was considered a high priority. There was universal agreement that sources of funding and conflicts of interest needed to be disclosed in presentations and all publications. All clinical research studies should be registered with appropriate authorities. There was substantial enthusiasm for a clinical research network with quality standards for membership and an advisory research core available to investigators. Such a network should be funded and actively managed to insure long-term viability. The governance of such an entity needs to be established by the wound care community. The present trend to integrate patients into the clinical research process was endorsed and there was enthusiasm to develop patient advocacy for wound healing research.

Macrophage PPARγ and impaired wound healing in type 2 diabetes.

Macrophages undergo a transition from pro-inflammatory to healing-associated phenotypes that is critical for efficient wound healing. However, the regulation of this transition during normal and impaired healing remains to be elucidated. In our studies, the switch in macrophage phenotypes during skin wound healing was associated with up-regulation of the peroxisome proliferator-activated receptor (PPAR)γ and its downstream targets, along with increased mitochondrial content. In the setting of diabetes, up-regulation of PPARγ activity was impaired by sustained expression of IL-1ß in both mouse and human wounds. In addition, experiments with myeloid-specific PPARγ knockout mice indicated that loss of PPARγ in macrophages is sufficient to prolong wound inflammation and delay healing. Furthermore, PPARγ agonists promoted a healing-associated macrophage phenotype both in vitro and in vivo, even in the diabetic wound environment. Importantly, topical administration of PPARγ agonists improved healing in diabetic mice, suggesting an appealing strategy for down-regulating inflammation and improving the healing of chronic wounds.

Amniotic membrane is a potential regenerative option for chronic non-healing wounds: a report of five cases receiving dehydrated human amnion/chorion membrane allograft.

A case series of five patients with a total of six chronic non-healing wounds (>30 day duration) were non-randomly selected to evaluate the performance, safety and handling properties of dehydrated human amnion/chorion membrane allograft, an amniotic membrane scaffolding product. The patients had lower extremity wounds that had previously failed standard of care within a university outpatient/inpatient wound healing programme. Five wounds treated with dehydrated amnion/chorion membrane allograft showed a mean 43% area reduction from baseline (51% median) at 3 weeks into treatment and completely healed with a 64-day median time to closure (SD ±27·6 days). One wound worsened at 3 weeks and was found to have a complete central vein obstruction that was treated with long-term mild compression but still eventually healed at 6 months. Removing this outlier, the four responding wounds had a 72% mean and 69% median change in area from baseline, at the 3 week point. All five patients received only one application of dehydrated human amnion/chorion membrane allograft, and there were no adverse events. The product was easy to use, administer and handle. In summary, dehydrated human amnion/chorion membrane allograft appears to be a safe, effective and easy to use therapy for chronic non-healing wounds. This study describes the details of these clinical cases and provides an overview of the current evidence on the use of amniotic tissue in clinical practice.

A treatment algorithm to identify therapeutic approaches for leg ulcers in patients with sickle cell disease.

Sickle cell leg ulcers (SCLUs) are a common complication of sickle cell disease (SCD). Patients who develop ulcers appear to have a more severe haemolysis-associated vasculopathy than individuals who do not develop them, and manifest other complications such as priapism and pulmonary hypertension. SCLUs are slow to heal and often recur, affecting both the emotional and physical well-being of patients. Here we summarise what is known about the pathophysiology of SCLUs, describe available treatment options and propose a treatment algorithm.

Skin blood flow response to locally applied mechanical and thermal stresses in the diabetic foot.

Diabetic foot ulcers are one of the most common complications in diabetics, causing significant disabilities and decreasing the quality of life. Impaired microvascular reactivity contributes to the development of diabetic foot ulcers. However, underlying physiological mechanisms responsible for the impaired microvascular reactivity in response to extrinsic causative factors of foot ulcers such as mechanical and thermal stresses have not been well investigated. A total of 26 participants were recruited into this study, including 18 type 2 diabetics with peripheral neuropathy and 8 healthy controls. Laser Doppler flowmetry was used to measure skin blood flow at the first metatarsal head in response to a mechanical stress at 300mmHg and a fast thermal stress at 42°C. Wavelet analysis of skin blood flow oscillations was used to assess metabolic, neurogenic and myogenic controls. Our results indicated that diabetics have significantly decreased metabolic, neurogenic and myogenic responses to thermal stress, especially in the neurogenic and myogenic controls during the first vasodilatory response and in the metabolic control during the second vasodilatory response. Diabetics have a significantly decreased myogenic response to mechanical stress during reactive hyperemia. Our findings demonstrate that locally applied mechanical and thermal stresses can be used to assess microvascular reactivity and risk of diabetic foot ulcers.

Activated mesenchymal stem cells increase wound tensile strength in aged mouse model via macrophages.

BACKGROUND: Wound healing is impaired in the aged. Mesenchymal stem cells (MSCs) can exert beneficial effects in wounds; however, promoting healing in the challenging setting of aged skin may require additional potency. MSCs can enhance the production of pro-regenerative cytokines and growth factors when activated with interferon gamma. We hypothesized that the increased potency of activated MSC could be used to facilitate wound healing in the aged mice. METHODS: Young and old C57BL6 mice underwent incisional wounds and were treated with naive MSCs, activated MSCs, or vehicle to examine MSC effects on tensile strength in the aged skin. To test whether the benefits of MSC treatment could be attributed to the participation of host macrophages, liposomal clodronate was used to deplete host macrophages. RESULTS: In older mice, tensile strength of healing wounds was significantly lower than that in younger mice. Older mice treated with activated MSCs showed significant increases in tensile strength restoring the strength to that observed in younger mice. Macrophage depletion abrogated the beneficial effect of MSC. CONCLUSIONS: Activated MSCs restored wound tensile strength in the aged mice, and this effect was dependent on host macrophage activity. These data provide encouraging support for the development of activated MSC therapies for enhanced tissue regeneration, especially for older population groups.

Comparison of muscle and skin perfusion over the ischial tuberosities in response to wheelchair tilt-in-space and recline angles in people with spinal cord injury.

OBJECTIVE: To compare the efficacy of wheelchair tilt-in-space and recline on enhancing muscle and skin perfusion over the ischial tuberosities in people with spinal cord injury (SCI). DESIGN: Repeated-measures and before-after trial design. SETTING: University research laboratory. PARTICIPANTS: Power wheelchair users with SCI (N=20). INTERVENTIONS: Six combinations of wheelchair tilt-in-space and recline angles were presented to participants in a random order. The testing protocol consisted of a baseline 5 minutes sitting with no tilt/recline and 5 minutes positioned in a tilted and reclined position at each of 6 conditions, including: (1) 15° tilt-in-space and 100° recline, (2) 25° tilt-in-space and 100° recline, (3) 35° tilt-in-space and 100° recline, (4) 15° tilt-in-space and 120° recline, (5) 25° tilt-in-space and 120° recline, and (6) 35° tilt-in-space and 120° recline. MAIN OUTCOME MEASURES: Muscle and skin perfusion were assessed by near-infrared spectroscopy and laser Doppler flowmetry, respectively. RESULTS: Muscle perfusion was significantly increased at 25° and 35° tilt-in-space when combined with 120° recline, and skin perfusion was significantly increased at 3 tilt-in-space angles (15°, 25°, 35°) when combined with 120° recline and at 35° tilt-in-space when combined with 100° recline (P<.05). Even in the positions of increased muscle perfusion and skin perfusion (25° and 35° of tilt-in-space combined with 120° of recline), the amount of muscle perfusion change was significantly lower than the amount of skin perfusion change (P<.05). CONCLUSIONS: Our results indicate that a larger angle of tilt-in-space and recline is needed to improve muscle perfusion compared with skin perfusion. A position of 25° tilt-in-space combined with 120° recline is effective in enhancing muscle and skin perfusion of weight-bearing soft tissues at the ischial tuberosities.

Characteristics of venous leg ulcer patients at a tertiary wound care center.

OBJECTIVE: The objective of this study was to assess patient, wound, care, and reflux characteristics of venous leg ulcers (VLUs) to update and improve knowledge of disease etiology, identify barriers to healing, and improve treatment. METHODS: Patients diagnosed with VLUs treated at the Stanford Advanced Wound Care Center between 2018 and 2019 were identified from the Healogics iHeal database. We identified 327 VLU entries, of which 133 were patients who had multiple or recurring wounds. An additional 27 patients were labeled as misdiagnosis, resulting in a final patient sample of 167. Patient demographics, wound, care, and ultrasound data for these patients were extracted from the Stanford electronic medical records regarding characteristics. The initial data analysis suggested possible differences in VLU characteristics depending on patient age and body mass index (BMI), which was then further analyzed. RESULTS: Of the 167 VLU patients assessed, 53.9% were male and 46.1% were female. The mean age was 74.7 years, and the average BMI was 30.2 kg/m2, including 41.1% of patients with a BMI over 30 kg/m2. Approximately 50% of wounds were presented in multiples, had cellulitis, or were recurring, and 39.5% were caused by trauma. Most common venous reflux patterns on duplex ultrasound examination were below-knee great saphenous vein reflux and calf perforator reflux, which was identified in 37.7% and 29.3% of the patients, respectively. Axial great saphenous vein reflux was detected in 14.4% of patients. When looking at the patient sample under 60 years of age, 67.7% were male, 61.3% presented with venous skin changes, and 51.6% had diabetes. In the patients older than 60, only 51.9% were male, 37.6% presented with venous skin changes, and 31.6% had diabetes. BMI was greater in the patients under age 60, with an average of 39.2 kg/m2, compared with 28.2 kg/m2 in those above 60. Of the patients with a BMI ≥30 kg/m2, 64.3% had multiple wounds, 61.4% had recurring wounds, and 56.5% had venous skin changes. In contrast, in patients with BMI <30 kg/m2, 47.4% had multiple wounds, 39.2% had recurring wounds, and 32.0% had venous skin changes. CONCLUSIONS: VLU pathology appears to differ depending on patient demographics and characteristics. Different drivers may influence disease cause, progression, and prognosis, making a standard approach to VLUs difficult. Our findings suggest that identifying different subtypes of VLUs and adapting an algorithm of care with a personalized treatment may help optimize management of these patients.

Outpatient Wound Clinics During COVID-19 Maintained Quality but Served Fewer Patients.

OBJECTIVE: To evaluate the impact of COVID-19-related disruptions on care continuity and outcomes of chronic wounds. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Electronic medical records for 152,225 chronic wounds from a network of 488 wound care clinics in 45 US states and the District of Columbia. METHODS: Wound and patient characteristics, the number of chronic wounds newly seen at the clinics, and 12-week healing rates were compared between the first 2 quarters of 2019 and 2020. Multivariable regression models were constructed to evaluate whether the pandemic was associated with a statistically significant change in the probability of 12-week wound healing after risk adjustment. RESULTS: During the pandemic, wound and patient characteristics did not change compared to the previous year. Case volume dropped as much as 40% in April 2020 but returned to the previous year's level by June. No systematic changes in measures of care continuity were observed. Unadjusted 12-week healing rates remained stable at 0.502 in 2019 and 0.503 in 2020. Likewise, risk-adjusted 12-week healing rates were 0.504 and 0.505 in 2019 and 2020, respectively, but the difference was not statistically significant. States with stricter lockdowns saw a greater decline in case volume. However, the pandemic was not associated with a statistically significant change in the probability of 12-week wound healing in most states. The percentage of wounds with 1 or more telehealth visits increased from 0.14% in 2019 to 1.04% in 2020. CONCLUSIONS AND IMPLICATIONS: Despite COVID-19-related disruptions, our results suggest that wound care clinics maintained standards of care and outcomes for patients who sought care. This positive result should not detract from the problem that the number of new wounds seen at the clinics dropped sharply. Further research should evaluate outcomes in patients with unattended chronic wounds.

Association of wound healing with quality and continuity of care and sociodemographic characteristics.

OBJECTIVES: To evaluate the association between clinics' wound healing performance and clinic-level measures of care continuity, clinical quality, and sociodemographic characteristics of the population in their catchment areas. STUDY DESIGN: In this cross-sectional analysis, we analyzed electronic health records for 180,336 chronic wounds from 480 wound care clinics during the 2018 calendar year. METHODS: We measured healing performance using a clinic's observed to expected (O/E) ratio, which is based on the rate at which chronic wounds were predicted to heal within 12 weeks given its case mix and the actual healing rate. We compared the top and bottom quintiles, in terms of the O/E ratio, of clinics. Multivariable regression was used to estimate the effect of the clinic-level measures on the O/E ratio. RESULTS: Clinics in the top quintile had higher rates of care continuity and quality measures, as well as a lower proportion of disadvantaged populations in their catchment areas. In the regression model, 10% increases in a clinic's rate of weekly provider visits, nurse visits, and debridement were associated with 2.5%, 3.0% and 0.7% increases, respectively, in the O/E ratio. The weekly provider visit rate had a greater marginal effect when the proportion of African American residents in the clinic's catchment area was larger. CONCLUSIONS: Clinic-level measures of care continuity, clinical quality, and sociodemographic composition of their catchment areas' population explain a meaningful part of differences in clinics' wound healing performance. Better care continuity appears to have a greater beneficial effect in disadvantaged populations.

Atypical ulcers: a stepwise approach for clinicians.

Chronic ulcers are associated with significant morbidity and mortality. Typical ulcers are due to venous insufficiency, diabetes, ischemia, pressure, and lymphedema. A chronic ulcer that does not respond to standard therapies should be reevaluated for potential atypical etiologies. Atypical ulcers are less common and more difficult to diagnose due to a wide range of possible etiologies, including inflammatory (autoimmune), neoplastic, vasculopathy, hematologic, infectious, drug-induced, or external. No standardized approach to the management of complex atypical ulcers exists. In this review, a stepwise approach to atypical ulcers is proposed with the aim of assisting physicians in their identification and diagnosis. If perfusion is adequate and there are no signs of infection, then the authors recommend obtaining an ulcer biopsy for microbiologic, DIF, and histopathologic evaluation as the criterion standard for diagnosis. Laboratory testing, including an autoimmune panel, a hypercoagulable panel, and an infectious diseases panel, can further aid in diagnosis. Atypical ulcers often require multidisciplinary care, with input from specialists in rheumatology, dermatology, infectious diseases, wound care, vascular surgery, hematology, and oncology. Effective communication within the health care team is essential for accurate diagnosis and management of atypical ulcers. Active dialogue between providers can improve consult efficiency and ultimately lower the cost of care.

Clinical Vignettes Part I.

Patients with sickle cell disease and/or (rarely) trait are at increased risk for developing recurrent episodes of priapism, also known as stuttering priapism, and major ischemic priapism. Treatment of acute ischemic priapism is reactive; whereas ideal management consists of preventative approaches to ultimately promote the best improvement in patient's quality of life. Leg ulcers in patients with sickle cell disease (SCD) are quite common, with ∼20 % of patients with HBSS reporting either having an active or a past ucler. They can be confused with venous ulcers, with lower extremity hyperpigmentation confounding further the diagnosis. Several factors believed to contribute to the development of leg ulcers in patients with SCD are discussed in this article. Sickle cell liver disease (SCLD) occurs because of a wide variety of insults to the liver that happen during the lifetime of these patients. SCLD includes a range of complications of the hepatobiliary system and is increasing in prevalence with the aging adult sickle population. Liver nodular regenerative hyperplasia (NRH) is more common than realized and underappreciated as a diagnosis and requires liver biopsy with reticulin staining. Undiagnosed, the insidious damage from liver NRH can lead to noncirrhotic portal hypertension or cirrhosis.

Combat Wound Initiative program.

The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care.

Development of a Model to Predict Healing of Chronic Wounds Within 12 Weeks.

Objective: Chronic wounds represent a highly prevalent but little recognized condition with substantial implications for patients and payers. While better wound care products and treatment modalities are known to improve healing rates, they are inconsistently used in real-world practice. Predicting healing rates of chronic wounds and comparing to actual rates could be used to detect and reward better quality of care. We developed a prediction model for chronic wound healing. Approach: We analyzed electronic medical records (EMRs) for 620,356 chronic wounds of various etiologies in 261,398 patients from 532 wound care clinics in the United States. Patient-level and wound-level parameters influencing wound healing were identified from prior research and clinician input. Logistic regression and classification tree models to predict the probability of wound healing within 12 weeks were developed using a random sample of 70% of the wounds and validated in the remaining data. Results: A total of 365,659 (58.9%) wounds were healed by week 12. The logistic and classification tree models predicted healing with an area under the curve of 0.712 and 0.717, respectively. Wound-level characteristics, such as location, area, depth, and etiology, were more powerful predictors than patient demographics and comorbidities. Innovation: The probability of wound healing can be predicted with reasonable accuracy in real-world data from EMRs. Conclusion: The resulting severity adjustment model can become the basis for applications like quality measure development, research into clinical practice and performance-based payment.