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.

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.

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.

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.

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.

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.

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.

Push-pull theory: using mechanotransduction to achieve tissue perfusion and wound healing in complex cases.

Wound healing has evolved from gauze therapy to the use of proteomics, gene therapy, and cellular-based therapies in the short time span of 45 years. Education for health care providers has not kept pace with the logarithmic acceleration in technology development and treatment options. A patient with a non-healing wound requires a comprehensive work-up, including a focus on six primary points of interest. These points include the status of tissue perfusion, role of bacterial contamination, pressure applied to the tissue, the immune status of the host, co-morbid medical conditions including the patient's psychosocial status, and lastly, the status of the wound itself. Even after re-establishing macrovascular flow, many wounds either fail to improve or paradoxically worsen. Potential mechanisms for these unexpected findings include reperfusion injury, no-reflow, and the presence of stunned/hibernating tissue. Using the concept of mechanotransduction, the clinician can simulate normal pulsatile blood flow and re-establish adequate microvascular perfusion. Treatment regimens may include negative pressure therapy, electrical stimulation, ultrasound therapy, and other energy-based modalities.

Maintenance debridement in the treatment of difficult-to-heal chronic wounds. Recommendations of an expert panel.

INTRODUCTION: Maintenance debridement has been proposed as a therapeutic intervention to address the problem of chronic wounds characterized by an adequate wound bed but absent or slow healing. A panel of experts convened to address the rationale and method of maintenance debridement. PURPOSE: The goals of the panel were to summarize the scientific rationale for maintenance debridement, discuss the biochemical and cellular abnormalities in the wound bed, and provide a working algorithm for how maintenance debridement should be used. METHODS: A multidisciplinary panel of wound healing and wound care experts comprising the fields of nursing, dermatology, internal medicine, and surgery was assembled to address maintenance debridement from different points of view and offer a unified approach. FINDINGS: The chronic wound contains a number of microbial, biochemical, and cellular features and abnormalities that prevent or slow its progression to healing despite a seemingly adequate wound bed. Under these circumstances, maintenance debridement is proposed as a way to remove tissues that are colonized with an excessive bacterial burden and diminish what can be described as a biochemical and cellular burden that impairs healing. A working clinical algorithm is proposed. CONCLUSION: Maintenance debridement is a proactive way to "jump-start" the wound and keep it in a healing mode, even when traditional debridement may not appear necessary because of a seemingly "healthy" wound bed.

Impact of Hyperbaric Oxygen on More Advanced Wagner Grades 3 and 4 Diabetic Foot Ulcers: Matching Therapy to Specific Wound Conditions.

Objective: The goal of this research was to identify a population of diabetic foot ulcer patients who demonstrate a significant response to hyperbaric oxygen therapy (HBOT) using a large sample size to provide guidance for clinicians when treating these complicated patients. Approach: The effect of HBOT on diabetic foot ulcers, Wagner grades 3 and 4, was evaluated using a retrospective observational real-world data set. The study reported on the overall healing rate, (74.2%) at the population level, for >2 million wounds. Results: When a subgroup of patients of only foot ulcers with a Wagner grade 3 or 4 were considered, the healing rate was only 56.04%. The use of HBOT, without filtering for the number of treatments received, improved the healing rate to 60.01% overall. Healing rates for this same subgroup, however, were improved to 75.24% for patients who completed the prescribed number of hyperbaric treatments. Innovation: This observational study discusses the importance of reporting at the population level, specific wound etiology level, a risk-stratified level, and to then overlay the effect of treatment adherence on those outcomes to provide clinicians with a comprehensive understanding of when to prescribe an advanced modality such as hyperbaric oxygen. Conclusion: The authors provide healing outcomes data from several prior HBOT studies as well as other advanced modalities that have been used in diabetic foot ulcer care for comparison and context.

Use of a National Electronic Health Record Network to Describe Characteristics and Healing Patterns of Sickle Cell Ulcers.

Objective: Sickle cell ulcers affect as many as 15% of patients with sickle cell disease in the United States and severely impact quality of life. An understanding of baseline healing patterns is important to inform study design for future trials that test therapies for this disease. Approach: In this study, an electronic wound management system was leveraged to analyze retrospective data on 133 unique sickle cell patients who were treated across 114 wound healing centers, and to describe their characteristics and healing patterns as compared with those of venous ulcer patients. The data included 198 care episodes for 427 wounds. Results: Patients with sickle cell ulcers were younger and had fewer comorbid diseases than those with venous ulcers. Larger size and longer duration were predictors of poor healing. Between the first and fourth assessments, mean change in area for sickle cell ulcers showed a 58% increase, compared with a 13% decrease for venous ulcers. Kaplan-Meier curves showed poorer healing in sickle cell ulcers than in venous ulcers across all categories of size and duration. Patients with sickle cell ulcers had longer care episodes and were more likely to re-present for care. Innovation: This study reports on the largest data set of sickle cell ulcer patients analyzed to date in the published literature to provide a more detailed understanding of wound healing patterns of this disease. Conclusion: A national network of electronic health records can effectively identify a large number of patients with sickle cell ulcers to support analysis of epidemiology, healing patterns, and health care utilization.

A biochemical approach to wound healing through the use of modalities.

Wound healing is a complex pathway that is energy dependent. Nonhealing wounds frequently require the use of physical modalities to achieve healing. There is much debate over which treatment modality to use, with varying clinical results in the literature. This review paper describes a common biochemical pathway that helps the clinician understand, at a molecular level, how the transference of energy to a wound can result in positive clinical results. The mechanisms of action for ultraviolet light, electrical stimulation, and ultrasound are reviewed along with a proposed biochemical roadmap. An emphasis on protein biochemistry is supported with an extensive review of the literature.

Surgical palliative care of advanced wounds.

The history of surgery is rich with accomplishments in wound care, a legacy that recently has been abandoned by many surgeons only to be taken up by nonsurgical providers. When dealing with advanced wounds at the end of life, such as pressure ulcers or venous stasis ulcers, goals of treatment are relief of pain, elimination of odor, and control of wound exudates and infection. Benefits and risks of surgical intervention must be discussed with the patient and family in terms of the patient's perceived prognosis, extent of tissue necrosis and infection, the rate of deterioration, and the underlying wound pathogenesis. When appropriate, the role of surgery looms large in the treatment of chronic, advanced wounds, especially when minimally invasive surgical techniques are used.

:wound healing outcomes: the impact of site of care and patient stratification.

UNLABELLED:  As healthcare providers prepare for pay for performance (P4P) and outcomes-based reimbursement strategies, it is increasingly important to document clinical results. Historically, healing rates have been reported from hospital-based, outpatient wound clinics. Time-to-healing curves from one site of care may not accurately reflect the entire healing "episode of care." Few outpatients from a wound clinic require hospitalization and even fewer are admitted to sub-acute care. Care setting and population risk strata must be clearly identified before comparing wound outcomes data. AIM: Primary objectives were to determine comparability of complete healing and 50% wound volume reduction of current and prior sub-acute care programs. Predictive value of Minimum Data Set (MDS 2.0) items on admission was also explored in discriminating healing versus nonhealing patients. METHODS: Wound outcomes were analyzed for all patients (N = 101) treated at a dedicated sub-acute wound unit from January 2006 through April 2007 in a prospective, longitudinal, intent-to-treat, cohort study. Results were compared to prior sub-acute care wound outcomes reported by a similarly composed team using similar protocols. RESULTS: Of 101 evaluable patients with 209 wounds, 41.6% healed in a median of 7.9 weeks while 31.6% achieved > 50% volume reduction. Outcomes were similar to prior sub-acute results, but less than the 72%-74% healing rate reported by a similar team in hospital outpatient clinic programs. Minimum Data Set comorbidities analyzed did not significantly predict nonhealing. CONCLUSION: To allow risk-adjusted P4P and reimbursement metrics, wound outcome reports should include clinical team involved, protocol utilization, care setting, and case mix severity to control for variables associated with different settings.

Baseline factors affecting closure of venous leg ulcers.

OBJECTIVE: The objective of this study was to characterize factors associated with closure of venous leg ulcers (VLUs) in a pooled analysis of subjects from three randomized clinical trials. METHODS: Closure of VLUs after treatment with HP802-247, an allogeneic living cell therapy consisting of growth-arrested human keratinocytes and fibroblasts, vs standard therapy with compression bandaging was evaluated in three phase 3 clinical trials of similar design. Two trials enrolled subjects with VLUs ranging from 2 cm2 to 12 cm2 in area with 12-week treatment periods; the third trial enrolled subjects with VLUs between >12 cm2 and ≤36 cm2 with a 16-week treatment period. The first trial went to completion but failed to demonstrate a benefit to therapy with HP802-247 compared with placebo, and because of this, the remaining trials were terminated before completion. On the basis of no differences in outcomes between groups, subjects from both HP802-247 and control groups were pooled across all three studies. Cox proportional hazards regression analysis was employed to evaluate factors associated with VLU closure. RESULTS: This analysis included data from 716 subjects with VLU. Factors evaluated for association with healing included age, gender, race, diabetes, glycated hemoglobin level, body mass index, treatment (HP802-247 vs compression alone), and ulcer characteristics including location and area and duration at baseline. In an initial model including all of these putative factors, the following were significant at the P < .10 level: diagnosis of diabetes mellitus, gender, wound location (ankle or leg), baseline wound area, and wound duration at baseline. In a final model including only these factors, all but diabetes mellitus were significant at the P < .05 level. Effect sizes were as follows (hazard ratio [95% confidence interval]): female gender (1.384 [1.134-1.690]), wound location on the leg (1.490 [1.187-1.871]), smaller wound area at baseline (0.907 [0.887-0.927]), and shorter wound duration at baseline (0.971 [0.955-0.987]). CONCLUSIONS: Factors associated with VLU lesions including location, area, and duration were important predictors of healing. Women were more likely than men to achieve wound closure. Factors including body mass index, the presence of diabetes mellitus, and higher concentrations of glycated hemoglobin were not significant independent predictors of wound closure in this analysis.

Diabetes medications: Impact on inflammation and wound healing.

Chronic wounds are a common complication in patients with diabetes that often lead to amputation. These non-healing wounds are described as being stuck in a persistent inflammatory state characterized by accumulation of pro-inflammatory macrophages, cytokines and proteases. Some medications approved for management of type 2 diabetes have demonstrated anti-inflammatory properties independent of their marketed insulinotropic effects and thus have underappreciated potential to promote wound healing. In this review, the potential for insulin, metformin, specific sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors to promote healing is evaluated by reviewing human and animal studies on inflammation and wound healing. The available evidence indicates that diabetic medications have potential to prevent wounds from becoming arrested in the inflammatory stage of healing and to promote wound healing by downregulating pro-inflammatory cytokines, upregulating growth factors, lowering matrix metalloproteinases, stimulating angiogenesis, and increasing epithelization. However, no clinical recommendations currently exist on the potential for specific diabetic medications to impact healing of chronic wounds. Thus, we encourage further research that may guide physicians on providing personalized diabetes treatments that achieve glycemic goals while promoting healing in patients with chronic wounds.