Provisional matrix deposition in hemostasis and venous insufficiency: Tissue preconditioning for nonhealing venous ulcers

Significance: Chronic wounds represent a major burden on global healthcare systems and reduce the quality of life of those affected. Significant advances have been made in our understanding of the biochemistry of wound healing progression. However, knowledge regarding the specific molecular processes influencing chronic wound formation and persistence remains limited. Recent Advances: Generally, healing of acute wounds begins with hemostasis and the deposition of a plasma-derived provisional matrix into the wound. The deposition of plasma matrix proteins is known to occur around the microvasculature of the lower limb as a result of venous insufficiency. This appears to alter limb cutaneous tissue physiology and consequently drives the tissue into a ‘preconditioned’ state that negatively influences the response to wounding. Critical Issues: Processes, such as oxygen and nutrient suppression, edema, inflammatory cell trapping/extravasation, diffuse inflammation, and tissue necrosis are thought to contribute to the advent of a chronic wound. Healing of the wound then becomes difficult in the context of an internally injured limb. Thus, interventions and therapies for promoting healing of the limb is a growing area of interest. For venous ulcers, treatment using compression bandaging encourages venous return and improves healing processes within the limb, critically however, once treatment concludes ulcers often reoccur. Future Directions: Improved understanding of the composition and role of pericapillary matrix deposits in facilitating internal limb injury and subsequent development of chronic wounds will be critical for informing and enhancing current best practice therapies and preventative action in the wound care field.

The impact of psychosocial factors on adherence to compression therapy to prevent recurrence of venous leg ulcers

Aims To identify self-care activities undertaken and determine relationships between self-efficacy, depression, quality of life, social support and adherence to compression therapy in a sample of patients with chronic venous insufficiency. Background Up to 70% of venous leg ulcers recur after healing. Compression hosiery is a primary strategy to prevent recurrence, however, problems with adherence to this strategy are well documented and an improved understanding of how psychosocial factors influence patients with chronic venous insufficiency will help guide effective preventive strategies. Design Cross-sectional survey and retrospective medical record review. Method All patients previously diagnosed with a venous leg ulcer which healed between 12–36 months prior to the study were invited to participate. Data on health, psychosocial variables and self-care activities were obtained from a self-report survey and data on medical and previous ulcer history were obtained from medical records. Multiple linear regression modelling was used to determine the independent influences of psychosocial factors on adherence to compression therapy. Results In a sample of 122 participants, the most frequently identified self-care activities were application of topical skin treatments, wearing compression hosiery and covering legs to prevent trauma. Compression hosiery was worn for a median of 4 days/week (range 0–7). After adjustment for all variables and potential confounders in a multivariable regression model, wearing compression hosiery was found to be significantly positively associated with participants’ knowledge of the cause of their condition (p=0.002), higher self-efficacy scores (p=0.026) and lower depression scores (p=0.009). Conclusion In this sample, depression, self-efficacy and knowledge were found to be significantly related to adherence to compression therapy. Relevance to clinical practice These findings support the need to screen for and treat depression in this population. In addition, strategies to improve patient knowledge and self-efficacy may positively influence adherence to compression therapy.

National Institute for Clinical Studies Report for Phase 1, Evidence Uptake Network : Best Practice Community Care for Clients with Chronic Venous Leg Ulcers

Chronic leg ulcers cause significant pain, cost, decreased quality of life and morbidity for a considerable segment of the older population (Graham et al., 2003a). At any given time the prevalence of patients with open leg ulcers receiving treatment is between 0.11% - 0.18% (Briggs & Closs 2003). Chronic leg ulcers occur in approximately 1 - 2% of the over 60 population in the US, UK, Europe and Australia (Baker & Stacey 1994; Johnson 1995; Lees & Lambert 1992; Margolis et al. 2002). Considerable research has been undertaken to determine the best treatment practices that will aid in the management and the healing of these ulcers, and practical and effective strategies and techniques for healing venous leg ulcers have been trialled to demonstrate their beneficial effects (Nelson et al. 2004; Cullum et al. 2001)...

Identification of symptom clusters in patients with chronic venous leg ulcers

Context Patients with venous leg ulcers experience multiple symptoms, including pain, depression, and discomfort from lower leg inflammation and wound exudate. Some of these symptoms impair wound healing and decrease quality of life (QOL). The presence of co-occurring symptoms may have a negative effect on these outcomes. The identification of symptom clusters could potentially lead to improvements in symptom management and QOL. Objectives To identify the prevalence and severity of common symptoms and the occurrence of symptom clusters in patients with venous leg ulcers. Methods For this secondary analysis, data on sociodemographic characteristics, medical history, venous history, ulcer and lower limb clinical characteristics, symptoms, treatments, healing, and QOL were analyzed from a sample of 318 patients with venous leg ulcers who were recruited from hospital outpatient and community nursing clinics for leg ulcers. Exploratory factor analysis was used to identify symptom clusters. Results Almost two-thirds (64%) of the patients experienced four or more concurrent symptoms. The most frequent symptoms were sleep disturbance (80%), pain (74%), and lower limb swelling (67%). Sixty percent of patients reported three or more symptoms at a moderate-to-severe level of intensity (e.g., 78% reported disturbed sleep frequently or always; the mean pain severity score was 49 of 100, SD 26.5). Exploratory factor analysis identified two symptom clusters: pain, depression, sleep disturbance, and fatigue; and swelling, inflammation, exudate, and fatigue. Conclusion Two symptom clusters were identified in this sample of patients with venous leg ulcers. Further research is needed to verify these symptom clusters and to evaluate their effect on patient outcomes.

Perspectives about exercise from adults with venous leg ulcers : an exploratory study

Objective Exercise has the potential to offer a range of health benefits in addition to improving healing outcomes for people with venous leg ulcers. However despite evidence based recommendations, most of these individuals do not engage in regular exercise. The aim of this study was to gain an understanding of the perspectives of adults with venous leg ulcers, in relation to exercise. Method This was a qualitative design using semi-structured interviews and discussions. Ten participants with venous leg ulceration volunteered to participate. Recruitment was through a specialist wound clinic. Verbatim data were collected by an experienced moderator using a semi-structured guide. Data saturation was reached after three group discussions and two interviews. A random selection of transcripts was sent back to the participants for verification. Thematic content analysis was used to determine major themes and categories. Two transcripts were independently analysed, categories and themes independently developed, cross checked and found comparable. Remaining transcripts were analysed using developed categories and codes. Results Regardless of their current exercise routine, participants reported exercising prior to venous leg ulceration and expressed an interest in either becoming active or maintaining an active lifestyle. Overall four themes emerged from the findings: i) participant understanding of the relationship between chronic venous insufficiency and exercise patterns, ii) fear of harm impacts upon positive beliefs and attitudes to exercise, iii) perceived factors limit exercise and iv) structured management facilitates exercise. Conclusion The value of exercise in improving outcomes in venous leg ulcers lies in its capacity to promote venous return and reduce the risk of secondary conditions in this population. Despite motivation and interest in being exercise active, people with venous leg ulcers report many obstacles. Further exploration of mechanisms that assist this patient population and promote understanding about management of barriers, coupled with promotion of enabling factors is vital for improving their exercise participation.

Factors associated with recurrence of venous leg ulcers : a survey and retrospective chart review

Background: Chronic venous leg ulcers have a significant impact on older individuals’ well-being and health care resources. Unfortunately after healing, up to 70% recur. ----- Objective: To examine the relationships between leg ulcer recurrence and physical activity, compression, nutrition, health, psychosocial indicators and self-care activities in order to provide information for preventive strategies. ----- Design: Survey and retrospective chart review Settings: Two metropolitan hospital and three community-based leg ulcer clinics. ----- Subjects: A sample of 122 community living patients with leg ulcer of venous aetiology which had healed between 12 and 36 months prior to the survey. ---- Methods: Data were collected from medical records on demographics, medical history and previous ulcer history and treatments; and from self-report questionnaires on physical activity, nutrition, psychosocial measures, ulcer recurrences and history, compression and other self-care activities. All variables significantly associated with recurrence at the bivariate level were entered into a logistic regression model to determine their independent influences on recurrence. ----- Results: Median follow-up time was 24 months (range 12–40 months). Sixty-eight percent of participants had recurred. Bivariate analysis found recurrence was positively associated with ulcer duration, cardiac disease, a Body Mass Index ≤20, scoring as at-risk of malnutrition and depression; and negatively associated with increased physical activity, leg elevation, wearing Class 2 (20–25mmHg) or Class 3 (30–40mmHg) compression hosiery, and higher self-efficacy scores. After adjusting for all variables, an hour/day of leg elevation (OR=0.04, 95% CI=0.01–0.17), days/week in Class 2 or 3 compression hosiery (OR=0.53, 95% CI=0.34–0.81), Yale Physical Activity Survey score (OR=0.95, 95% CI=0.92–0.98), cardiac disease (OR=5.03, 95% CI=1.01–24.93) and General Self-Efficacy scores (OR=0.83, 95% CI=0.72–0.94) remained significantly associated (p<0.05) with recurrence. ----- Conclusions: Results indicate a history of cardiac disease is a risk factor for recurrence; while leg elevation, physical activity, compression hosiery and strategies to improve self-efficacy are likely to prevent recurrence.

Relationships between preventive activities, psychosocial factors and recurrence of venous leg ulcers : a prospective study

Aim To identify relationships between preventive activities, psychosocial factors and leg ulcer recurrence in patients with chronic venous leg ulcers. Background Chronic venous leg ulcers are slow to heal and frequently recur, resulting in years of suffering and intensive use of health care resources. Methods A prospective longitudinal study was undertaken with a sample of 80 patients with a venous leg ulcer recruited when their ulcer healed. Data were collected from 2006–2009 from medical records on demographics, medical history and ulcer history; and from self-report questionnaires on physical activity, nutrition, preventive activities and psychosocial measures. Follow-up data were collected via questionnaires every three months for 12 months after healing. Median time to recurrence was calculated using the Kaplan-Meier method. A Cox proportional-hazards regression model was used to adjust for potential confounders and determine effects of preventive strategies and psychosocial factors on recurrence. Results: There were 35 recurrences in a sample of 80 participants. Median time to recurrence was 27 weeks. After adjustment for potential confounders, a Cox proportional hazards regression model found that at least an hour/day of leg elevation, six or more days/week in Class 2 (20–25mmHg) or 3 (30–40mmHg) compression hosiery, higher social support scale scores and higher General Self-Efficacy scores remained significantly associated (p<0.05) with a lower risk of recurrence, while male gender and a history of DVT remained significant risk factors for recurrence. Conclusion Results indicate that leg elevation, compression hosiery, high levels of self-efficacy and strong social support will help prevent recurrence.

A longitudinal assessment of chronic wound fluid to detect biochemical indicators of healing

Chronic venous leg ulcers are a detrimental health issue plaguing our society, resulting in long term pain, immobility and decreased quality of life for a large proportion of sufferers. The frequency of these chronic wounds has led current research to focus on the wound environment to provide important information regarding the prolonged, fluctuated or static healing patterns of these wounds. Disruption to the normal wound healing process results in release of multiple factors in the wound environment that could correlate to wound chronicity. These biochemical factors can often be detected through non-invasively sampling chronic wound fluid (CWF) from the site of injury. Of note, whilst there are numerous studies comparing acute and chronic wound fluids, there have not been any reports in the literature employing a longitudinal study in order to track biochemical changes in wound fluid as patients transition from a non-healing to healed state. Initially the objective of this study was to identify biochemical changes in CWF associated with wound healing using a proteomic approach. The proteomic approach incorporated a multi-dimensional liquid chromatography fractionation technique coupled with mass spectrometry (MS) to enable identification of proteins present in lower concentrations in CWF. Not surprisingly, many of the proteins identified in wound fluid were acute phase proteins normally expressed during the inflammatory phase of healing. However, the number of proteins positively identified by MS was quite low. This was attributed to the diverse range in concentration of protein species in CWF making it challenging to detect the diagnostically relevant low molecular weight proteins. In view of this, SELDI-TOF MS was also explored as a means to target low molecular weight proteins in sequential patient CWF samples during the course of healing. Unfortunately, the results generated did not yield any peaks of interest that were altered as wounds transitioned to a healed state. During the course of proteomic assessment of CWF, it became evident that a fraction of non-proteinaceous compounds strongly absorbed at 280 nm. Subsequent analyses confirmed that most of these compounds were in fact part of the purine catabolic pathway, possessing distinctive aromatic rings and which results in high absorbance at 254 nm. The accumulation of these purinogenic compounds in CWF suggests that the wound bed is poorly oxygenated resulting in a switch to anaerobic metabolism and consequently ATP breakdown. In addition, the presence of the terminal purine catabolite, uric acid (UA), indicates that the enzyme xanthine oxidoreductase (XOR) catalyses the reaction of hypoxanthine to xanthine and finally to UA. More importantly, the studies provide evidence for the first time of the exogenous presence of XOR in CWF. XOR is the only enzyme in humans capable of catalysing the production of UA in conjunction with a burst of the highly reactive superoxide radical and other oxidants like H2O2. Excessive release of these free radicals in the wound environment can cause cellular damage disrupting the normal wound healing process. In view of this, a sensitive and specific assay was established for monitoring low concentrations of these catabolites in CWF. This procedure involved combining high performance liquid chromatography (HPLC) with tandem mass spectrometry and multiple reaction monitoring (MRM). This application was selective, using specific MRM transitions and HPLC separations for each analyte, making it ideal for the detection and quantitation of purine catabolites in CWF. The results demonstrated that elevated levels of UA were detected in wound fluid obtained from patients with clinically worse ulcers. This suggests that XOR is active in the wound site generating significant amounts of reactive oxygen species (ROS). In addition, analysis of the amount of purine precursors in wound fluid revealed elevated levels of purine precursors in wound fluid from patients with less severe ulcers. Taken together, the results generated in this thesis suggest that monitoring changes of purine catabolites in CWF is likely to provide valuable information regarding the healing patterns of chronic venous leg ulcers. XOR catalysis of purine precursors not only provides a method for monitoring the onset, prognosis and progress of chronic venous leg ulcers, but also provides a potential therapeutic target by inhibiting XOR, thus blocking UA and ROS production. Targeting a combination of these purinogenic compounds and XOR could lead to the development of novel point of care diagnostic tests. Therefore, further investigation of these processes during wound healing will be worthwhile and may assist in elucidating the pathogenesis of this disease state, which in turn may lead to the development of new diagnostics and therapies that target these processes.

Identifying risk factors and protective factors for venous leg ulcer recurrence using a theoretical approach : a longitudinal study

Background The high recurrence rate of chronic venous leg ulcers has a significant impact on an individual’s quality of life and healthcare costs. Objectives This study aimed to identify risk and protective factors for recurrence of venous leg ulcers using a theoretical approach by applying a framework of self and family management of chronic conditions to underpin the study. Design Secondary analysis of combined data collected from three previous prospective longitudinal studies. Setting The contributing studies’ participants were recruited from two metropolitan hospital outpatient wound clinics and three community-based wound clinics. Participants Data were available on a sample of 250 adults, with a leg ulcer of primarily venous aetiology, who were followed after ulcer healing for a median follow-up time of 17 months after healing (range: 3 to 36 months). Methods Data from the three studies were combined. The original participant data were collected through medical records and self-reported questionnaires upon healing and every 3 months thereafter. A Cox proportion-hazards regression analysis was undertaken to determine the influential factors on leg ulcer recurrence based on the proposed conceptual framework. Results The median time to recurrence was 42 weeks (95% CI 31.9–52.0), with an incidence of 22% (54 of 250 participants) recurrence within three months of healing, 39% (91 of 235 participants) for those who were followed for six months, 57% (111 of 193) by 12 months, 73% (53 of 72) by two years and 78% (41 of 52) of those who were followed up for three years. A Cox proportional-hazards regression model revealed that the risk factors for recurrence included a history of deep vein thrombosis (HR 1.7, 95% CI 1.07–2.67, p=0.024), history of multiple previous leg ulcers (HR 4.4, 95% CI 1.84–10.5, p=0.001), and longer duration (in weeks) of previous ulcer (HR 1.01, 95% CI 1.003–1.01, p<0.001); while the protective factors were elevating legs for at least 30 minutes per day (HR 0.33, 95% CI 0.19–0.56, p<0.001), higher levels of self-efficacy (HR 0.95, 95% CI 0.92–0.99, p=0.016), and walking around for at least three hours/day (HR 0.66, 95% CI 0.44–0.98, p=0.040). Conclusions Results from this study provide a comprehensive examination of risk and protective factors associated with leg ulcer recurrence based on the chronic disease self and family management framework. These results in turn provide essential steps towards developing and testing interventions to promote optimal prevention strategies for venous leg ulcer recurrence.

Elevated uric acid correlates with wound severity

Chronic venous leg ulcers are a major health issue and represent an often overlooked area of biomedical research. Nevertheless, it is becoming increasingly evident that new approaches to enhance healing outcomes may arise through better understanding the processes involved in the formation of chronic wounds. We have for the first time shown that the terminal purine catabolite uric acid (UA) is elevated in wound fluid (WF) from chronic venous leg ulcers with relative concentrations correlating with wound chronicity. We have also shown a corresponding depletion in UA precursors, including adenosine, with increased wound severity. Further, we have shown that xanthine oxidase, the only enzyme in humans that catalyses the production of UA in conjunction with a burst of free radicals, is active in chronic WF. Taken together, this provides compelling evidence that xanthine oxidase may play a critical role in the formation of chronic wounds by prolonging the inflammatory process.

Identifying relationships between symptom clusters and quality of life in adults with chronic mixed venous and arterial leg ulcers

The objective of this study was to identify symptom clusters and their effect on quality of life (QOL) of adults with chronic leg ulcers of mixed venous and arterial aetiology. A secondary analysis of data from four existing prospective longitudinal studies conducted by a wound healing research group in Australia was undertaken. A total of 110 patients who met the inclusion criteria were selected for this study. Exploratory factor analysis (EFA) was used to identify symptom clusters and correlational analyses to examine relationships between the identified symptom clusters and QOL. The EFA identified two distinct symptom clusters: a 'systemic symptom cluster' consisting of pain, fatigue and depressive symptoms; and a 'localised-leg symptom cluster' including pain, fatigue, oedema, lower limb inflammation and exudate. Physical QOL correlated significantly with the systemic symptom cluster (r = -0·055, P < 0·0001) and the localised-leg symptom cluster (r = -0·054, P < 0·0001), whereas mental QOL was associated only with the systemic symptom cluster (r = -0·038, P = 0·01). The results suggest that appropriate intervention strategies targeting specific symptom clusters should be developed. Targeting patients with symptom clusters is particularly important because they are at high risk and the most vulnerable for reduced QOL.

Identification of factors contributing to recurrence of venous leg ulcers

Background and Significance Venous leg ulcers are a significant cause of chronic ill-health for 1–3% of those aged over 60 years, increasing in incidence with age. The condition is difficult and costly to heal, consuming 1–2.5% of total health budgets in developed countries and up to 50% of community nursing time. Unfortunately after healing, there is a recurrence rate of 60 to 70%, frequently within the first 12 months after heaing. Although some risk factors associated with higher recurrence rates have been identified (e.g. prolonged ulcer duration, deep vein thrombosis), in general there is limited evidence on treatments to effectively prevent recurrence. Patients are generally advised to undertake activities which aim to improve the impaired venous return (e.g. compression therapy, leg elevation, exercise). However, only compression therapy has some evidence to support its effectiveness in prevention and problems with adherence to this strategy are well documented. Aim The aim of this research was to identify factors associated with recurrence by determining relationships between recurrence and demographic factors, health, physical activity, psychosocial factors and self-care activities to prevent recurrence. Methods Two studies were undertaken: a retrospective study of participants diagnosed with a venous leg ulcer which healed 12 to 36 months prior to the study (n=122); and a prospective longitudinal study of participants recruited as their ulcer healed and data collected for 12 months following healing (n=80). Data were collected from medical records on demographics, medical history and ulcer history and treatments; and from self-report questionnaires on physical activity, nutrition, psychosocial measures, ulcer history, compression and other self-care activities. Follow-up data for the prospective study were collected every three months for 12 months after healing. For the retrospective study, a logistic regression model determined the independent influences of variables on recurrence. For the prospective study, median time to recurrence was calculated using the Kaplan-Meier method and a Cox proportional-hazards regression model was used to adjust for potential confounders and determine effects of preventive strategies and psychosocial factors on recurrence. Results In total, 68% of participants in the retrospective study and 44% of participants in the prospective study suffered a recurrence. After mutual adjustment for all variables in multivariable regression models, leg elevation, compression therapy, self efficacy and physical activity were found to be consistently related to recurrence in both studies. In the retrospective study, leg elevation, wearing Class 2 or 3 compression hosiery, the level of physical activity, cardiac disease and self efficacy scores remained significantly associated (p<0.05) with recurrence. The model was significant (p <0.001); with a R2 equivalent of 0.62. Examination of relationships between psychosocial factors and adherence to wearing compression hosiery found wearing compression hosiery was significantly positively associated with participants’ knowledge of the cause of their condition (p=0.002), higher self-efficacy scores (p=0.026) and lower depression scores (p=0.009). Analysis of data from the prospective study found there were 35 recurrences (44%) in the 12 months following healing and median time to recurrence was 27 weeks. After adjustment for potential confounders, a Cox proportional hazards regression model found that at least an hour/day of leg elevation, six or more days/week in Class 2 (20–25mmHg) or 3 (30–40mmHg) compression hosiery, higher social support scale scores and higher General Self-Efficacy scores remained significantly associated (p<0.05) with a lower risk of recurrence, while male gender and a history of DVT remained significant risk factors for recurrence. Overall the model was significant (p <0.001); with an R2 equivalent 0.72. Conclusions The high rates of recurrence found in the studies highlight the urgent need for further information in this area to support development of effective strategies for prevention. Overall, results indicate leg elevation, physical activity, compression hosiery and strategies to improve self-efficacy are likely to prevent recurrence. In addition, optimal management of depression and strategies to improve patient knowledge and self-efficacy may positively influence adherence to compression therapy. This research provides important information for development of strategies to prevent recurrence of venous leg ulcers, with the potential to improve health and decrease health care costs in this population.

Understanding the relationships between the calf muscle pump, ankle range of motion and healing for adults with venous leg ulcers: a review of the literature

Exercise offers the potential to improve circulation, wound healing outcomes, and functional and emotional wellbeing for adults experiencing venous leg ulceration. Individuals with chronic leg ulcers typically have multiple comorbidities such as arthritis, asthma, chronic obstructive airways disease, cardiac disease or neuromuscular disorders, which would also benefit from regular exercise. The aim of this review is to highlight the relationships between the calf muscle pump and venous return and range of ankle motion for adults with venous leg ulcers. The effect of exercise will also be considered in relation to the healing rates for adults experiencing venous leg ulceration. The findings suggest there is evidence that exercises which engage the calf muscle pump improve venous return. Ankle range of motion, which is crucial for complete activation of the calf muscle pump, can also be improved with simple, home-based exercise programs. However, observational studies still report that venous leg ulcer patients are less physically active than age-matched controls. Therefore, the behavioural reasons for not exercising must be considered. Only two studies, both underpowered, have assessed the effect of exercise on the healing rates of venous leg ulcers. In conclusion, exercise is feasible with this patient population. However, future studies with larger sample sizes are needed to provide stronger evidence to support the therapeutic benefit of exercise as an adjunct therapy in wound care.

CPD : Using evidence based clinical practice guidelines in the management of anaemia in patients with chronic renal failure

Anaemia is a chronic problem in patients with renal insufficiency, especially chronic renal failure (CRF). In patients with CRF, anaemia is primarily due to a deficiency in erythropoietin (EPO), a glycoprotein growth factor that stimulates RBC production. The long-term effects and burden of anaemia for patients with CRF can be physical, emotional and financial. With efficient, systematic management of anaemia, clinicians have the potential to realise not only better clinical outcomes for CRF patients but also significant cost savings for them and the health system. During the last decade, significant advances have been made in clinicians’ understanding of how best to manage anaemia in this vulnerable population. One of the most important efforts to improve clinical practice has been the development of best practice guidelines.