An overview of systematic reviews of clinical studies of platelet-rich plasma for venous ulcers.

To evaluate the clinical evidence of platelet-rich plasma (PRP) in the treatment of venous ulcers (VUs). Electronic searches were conducted through the Cochrane Library, Web of Science, Embase and PubMed. AMSTAR-2 was used to assess the methodological quality. The quality of evidence was assessed using the GRADE system. According to AMSTAR-2, the methodological quality of the included reviews was generally inadequate owing to the limitations of entries 2, 4 and 7. Due to bias risk and imprecision, the evidence quality of the outcome measures was inadequate. In conclusion, PRP may have a therapeutic effect on VUs. However, this conclusion must be treated with caution due to methodological flaws of the included systematic reviews and meta-analyses.

Patterns of use of advanced wound matrices in the Veterans Administration clinics.

Chronic wounds are a common and costly health issue affecting millions of individuals in the United States, particularly those with underlying conditions such as diabetes, venous insufficiency, and peripheral artery disease. When standard treatments fail, advanced wound care therapies, such as skin substitutes, are often applied. However, the clinical effectiveness, indications, and comparative benefits of these therapies have not been well established. In this study, we report on the usage of both acellular and cellular, single and bilayer, natural and synthetic, dermal, and epidermal skin substitutes in a VA hospital system. We performed a retrospective chart review to understand the ordering and usage patterns of advanced wound therapies for patients with chronic wounds at the VA Northern California Health Care System. We examined types of products being recommended, categories of users recommending the products, indications for orders, and rate of repeated orders. Neuropathic, venous, or pressure ulcers were the main indications for using advanced wound matrices. Only 15.6% of patients for whom the matrices were ordered had supporting laboratory tests. Exactly 34.3% of the ordered matrices were not applied. And the use of wound matrices resulted in increased costs per patient visit of $1018-$3450. Our study sheds light on the usage patterns of these therapies in a VA healthcare facility and highlights the need for more robust evidence-based studies to determine the true benefits, efficacy, and cost-effectiveness of these innovative treatment options.

Exploring causal correlations between inflammatory cytokines and varicose veins: A Mendelian randomization analysis.

This study aimed to investigate the causal relationship between inflammatory cytokines and the risk of varicose veins. The data were sourced from genome-wide association studies (GWAS) of European individuals. Multiple Mendelian randomization (MR) methods were used to evaluate the association between inflammatory cytokines and varicose veins. The study found significant associations between elevated levels of certain inflammatory biomarkers (e.g., CASP-8, Vascular endothelial growth factor A levels (VEGF_A)) and an increased risk of varicose veins, while others (e.g., 4EBP1, MMP-10) showed a protective effect. The MR-Egger Intercept and heterogeneity tests indicated no significant pleiotropy or heterogeneity. This comprehensive MR analysis identifies several cytokines as potential contributors to the pathogenesis of varicose veins, offering insights into novel therapeutic targets. Our findings underscore the importance of inflammation in varicose veins and suggest that targeting specific cytokines could be a promising strategy for the treatment and prevention of varicose veins.

Understanding CEAP Classification: Insights from an Italian Survey on Corona Phlebectatica and Recurrent Active Venous Ulcers by Vascular Specialists.

Background and Objectives: The clinical relevance of "corona phlebectatica" and the management of risk factors for recurrence of venous ulcers in patients with chronic venous disease may be variable based on vascular specialists in different geographical areas of Italy. The aim of the present survey is to evaluate the management of patients with chronic venous disease by vascular specialists in different areas of the national territory. In particular, this involves ascertaining the clinical/prognostic relevance attributed to the presence of the "corona phlebectatica" as well as to the management of risk factors related to recurrence of venous ulcers. Materials and Methods: The web-based survey aimed at vascular medicine specialists with particular interest in venous disease. A questionnaire was developed, based on 12 questions, in relation to clinical assessment, risk factor management, and therapy in patients with chronic venous disease. Results: Almost all of the specialists involved actively participated in the survey, declaring that they personally manage chronic venous disease overall. There was a strong agreement in the prognostic consideration attributed to the presence of "corona phlebectatica" and to the management of risk factors for venous ulcer recurrence, regardless of the different geographical areas of interest. Conclusions: Accordingly with the results of this self-assessment survey, the skills and experience of the specialists involved appear to be of a good standard, both in the clinical evaluation and in the management of the progression of chronic venous disease. However, the need to reach more cultural insights into the correlations between chronic venous disease and risk factors correlated with disease progression emerges. Moreover, there was the need for a greater and tighter overall clinical control of a patient with chronic venous disease, also in relation to the presence of comorbidities.

First pilot case-control interventional study using autologous extracellular vesicles to treat chronic venous ulcers unresponsive to conventional treatments.

Current therapeutic approaches for chronic venous ulcers (CVUs) still require evidence of effectiveness. Diverse sources of extracellular vesicles (EVs) have been proposed for tissue regeneration, however the lack of potency tests, to predict in-vivo effectiveness, and a reliable scalability have delayed their clinical application. This study aimed to investigate whether autologous serum-derived EVs (s-EVs), recovered from patients with CVUs, may be a proper therapeutic approach to improve the healing process. A pilot case-control interventional study (CS2/1095/0090491) has been designed and s-EVs recovered from patients. Patient eligibility included two or more distinct chronic lesions in the same limb with 11 months as median persistence of active ulcer before enrollment. Patients were treated three times a week, for 2 weeks. Qualitative CVU analysis demonstrated that s-EVs-treated lesions displayed a higher percentage of granulation tissue compared to the control group (Sham) (s-EVs 3 out of 5: 75-100 % vs Sham: none), further confirmed at day 30. s-EVs-treated lesions also displayed higher sloughy tissue reduction at the end of treatment even increased at day 30. Additionally, s-EV treatment led to a median surface reduction of 151 mm2 compared to 84 mm2 in the Sham group, difference even more evident at day 30 (s-EVs 385 mm2vs Sham 106 mm2p = 0.004). Consistent with the enrichment of transforming growth factor-ß1 in s-EVs, histological analyses showed a regenerative tissue with an increase in microvascular proliferation areas. This study first demonstrates the clinical effectiveness of autologous s-EVs in promoting the healing process of CVUs unresponsive to conventional treatments.

Clinical validation of a smartphone application for automated wound measurement in patients with venous leg ulcers.

Chronic wounds are associated with significant clinical, economic and quality-of-life burden. Despite the variety of wound imaging systems available in the market for wound assessment and surveillance, few are clinically validated among patients of Asian ethnicity. We aimed to clinically validate the accuracy of a smartphone wound application (Tissue Analytics [TA], Net Health Systems Inc, Florida, USA), versus conventional wound measurements (visual approximation and paper rulers), in patients of Asian ethnicity with venous leg ulcers (VLU). A prospective cohort study of patients presenting with VLU to a specialist wound nurse clinic over a 5-week duration was conducted. Each patient received seven wound measurements: one by a trained wound nurse clinician, and three separate wound measurements using TA on each of the iOS and Android operating systems. Inter-rater and intra-rater reliability between clinical and TA-based measurements were analysed using intra-class correlation statistics, with values of <0.5, 0.5 to 0.75, 0.75 to 0.9, and >0.9 indicating poor, moderate, good and excellent reliability, respectively. 82 patients (51% males), with a mean age at 65.8 years, completed the 5-week study duration. 25 (30%) had underlying diabetes mellitus. Chinese, Malay and Indian ethnicity comprised 68%, 12% and 11%, respectively. The VLU healed in 26 (32%) of patients within the study period. In total, 358 wound episodes with 2334 wound images were analysed. Inter-rater reliability for length, width and area between wound nurse measurements and TA application measurements was good (range 0.799-0.919, P < 0.001). Separate measurements of intra-rater reliability for length, width and area within the iOS or Android systems were excellent (range 0.967-0.985 and range 0.977-0.984 respectively, P < 0.001). Inter-rater reliability between TA used on the iOS and Android systems was also excellent (0.987-0.989, P < 0.001). Tissue Analytics, a smartphone wound application, is a useful adjunct for wound assessment and surveillance in VLU patients of Asian ethnicity.

Implementing a new regimen to manage a difficult-to-heal lymphovenous leg ulcer.

The case study described in this article shows the use of different approaches and techniques that need to be utilised when treating patients presenting with a combination of venous and lymphatic disease (lymphovenous) in order to improve complex wound outcomes. The author highlights how lymphoedema can affect the wound healing process by increasing the risk of recurrent infection and a hardening of the tissues (fibrosis), reducing oxygenation and lymphatic flow to the wound, leading to chronic complex wounds.

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.

Radiofrequency ablation for markedly incompetent perforators versus compression therapy in the management of post-phelebtic venous ulcers: A randomized controlled trial.

BACKGROUND: Venus ulcers developed mainly due to reflux of incompetent venous valves in perforating veins. PATIENTS AND METHODS: In this randomized controlled trial, 119 patients recruited over two years, with post-phelebtic venous leg ulcers, were randomly assigned into one of two groups: either to receive radiofrequency ablation of markedly incompetent perforators (Group A, n = 62 patients) or to receive conventional compression therapy (Group B, n = 57 patients). Follow-up duration required for ulcer healing continued for 24 months post randomization. RESULTS: Statistically significant shorter time to healing (ulcer complete healing or satisfactory clinical improvement) between both groups (56 patients, 90.3% of cases in Group A versus 44 patients 77.2% of cases in Group B) over the follow-up period of 24 months was attained (p = 0.001). Also, significantly different ulcer recurrence was recorded between both groups, 8 patients (12.9%) in Group A versus 19 patients (33.3%) in Group B (p = 0.004). CONCLUSION: In absence of deep venous obstruction, the monopolar radiofrequency ablation for incompetent perforators is a feasible and effective method that surpasses the traditional compression protocol for incompetent perforator-induced venous ulcers in terms of time required for healing even in the presence of unresolved deep venous valvular reflux.

Proteus mirabilis resistant to carbapenems isolated from a patient with a venous leg ulcer: a case report.

OBJECTIVE: The aim of the study was to phenotypically investigate the expression of the enzyme Klebsiella pneumoniae carbapenemase (KPC) in a Proteus mirabilis sample resistant to carbapenems, isolated from the wound of a patient with a venous leg ulcer (VLU) treated at an outpatient referral service. METHOD: This was a case study conducted with a patient who had a VLU on the lower left limb. Samples were taken for the examination of microbiological material from the patient's wound, using an aseptic technique. The colonies extracted were submitted to Gram staining and biochemical tests to identify the strain. In addition, an antimicrobial susceptibility test, E-test and a modified Hodge test were performed. RESULTS: The identified microorganism was Proteus mirabilis, which showed resistance to cefuroxime and the carbapenems imipenem and meropenem. As well as the minimum inhibitory concentration (MIC) of 3.0µg/ml for imipenem, demonstrating resistance, there was no KPC production by the tested isolate, which presented a negative modified Hodge test. CONCLUSION: The results highlight the importance of microbiological surveillance, aimed at reducing morbidity and mortality rates associated with infection by multiresistant bacteria.

Chronic venous insufficiency: a comprehensive review of management.

Chronic venous insufficiency is an extensive progressive disease in need of public health attention. This insidious disease is a growing burden on patient quality of life and the health economy. Chronic venous insufficiency has become more pronounced in global populations, especially in regions exhibiting a higher rate of risk factors. It is critical for healthcare providers to recognise and intervene early to prevent ongoing and debilitating complications. This article provides a comprehensive review of chronic venous insufficiency outlining the anatomy, pathophysiology, clinical presentation, assessment and management options.

Neuromuscular stimulation of the common peroneal nerve increases arterial and venous velocity in patients with venous leg ulcers.

Activation of the venous muscle pumps by neuromuscular stimulation of the common peroneal nerve has been previously shown to increase venous and arterial flow in the legs of healthy subjects. The aim of this study is to determine whether a similar effect is observed in patients with chronic venous leg ulcers. 1 Hz intermittent electrostimulation of the common peroneal nerve was applied to 14 patients with ulcers between 1 and 10 cm in diameter, eliciting a small, painless, regular, muscular twitch of the leg. Flow was measured using Duplex ultrasound in the popliteal vein and the popliteal artery. Peak arterial velocity increased from 57 to 78 cm/s (P = .001) in sitting position, and from 79 to 98 cm/s in recumbent position (P = .001). Peak venous velocity increased from 10 to 33 cm/s (P = .001) sitting, and from 14 to 47 cm/s (P = .001) recumbent. Significant increases were observed in both venous and arterial blood flow in the lower limb. This suggestsed that activation of the venous muscle pump and improvement of arterial flow assisted oxygen delivery at the wound site. Moreover this may be a worthwhile intervention to assist in the healing of venous leg ulcers, and may provide a mechanistic explanation for the increased healing rates previously reported with neuromuscular stimulation of the common peroneal nerve.

Persistent venous leg ulcers complicated by linear morphea: a case report.

Soft tissue ulceration resulting from chronic venous insufficiency is a common condition that requires standardised long-term therapy, which has been thoroughly established. We report a patient with a five-year history of persistent venous stasis ulcers despite treatment consistent with traditional wound care. Resolution of the ulcers began only upon deviation from conventional therapy. This report considers non-standard treatments in patients with venous ulcers that do not progress.

Transilluminated powered phlebectomy in the treatment of large area venous leg ulcers: A case-control study with 3 years follow-up.

OBJECTIVE: To evaluate the efficacy, safety and long-term outcome of TIPP for the adjunct therapy of superficial venous reflux-related VLUs. METHODS: A total of 93 consecutive patients (104 legs) with superficial venous insufficiency-related VLUs who underwent TIPP (53 legs) or conventional phlebectomy (51 legs) between January 2010 and December 2013 were retrospectively studied. RESULTS: Compared to patients in the conventional phlebectomy group, TIPP patients had larger ulcer areas before surgery (P < 0.005). However, TIPP group required a significantly shorter operation time (P < 0.005), fewer incisions (P < 0.005) but less ulcer healing time (1.25 month vs 2.5 months, P < 0.05). No significant difference in in-hospital and follow-up complications was found between the two groups. For long-term outcome, TIPP group leaded a lower ulcer recurrence rate at 36 months (13.2% vs 29.4%, P < 0.05). CONCLUSION: TIPP may be an adjunct surgical method contributes to healing of VLUs, especially for large ulcer areas.

An overview of the relationship between anaemia, iron, and venous leg ulcers.

The factors preventing healing in venous leg ulcers are still not fully understood. Iron-mediated tissue damage has been hypothesised, yet anecdotally anaemia is also thought to have a negative effect on wound healing. This article summarises the current evidence for these theories and their likely effects in the context of venous ulceration. A comprehensive search of the literature was conducted. Studies suggest that a number of forms of iron including haemosiderin and ferritin are implicated in progression of venous disease, ulcer formation, and impaired healing, which is thought to be primarily free radical mediated. There is a paucity of evidence for the role of iron deficiency and anaemia on ulcer healing; however, there is likely to be a highly complex interplay between the damaging effects of iron on local tissues and the negative effects of anaemia-mediated tissue hypoxia. Studies looking at options to increase local oxygen delivery such as topical haemoglobin suggest that this may have an impact on some aspects of healing, but findings are generally inconclusive. There is growing evidence that locally elevated iron levels may have a detrimental effect on ulcer healing and formation; however, more robust research is needed.

Exercise fidelity and progression in a supervised exercise programme for adults with venous leg ulcers.

Despite exercise being included in the recommended advice for patients with venous leg ulcers, there is a fear shared by clinicians and patients that exercise may be either inappropriate or harmful and actually delay rather than promote healing. Therefore, before implementing a larger-scale study exploring the effects of a supervised exercise programme in patients with venous ulcers being treated with compression therapy, it is important to assess exercise safety as well as fidelity and progression in a feasibility study. Eighteen participants randomised in the exercise group were asked to undertake 36 (3 times/week for 12 weeks) 60-min exercise sessions, each comprising moderate-intensity aerobic, resistance, and flexibility exercise components. For the purposes of this paper, we analysed the data collected during the exercise sessions. The overall session attendance rate was 79%, with 13 of 18 participants completing all sessions. No in-session adverse events were reported; 100% aerobic components and 91% of resistance components were completed within the desired moderate-intensity target. Similarly, 81% of aerobic components and 93% of flexibility components were completed within the prescribed duration targets. Our data showed that patients with venous ulcers could safely follow a supervised exercise programme incorporating moderate-intensity aerobic, resistance, and flexibility components.

Refractory venous leg ulcers: observational evaluation of innovative new technology.

This observational case series reports the evaluation of a novel neuromuscular electrical stimulation device (geko™) that stimulates the common peroneal nerve at the fibular head as an adjunctive therapy in patients with non-healing venous leg ulcers. The aim was to evaluate and determine if the geko™ device was effective in this population and should be added to the medical supply formulary. Patients whose wounds had failed to heal within 24 weeks of standard therapy were identified in two community settings in Ontario. A total of 11 patients consented to the evaluation with a combined 107-year history of recalcitrant leg ulcers. Although the pre-geko™ healing rate was unknown, all ulcers were considered non-healing. With geko™, the average weekly percentage reduction in surface area for all patients was 4·5% and for the six adherent to geko™ and best practices 7·0%. By comparison, the average weekly percentage reduction for measurable wounds in the five non-adherent patients was 1·8%. Requirements for success appear to include an arterial status adequate for healing, effective and prompt management of wound infections and adherence to the treatment schedule. The geko™ device has been added to the medical supply formulary in one centre and is pending in the other.

A single-arm trial indirect comparison investigation: a proof-of-concept method to predict venous leg ulcer healing time for a new acellular synthetic matrix matched to standard care control.

To compare data on time to healing from two separate cohorts: one treated with a new acellular synthetic matrix plus standard care (SC) and one matched from four large UK pragmatic, randomised controlled trials [venous leg ulcer (VLU) evidence network]. We introduce a new proof-of-concept strategy to a VLU clinical evidence network, propensity score matching and sensitivity analysis to predict the feasibility of the new acellular synthetic matrix plus SC for success in future randomised, controlled clinical trials. Prospective data on chronic VLUs from a safety and effectiveness study on an acellular synthetic matrix conducted in one wound centre in the UK (17 patients) and three wound centres in Australia (36 patients) were compared retrospectively to propensity score-matched data from patients with comparable leg ulcer disease aetiology, age, baseline ulcer area, ulcer duration, multi-layer compression bandaging and majority of care completed in specialist wound centres (average of 1 visit per week), with the outcome measures at comparable follow-up periods from patients enrolled in four prospective, multicentre, pragmatic, randomised studies of venous ulcers in the UK (the comparison group; VLU evidence network). Analysis using Kaplan-Meier survival curves showed a mean healing time of 73·1 days for ASM plus SC (ASM) treated ulcers in comparison with 83·5 days for comparison group ulcers treated with SC alone (Log rank test, χ2 5·779, P = 0·016) within 12 weeks. Sensitivity analysis indicates that an unobserved covariate would have to change the odds of healing for SC by a factor of 1·1 to impact the baseline results. Results from this study predict a significant effect on healing time when using a new ASM as an adjunct to SC in the treatment of non-healing venous ulcers in the UK, but results are sensitive to unobserved covariates that may be important in healing time comparison.

Managing exudate and maceration in venous leg ulceration within the acute health setting.

Exudate has beneficial effects in normal wound healing but detrimental consequences for chronic wounds. Practitioners need to identify and treat its cause, and manage the exudate and prevent if from damaging periwound skin. Management involves dressings of the most appropriate absorbency and other products, and avoiding maceration of periwound skin; compression therapy is the gold standard treatment for treating oedema and venous leg ulceration. Nurses in acute settings may not have the skills to implement or maintain compression therapy; this article is intended for nurses who may have to manage these patients temporarily while they are admitted to secondary care and may not have the skills.

Recalcitrant Venous Leg Ulcers May Heal by Outpatient Treatment of Venous Disease Even in the Presence of Concomitant Arterial Occlusive Disease.

OBJECTIVE/BACKGROUND: Peripheral arterial occlusive disease (PAOD) is reported in about 15-20% of patients with venous leg ulcers (VLU). In such cases arterial recanalization is often recommended, and compression therapy is considered a contraindication when the ankle brachial pressure index (ABPI) is < 0.8. The aim of this study was to compare the outcome of patients with recalcitrant VLU, both without any arterial impairment ("pure venous recalcitrant leg ulcer" [pvRLU]) and with associated PAOD ("mixed arterial and venous recalcitrant leg ulcer" [mavRLU]), by treating only the venous disease. METHODS: The records of 180 outpatients with recalcitrant ulcers treated between January 2011 and July 2014 were reviewed retrospectively. In total, 109 were affected by pvRLU and 71 by mavRLU, with moderate PAOD defined by an ABPI between 0.5 and 0.8. In addition to the same local wound dressing, the patients received ultrasound guided foam sclerotherapy of the refluxing superficial veins and a modified inelastic compression with a pressure ≤ 40 mmHg. No patient was referred for arterial revascularization. The patients were followed until ulcer healing. RESULTS: Patients with pvRLU and mavRLU showed comparable demographic characteristics. Twenty-five patients were lost to follow up and the outcomes were analyzed in 93 patients with pVLU (85.4%) and in 62 patients with mavRLU (87.4%). The maximum time to complete healing was 48 weeks in the pvRLU group and 52 weeks in the mavRLU group (p = .009), The median healing time was 23 (pvRLU) versus 25.5 weeks (mavRLU) (p = .030). Deep venous incompetence (p < .001), ulcer surface area (p < .001), arterial disease (p = .002), and ulcer duration (p < .010) were risk factors for prolonged healing. CONCLUSION: Treatment of recalcitrant leg ulcers by treating venous incompetence by foam sclerotherapy and modified compression is successful, even if underlying moderate PAOD is not actively treated.