Low molecular weight heparin improves healing of chronic venous ulcers especially in the elderly

Venous ulcers are common, especially in the elderly, accounting for more than 50% of all lower extremity ulcers with important socioeconomic problems. Improving extracellular matrix functioning, by heparin administration, seems to be a way to support wound healing. A total of 284 patients with venous ulcers were recruited in a 4‐year period. All patients were subjected to the most appropriate treatment after considering their preference (compression therapy followed or not by vein surgery). Patients were randomised into two groups of 142 persons in each (group A and group B as cases and controls, respectively). Patients of group A, in addition to the basic treatment as described earlier, received administration of nadroparin 2850 IU/0.3 ml through subcutaneous injection once a day for 12 months, whereas group B patients received basic treatment alone. Healing was assessed by means of direct ulcer tracing with computerised planimetry. Group A showed a healing rate of 83·80% at 12 months, whereas that of group B was 60·56%. Results by age group surprisingly showed that the group of older patients took the most advantage from long‐term treatment with low molecular weight heparin; this group also had lowest recurrence rate.     

Extracellular matrix assessment of infected chronic venous leg ulcers: role of metalloproteinases and inflammatory cytokines

Chronic venous ulcer (CVU) represents a dreaded complication of chronic venous disease (CVD). The onset of infection may further delay the already precarious healing process in such lesions. Some evidences have shown that matrix metalloproteinases (MMPs) are involved and play a central role in both CVUs and infectious diseases. Two groups of patients were enrolled to evaluate the expression of MMPs in infected ulcers and the levels of inflammatory cytokines as well as their prevalence. Group I comprised 63 patients (36 females and 27 males with a median age of 68·7 years) with infected CVUs, and group II (control group) comprised 66 patients (38 females and 28 males with a median age of 61·2 years) with non‐infected venous ulcers. MMP evaluation and dosage of inflammatory cytokines in plasma and wound fluid was performed by means of enzyme‐linked immunosorbent assay test; protein extraction and immunoblot analysis were performed on biopsied wounds. The first three most common agents involved in CVUs were Staphylococcus aureus (38·09%), Corynebacterium striatum (19·05%) and Pseudomonas aeruginosa (12·7%). In this study, we documented overall higher levels of MMP‐1 and MMP‐8 in patients with infected ulcers compared to those with uninfected ulcers that showed higher levels of MMP‐2 and MMP‐9. We also documented higher levels of interleukin (IL)‐1, IL‐6, IL‐8, vascular endothelial growth factor and tumour necrosis factor‐alpha in patients with infected ulcers with respect to those with uninfected ulcers, documenting a possible association between infection, MMP activation, cytokine secretions and symptoms. The present results could represent the basis for further studies on drug use that mimic the action of tissue inhibitors of metalloproteinases in order to make infected CVU more manageable.     

Feasibility of an electrostimulation system treatment for wound healing: a case series of patients with chronic ulcers in Barbados

Major advances have been made in the development of new therapies for chronic wounds. Fenzian?, an electrostimulation system (ES), has been clinically used for a variety of conditions. The ES was recently tested in the Barbadian population for tolerability and acceptability by asthma patients, with encouraging results. Barbados has an estimated 170 people with diabetes having some form of lower‐extremity amputation annually. Here, we describe a case series of 21 chronic ulcer patients with diabetes recruited as inpatients (n = 10) and outpatients (n = 11) in a pilot study to evaluate the feasibility and acceptability of ES in the Barbadian population. Results showed statistically significant improvement among those in the inpatient‐ versus outpatient‐recruited group for wound perimeter (P = 0·04), wound surface area (P = 0·03) and wound volume (P = 0·08). We also demonstrate that the improvement continued after cessation of ES treatment. Participants reported increased levels of pain at the end of treatment, and there was no statistically significant change in the reported quality of life. Our results showed greater improvements in reduction of ulcer size for participants from the inpatient‐ versus outpatient‐recruited group.     

The association of wound factors and symptoms of fatigue and pain with wound healing in chronic venous leg ulcers

The purpose of this study was: (1) to characterise the association of wound area, wound exudate C-reactive protein (CRP), broad-spectrum matrix metalloprotease protein (MMPs), and symptoms of fatigue and pain in individuals with chronic venous leg ulcers (CVLUs) over time and (2) to identify factors associated with the wound healing trajectory in CVLUs. Seventy four participants with CVLU who received weekly sharp debridement were recruited from a wound care clinic during the 8-week study period. To examine associations among wound CRP, MMPs, pain, fatigue, and wound healing trajectory over time, we calculated Bayes factors (BF) based on a linear mixed model. The mean age of participants was 71.8 (SD = 9.8) and the mean wound area was 2278 mm² (SD = 7085 mm²) at baseline. Higher fatigue was strongly associated with higher MMPs (BF = 9, 95% HDI: [−.05, .43]), lower CRP (BF = 11, 95% HDI: [−.02, .002]), and large areas of wound (BF = 20, 95% HDI: [−.001, .01]). Higher CRP and MMPs activity in wound exudate and higher fatigue were associated with a larger wound area. To facilitate wound healing, clinicians need to utilise the multifactorial approach, which includes wound treatment and management of symptoms such as pain and fatigue, because of the molecular and psycho-behavioural factors involved in wound healing.     

Role of matrix metalloproteinases in non‐healing venous ulcers

Chronic venous ulceration (CVU) of the lower limbs is a common condition affecting 1% of the adult population in Western countries, which is burdened with a high complication rate and a marked reduction in the quality of life often due to prolonged healing time. Several metalloproteinases (MMPs) such as MMP‐9 together with neutrophil gelatinase‐associated lipocalin (NGAL) appear to be involved in the onset and healing phases of venous ulcer, but it is still unclear how many biochemical components are responsible for prolonged healing time in those ulcers. In this study, we evaluate the role of MMP‐1 and MMP‐8 in long lasting and refractory venous ulcers. In a 2‐year period we enroled 45 patients (28 female and 17 male, median age 65) with CVU. The enroled population was divided into two groups: group I were patients with non‐healing ulcers (ulcers that had failed to heal for more than 2 months despite appropriate treatments) and group II were patients with healing ulcers (ulcers in healing phases). MMP‐1 and MMP‐8 were measured in fluids and tissues of healing and non‐healing ulcers by means of enzyme‐linked immunosorbent assay (ELISA) and Western blot analysis, respectively. In particular the patterns of the collagenases MMP‐1 and MMP‐8 in healing wounds were distinct, with MMP‐8 appearing in significantly greater amounts especially in the non‐healing group. Our findings suggest that MMP‐1, and MMP‐8 are overexpressed in long lasting CVU. Therefore, this dysregulation may represent the main cause of the pathogenesis of non‐healing CVU.     

Dystrophic calcification as a cause for non healing leg ulcers

Despite advances in molecular biology and a repertoire of other therapeutic options, chronic venous leg ulcers remain a significant problem within our society. There are various reasons, both local and systemic, which contribute to the non healing nature of such wounds. Among them, dystrophic calcification (DC) or calcified deposits within the ulcer bed, although rare, is an overlooked and a seldom reported cause. In the presence of DC, wound healing cannot proceed through a timely and orderly manner resulting in a non healing ulcer. In this article, we discuss the aetiology, pathophysiology and the management options of this rarely reported condition. We also report their clinical prognosis using a series of patients with venous ulcers complicated by DC leading to difficulties in healing.     

Hyperhomocysteinaemia and chronic venous ulcers

Chronic venous ulceration (CVU) is the major cause of chronic wounds of lower extremities, and is a part of the complex of chronic venous disease. Previous studies have hypothesised that several thrombophilic factors, such as hyperhomocysteinaemia (HHcy), may be associated with chronic venous ulcers. In this study, we evaluated the prevalence of HHcy in patients with venous leg ulcers and the effect of folic acid therapy on wound healing. Eighty‐seven patients with venous leg ulcers were enrolled in this study to calculate the prevalence of HHcy in this population. All patients underwent basic treatment for venous ulcer (compression therapy ± surgical procedures). Patients with HHcy (group A) received basic treatment and administered folic acid (1·2 mg/day for 12 months) and patients without HHcy (group B) received only basic treatment. Healing was assessed by means of computerised planimetry analysis. The prevalence of HHcy among patients with chronic venous ulcer enrolled in this study was 62·06%. Healing rate was significantly higher (P < 0·05) in group A patients (78·75%) compared with group B patients (63·33%). This study suggests a close association, statistically significant, between HHcy and CVU. Homocysteine‐lowering therapy with folic acid seems to expedite wound healing. Despite these aspects, the exact molecular mechanisms between homocysteine and CVU have not been clearly defined and further studies are needed.     

Efficacy and cost‐effectiveness of octenidine wound gel in the treatment of chronic venous leg ulcers in comparison to modern wound dressings

The aim of this study was to determine the efficacy, safety and cost‐effectiveness of an octenidine‐based wound gel in the treatment of chronic venous leg ulcers. For this purpose, 49 wounds were treated with either modern wound‐phase‐adapted dressings alone (treatment arm 1; n = 17), octenidine wound gel plus modern wound‐phase‐adapted dressings (treatment arm 2; n = 17) or octenidine wound gel alone (treatment arm 3; n = 15). During the study period of 42 days with dressing changes every 3–5 days, wound healing characteristics and treatment costs of different dressings were analysed. Wound size reduction was significantly better (P = 0·028) in both octenidine wound gel treatment arms compared to modern dressings alone with total reductions of 14·6%, 64·1% and 96·2% in treatment arms 1–3. Early wound healing was merely observed under octenidine wound gel treatment (n = 9), whereby lowest treatment costs were generated by octenidine wound gel alone (€20·34/dressing change). As a result, the octenidine wound gel is cost‐effective and well suitable for the treatment of chronic venous leg ulcers, considering both safety and promotion of wound healing.     

The role of adult tissue‐derived stem cells in chronic leg ulcers: a systematic review focused on tissue regeneration medicine

Wound healing is an articulated process that can be impaired in different steps in chronic wounds. Chronic leg ulcers are a special type of non‐healing wounds that represent an important cause of morbidity and public cost in western countries. Because of their common recurrence after conventional managements and increasing prevalence due to an ageing population, newer approaches are needed. Over the last decade, the research has been focused on innovative treatment strategies, including stem‐cell‐based therapies. After the initial interest in embryonic pluripotent cells, several different types of adult stem cells have been studied because of ethical issues. Specific types of adult stem cells have shown a high potentiality in tissue healing, in both in vitro and in vivo studies. Aim of this review is to clearly report the newest insights on tissue regeneration medicine, with particular regard for chronic leg ulcers.     

Potential prognostic factors for delayed healing of common,non‐traumatic skin ulcers: A scoping review

Healing of non‐traumatic skin ulcers is often suboptimal. Prognostic tools that identify people at high risk of delayed healing within the context of routine ulcer assessments may improve this, but robust evidence on which factors to include is lacking. Therefore, we scoped the literature to identify which potentially prognostic factors may warrant future systematic reviews and meta‐analyses. We conducted electronic searches in MEDLINE and Embase to identify studies in English published between 1997 and 2017 that tested the association between healing of the three most common non‐traumatic skin ulcers encountered by health care professionals (venous leg, diabetic foot, and pressure ulcers) and patient characteristics, ulcer characteristics, and results from clinical investigations. We included 42 studies that investigated factors which may be associated with the healing of venous leg ulcers (n = 17), diabetic foot ulcers (n = 15), and pressure ulcers (n = 10). Across ulcer types, ulcer characteristics were most commonly reported as potential prognostic factors for healing (n = 37), including the size of the ulcer area (n = 29) and ulcer duration at first assessment (n = 16). A total of 35 studies investigated the prognostic value of patient characteristics (n = 35), including age (n = 31), gender (n = 30), diabetes (n = 22), smoking status (n = 15), and history of deep vein thrombosis (DVT) (n = 13). Of these studies, 23 reported results from clinical investigations as potential prognostic factors, with the majority regarding vessel quality. Age, gender, diabetes, smoking status, history of DVT, ulcer area, and ulcer duration at time of first assessment warrant a systematic review and meta‐analysis to quantify their prognostic value for delayed ulcer healing.     

Effect of oxidised regenerated cellulose/collagen matrix on proteases in wound exudate of patients with chronic venous ulceration

Oxidised regenerated cellulose/collagen matrix (ORC/collagen matrix) modifies wound microenvironments by binding and inactivating excess levels of proteases such as elastase, plasmin and gelatinases in wound exudates. To compare levels of the gelatinases matrix metalloproteinase 2 (MMP-2), elastase and plasmin in wound exudates collected from chronic venous insufficiency patients with venous leg ulcers treated with either an ORC/collagen matrix or a standard control therapy. During a 12-week treatment period, wound exudate samples were obtained from a control group of 10 patients treated with a hydrocolloid dressing and a treatment group of 17 patients treated with a combination of ORC/collagen matrix and hydrocolloid dressing. On admission and days 5, 14 and every subsequent 14th day, ulcers were photographed to determine healing rate and changes in ulcer appearance, and MMP-2 concentration and the gelatinase, elastase and plasmin activities were analysed from wound exudates. The patients treated with ORC/collagen matrix showed a significant decrease in elastase, plasmin and gelastinase activity as compared with the control group, with no significant difference in the MMP-2 concentrations between the two groups. The results show a significant and immediate reduction in protease activity in wound exudates from venous leg ulcers treated with ORC/collagen.     

A meta-review of the impact of compression therapy on venous leg ulcer healing

This meta-review aimed to appraise and synthesise findings from existing systematic reviews that measured the impact of compression therapy on venous leg ulcers healing. We searched five databases to identify potential papers; three authors extracted data, and a fourth author adjudicated the findings. The AMSTAR-2 tool was used for quality appraisal and the certainty of the evidence was appraised using GRADEpro. Data analysis was undertaken using RevMan. We identified 12 systematic reviews published between 1997 and 2021. AMSTAR-2 assessment identified three as high quality, five as moderate quality, and four as low quality. Seven comparisons were reported, with a meta-analysis undertaken for five of these comparisons: compression vs no compression (risk ratio [RR]: 1.55; 95% confidence interval [CI] 1.34-1.78; P < .00001; moderate-certainty evidence); elastic compression vs inelastic compression (RR: 1.02; 95% CI: 0.96-1.08; P < .61 moderate-certainty evidence); four layer vs <four-layer bandage systems (RR: 1.07; 95% CI: 0.82-1.40; P < .63; moderate-certainty evidence); comparison between different four-layer bandage systems (RR: 1.08; 95% CI: 0.93-1.25; P = .34; moderate-certainty evidence); compression bandage vs compression stocking (RR 0.95; 95% CI 0.87-1.03; P = .18; moderate-certainty evidence). The main conclusion from this review is that there is a statistically significant difference in healing rates when compression is used compared with no compression, with moderate-certainty evidence. Otherwise, there is no statistically different difference in healing rates using elastic compression vs inelastic compression, four layer vs <four-layer bandage systems, different four-layer bandage systems, or compression bandages vs compression stockings.     

Effectiveness of the strategies of an orientation programme for the lifestyle and wound‐healing process in patients with venous ulcer: A randomised controlled trial

This study aimed to evaluate the effect of strategies of a lifestyle orientation programme on patients with venous ulcer in elastic compression therapy. This was a single‐blind, 2‐arm, randomised clinical controlled trial. The primary outcome included the reduction of the wound surface area. The secondary outcomes included the perception of pain, questionnaire of ulcer status, and quality of life. Seventy‐one patients with ulcers of venous aetiology were randomised into 2 arms: control group (CG) and intervention group (IG), with a 12‐week follow up. The CG was provided with the routine guidelines of the health services. Meanwhile, the IG was provided with lifestyle guidelines regarding the physiopathology of a venous ulcer, importance of compression therapy, physical exercises and rest in 4 face‐to‐face and 2 telephone interviews. The IG had significant improvement on the wound healing on 30, 60, and 90 days of follow up when compared with the CG (P = .0197; P = .0472; P = .0116). There were no statistical differences between groups; both had improvement in the quality of life and pain perception. Our results demonstrated that elastic compression therapy along with guidelines on lifestyle is effective adjunctive treatment to promote wound healing in patients with leg ulcers.     

Iliac vein recanalisation and stenting accelerate healing of venous leg ulcers associated with severe venous outflow obstruction

Obstruction involving the iliac veins and/or inferior vena cava is highly comorbid in patients with chronic venous leg ulcers and is a barrier to healing. Intervention with venous stenting is recommended to promote wound healing; however, there is limited data to quantify the effects of venous outflow restoration on wound healing. We retrospectively identified patients with venous ulcers and comorbid venous outflow obstruction. Data regarding demographics, wound size, degree of obstruction, interventions, wound healing and recurrence were collected. Intervention was performed when possible and patients were grouped based on whether or not the venous outflow was reopened successfully and maintained for at least 1 year. Outcomes, including time to wound healing, wound recurrence, stent patency and ulcer-free time, were measured. Patients who maintained a patent venous outflow tract experienced higher rates of wound healing (79.3%) compared to those with persistent outflow obstruction (22.6%) at 12 months (p < 0.001). Ulcer-free time for the first year was also greater with patent venous outflow (7.6 ± 4.4 months versus 1.8 ± 3.0 months, p < 0.0025). Patients with severe obstruction of the venous outflow tract experience poor healing of VLUs despite appropriate wound care. Healing time is improved and ulcer-free time increased after venous intervention with stenting to eliminate obstruction.     

Evaluation of a muscle pump‐activating device for non‐healing venous leg ulcers

This evaluation involves an innovative muscle pump‐activating device (geko™) as an adjunctive therapy with best practices for non‐healing venous leg ulcers (VLUs). Stimulating the common peroneal nerve (at the fibular head), the geko™ device creates a response that acts as foot and calf muscle pumps, increasing venous, arterial and microcirculatory flow. The aim was to evaluate and determine if the geko™ is effective in this population and if it should be added to the medical supply formulary. In all, 12 patients with 18 recalcitrant VLUs (defined as less than 30% reduction in wound size in 30 days with best practices) in two community settings in Ontario consented to the evaluation and were treated with the geko™ for up to 20 weeks. A total of 44% of wounds healed, and 39% decreased in size. One patient non‐adherent with the geko™ and best practices had deterioration in his or her wounds. With the patients as their own control, the mean weekly healing rate with the geko™ was 9·35% (±SD 0·10) compared to 0·06% (±SD 0·10) prior to baseline, which was statistically significant (P < 0·01). Three patients not in optimal therapy increased compression due to decreased pain, further enabling healing. This study was not a randomised investigation, although the patients acted as their own controls. A pragmatic evaluation reflects the reality of the community sector; in spite of best practices or evidence‐based care, therapy is not uniformly applied, with some participants unable to tolerate or indeed comply with optimal compression therapy. Rash occurred under the devices in 7 of 12 (58%) patients. One patient stopped the device due to rash, while another had to take breaks from using the device. Subsequently, the manufacturer (FirstKind Ltd) has developed a new device and protocol specific to the requirements of wound therapy to minimise this response. This small case series demonstrated the highly significant effectiveness of the geko™ device in these hard‐to‐heal VLUs. Further evaluations to determine dose and patient selection criteria are underway.     

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.     

Relationship between maceration and wound healing on diabetic foot ulcers in Indonesia: a prospective study

The aim of this study was to clarify the relationship between maceration and wound healing. A prospective longitudinal design was used in this study. The wound condition determined the type of dressings used and the dressing change frequency. A total of 62 participants with diabetic foot ulcers (70 wounds) were divided into two groups: non‐macerated (n = 52) and macerated wounds (n = 18). Each group was evaluated weekly using the Bates–Jensen Wound Assessment Tool, with follow‐ups until week 4. The Mann–Whitney U test showed that the changes in the wound area in week 1 were faster in the non‐macerated group than the macerated group (P = 0·02). The Pearson correlation analysis showed a moderate correlation between maceration and wound healing from enrolment until week 4 (P = 0·002). After week 4, the Kaplan–Meier analysis showed that the non‐macerated wounds healed significantly faster than the macerated wounds (log‐rank test = 19·378, P = 0·000). The Cox regression analysis confirmed that maceration was a significant and independent predictor of wound healing in this study (adjusted hazard ratio, 0·324; 95% CI, 0·131–0·799; P = 0·014). The results of this study demonstrated that there is a relationship between maceration and wound healing. Changes in the wound area can help predict the healing of wounds with maceration in clinical settings.     

The impact of a new intervention for venous leg ulcers: A within-patient controlled trial

A major obstacle to the development of new treatments for venous leg ulcers is the difficulty in generating evidence for their effectiveness. Randomised controlled trials using complete healing as the endpoint are seldom powered to be successful, owing to the heterogeneity of cohorts. A novel approach to the evaluation of treatments is presented, using a self-controlled trial model and two metrics of short-term healing rate as alternate endpoints: rate of wound margin advance, and percentage area reduction over 4 weeks. Two different treatment regimens are compared: multi-layer compression alone, versus multi-layer compression combined with activation of the venous leg pump by neuromuscular stimulation. With 60 patients, adding neuromuscular stimulation to multilayer compression resulted in a significant two-fold increase in the rate of wound healing over a 4-week period, both in terms of wound margin advance and in terms of percentage area reduction. The use of these short-term intermediate endpoint metrics together with a self-controlled study design offers potential for distinguishing between the relative efficacies of interventions more rapidly, with greater sensitivity, and with fewer subjects than a conventional RCT cohort model.     

Safety and performance evaluation of a next‐generation antimicrobial dressing in patients with chronic venous leg ulcers

The objective of this study was to investigate the safety and performance of AQUACEL? Ag+ dressing, a wound dressing containing a combination of anti‐biofilm and antimicrobial agents, in the management of chronic wounds. Patients (n = 42) with venous leg ulcers exhibiting signs of clinical infection were treated for 4 weeks with AQUACEL? Ag+ dressing, followed by management with AQUACEL? wound dressings for 4 weeks. Wound progression, wound size, ulcer pain and clinical evolution of the wound were assessed for up to 8 weeks. Adverse events were recorded throughout the study. AQUACEL? Ag+ dressing had an acceptable safety profile, with only one patient discontinuing from the study, because of a non‐treatment‐related adverse event. After 8 weeks, substantial wound improvements were observed: 5 patients (11·9%) had healed ulcers and 32 patients (76·2%) showed improvement in ulcer condition. The mean ulcer size had reduced by 54·5%. Patients reported less pain as the study progressed. Notable improvements were observed in patients with ulcers that were considered to require treatment with systemic antibiotics or topical antimicrobials at baseline (n = 10), with a mean 70·2% reduction in wound area. These data indicate that AQUACEL? Ag+ dressing has an acceptable safety profile in the management of venous leg ulcers that may be impeded by biofilm.     

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.