Controversies in the pathophysiology of leg ulcers in sickle cell disease.

Patients with sickle cell disease (SCD) often experience painful vaso-occlusive crises and chronic haemolytic anaemia, as well as various acute and chronic complications, such as leg ulcers. Leg ulcers are characterized by their unpredictability, debilitating pain and prolonged healing process. The pathophysiology of SCD leg ulcers is not well defined. Known risk factors include male gender, poor social conditions, malnutrition and a lack of compression therapy when oedema occurs. Leg ulcers typically start with spontaneous pain, followed by induration, hyperpigmentation, blister formation and destruction of the epidermis. SCD is characterized by chronic haemolysis, increased oxidative stress and decreased nitric oxide bioavailability, which promote ischaemia and inflammation and consequently impair vascular function in the skin. This cutaneous vasculopathy, coupled with venostasis around the ankle, creates an ideal environment for local vaso-occlusive crises, which can result in the development of leg ulcers that resemble arterial ulcers. Following the development of the ulcer, healing is hindered as a result of factors commonly observed in venous ulceration, including venous insufficiency, oedema and impaired angiogenesis. All of these factors are modulated by genetic factors. However, our current understanding of these genetic factors remains limited and does not yet enable us to accurately predict ulceration susceptibility.

Transcatheter Arterialization of Deep Veins in Chronic Limb-Threatening Ischemia.

BACKGROUND: Approximately 20% of patients with chronic limb-threatening ischemia have no revascularization options, leading to above-ankle amputation. Transcatheter arterialization of the deep veins is a percutaneous approach that creates an artery-to-vein connection for delivery of oxygenated blood by means of the venous system to the ischemic foot to prevent amputation. METHODS: We conducted a prospective, single-group, multicenter study to evaluate the effect of transcatheter arterialization of the deep veins in patients with nonhealing ulcers and no surgical or endovascular revascularization treatment options. The composite primary end point was amputation-free survival (defined as freedom from above-ankle amputation or death from any cause) at 6 months, as compared with a performance goal of 54%. Secondary end points included limb salvage, wound healing, and technical success of the procedure. RESULTS: We enrolled 105 patients who had chronic limb-threatening ischemia and were of a median age of 70 years (interquartile range, 38 to 89). Of the patients enrolled, 33 (31.4%) were women and 45 (42.8%) were Black, Hispanic, or Latino. Transcatheter arterialization of the deep veins was performed successfully in 104 patients (99.0%). At 6 months, 66.1% of the patients had amputation-free survival. According to Bayesian analysis, the posterior probability that amputation-free survival at 6 months exceeded a performance goal of 54% was 0.993, which exceeded the prespecified threshold of 0.977. Limb salvage (avoidance of above-ankle amputation) was attained in 67 patients (76.0% by Kaplan-Meier analysis). Wounds were completely healed in 16 of 63 patients (25%) and were in the process of healing in 32 of 63 patients (51%). No unanticipated device-related adverse events were reported. CONCLUSIONS: We found that transcatheter arterialization of the deep veins was safe and could be performed successfully in patients with chronic limb-threatening ischemia and no conventional surgical or endovascular revascularization treatment options. (Funded by LimFlow; PROMISE II study ClinicalTrials.gov number, NCT03970538.).

Early ABI Testing May Decrease Risk of Amputation for Patients With Lower Extremity Ulcers.

BACKGROUND: Patients with lower extremity wounds from diabetes mellitus or peripheral artery disease (PAD) have a risk of amputation as high as 25%. In patients with arterial disease, revascularization decreases the risk of amputation. We aimed to determine if the early assessment of arterial perfusion correlates with the risk of amputation. METHODS: We retrospectively reviewed patients referred to the vascular clinic over 18 months with Rutherford Grade 5 and 6 chronic limb-threatening ischemia to determine if patients had a pulse exam done at the time the wound was identified and when ankle brachial index (ABI) testing to evaluate perfusion was performed. Kaplan Meier analysis was used to determine if the timing of ABI testing affected the time to revascularization, wound healing, and risk of amputation. RESULTS: Ninety-three patients with lower extremity wounds were identified. Of these, 59 patients (63%) did not have a pulse exam performed by their primary care provider when the wound was identified. Patients were classified by when they underwent ankle brachial index testing to assess arterial perfusion. Twenty-four had early ABI (<30 days) testing, with the remaining 69 patients having late ABI testing. Patients in the early ABI group were more likely to have a pulse exam done by their PCP than those in the late group, 12 (50%) vs. 22 (32%), P = 0.03. Early ABI patients had a quicker time to vascular referral (13 days vs. 91 days, P < 0.001). Early ABI patients also had quicker times to wound healing than those in the late group (117 days vs. 287 days, P < 0.001). Finally, patients that underwent early ABI were less likely to require amputation (Fig. 1), although this did not reach statistical significance (P = 0.07). CONCLUSIONS: Early ABI testing expedites specialty referral and time to revascularization. It can decrease the time to wound healing. Larger cohort studies are needed to determine the overall effect of early ABI testing to decrease amputation rates.

Calcinose distrófica cutânea na doença venosa crônica de membros inferiores / Dystrophic calcinosis cutis in chronic venous disease of the lower limbs

Resumo As úlceras de membros inferiores, secundárias à doença venosa crônica (DVC), constituem um problema significativo de saúde pública no Brasil e representam cerca de 70% do total dessas úlceras. Apesar dos recentes avanços tecnológicos e das diversas opções terapêuticas utilizadas para essas lesões crônicas, existem diversos fatores que podem estar implicados na resistência ao tratamento. A calcificação distrófica cutânea (CDC) é uma condição rara e frequentemente subdiagnosticada, que, quando associada à DVC, pode estar associada à refratariedade no processo cicatricial. Neste artigo, relatamos um caso de CDC em paciente portador de DVC e discutimos a sua etiologia, fisiopatologia e possíveis opções de tratamento.

Abstract Lower limb ulcers secondary to chronic venous disease (CVD) are a significant public health problem in Brazil and account for about 70% of these ulcers. Despite recent technological advances and the various therapeutic options for treatment of these chronic injuries, several factors may be involved in resistance to treatment. Dystrophic calcinosis cutis (DCC) is a rare and often underdiagnosed condition that, when in conjunction with CVD, may be associated with a refractory healing process. In this article, we report a case of DCC in a patient with CVD and discuss its etiology, pathophysiology and possible treatment options.

Maggot Debridement Therapy for Chronic Leg and Foot Ulcers: A Review of Randomized Controlled Trials.

OBJECTIVE: To critically analyze the existing randomized controlled trials (RCTs) on the clinical, economic, and psychological implications of maggot debridement therapy (MDT). DATA SOURCES: An exhaustive literature search for English-language publications was conducted using MEDLINE, EMBASE, and PubMed. STUDY SELECTION: Keywords used for the search were based on the PICO (Population, Intervention, Comparison, Outcome) framework. The titles, abstracts, and relevant full-text articles were screened. Seven RCTs were selected after applying the inclusion and exclusion criteria. DATA EXTRACTION: Data pertaining to the primary and secondary outcomes of each study were extracted. DATA SYNTHESIS: The data extracted were evaluated and categorized into clinical, economic, and psychological outcomes pertaining to MDT. A judicious evaluation of these outcomes was made, and the following conclusions were drawn. CONCLUSIONS: There exists heterogeneity in the extant RCTs, but MDT appears to be effective for a quick early debridement. For diabetic foot ulcers, MDT improves debridement, controls infection, and enhances wound healing. In chronic peripheral vascular disease ulcers, it aids in early debridement, but the final outcome is equivocal. Further robust integrated health economic and parallel qualitative assessment studies are recommended to understand the cost-effectiveness and patient acceptability and experience.

Effectiveness of Ozone Therapy as an Adjunct Treatment for Lower-Limb Ulcers: A Systematic Review.

OBJECTIVE: To evaluate the effectiveness of topical ozone therapy as an adjuvant treatment in the healing of lower limb ulcers through a systematic literature review. DATA SOURCES: Three databases were used to search for studies conducted in the period up to and including September 2020: PubMed, Scopus, and the Web of Science. STUDY SELECTION: The search identified 44 studies, 7 of which met the eligibility criteria and were evaluated. DATA EXTRACTION: Study design, study location, number of patients, patient age, type of control, wound type, intervention type, equipment used to generate ozone (ozone generation), evaluation methodology, and main results were extracted from each study. DATA SYNTHESIS: A total of 506 patients 18 years or older with chronic wounds, such as venous or diabetic ulcers, on the lower limbs were enrolled. The majority of studies addressed diabetic foot ulcers. CONCLUSIONS: The ozone therapy protocols demonstrated a healing effect in all included studies, and none reported adverse effects. This reinforces the need for more controlled and randomized clinical trials to determine the effectiveness of this treatment and establish clinical criteria for its use.

Common, But Neglected: A Comprehensive Review of Leg Ulcers in Sickle Cell Disease.

OBJECTIVE: To compile available evidence to better understand the management of leg ulcers in sickle cell disease (SCD), as well as describe potential therapeutic steps that may be required to improve the quality of life of patients with SCD leg ulcers. DATA SOURCES: MEDLINE, PubMed, EMBASE, and Web of Science databases. STUDY SELECTION: A comprehensive search was conducted to retrieve relevant studies using the keywords "sickle cell disease and leg ulcer," "ulcer treatments, diagnosis and sickle cell," and "wound sickle cell." Studies published through July 2020 were included. DATA EXTRACTION: Two independent authors selected all studies that assessed the relationship between leg ulcer and SCD identified from online databases. DATA SYNTHESIS: The authors have summarized updated information on pathophysiology (vasculopathy linked to chronic hemolysis and endothelial dysfunction), diagnosis, and available treatment options to unravel the dermohematologic connection between leg ulcers and SCD. CONCLUSIONS: It is the authors' hope that this detailed discussion of the information available on leg ulcers and SCD will lead to a better appreciation of this clinical problem by the clinicians and researchers and in turn have a long-term positive effect on the quality of life of patients with SCD. Researchers should design new trials considering these insights and potential therapeutic approaches based on current knowledge.

The repetitive application of cold atmospheric plasma (CAP) improves microcirculation parameters in chronic wounds.

BACKGROUND: Chronic wounds, such as venous leg ulcers, diabetic foot ulcers, and pressure ulcers, impose a significant burden on patients and health care systems worldwide. Cold atmospheric plasma (CAP) accelerates wound healing and decreases bacterial load in chronic wounds in both in vitro and in vivo experiments. For the first time, we examined the effects of a repetitive application of CAP on the microcirculation in chronic wounds. HYPOTHESIS: The repetitive application of cold atmospheric plasma application further improves microcirculation in chronic wounds. METHODS: Twenty patients with chronic wounds were treated repetitively with CAP. The repetitive application consisted of three CAP sessions, each lasting 90 s and separated by a 10-minute microcirculation measuring period. Microcirculation parameters were assessed with combined Laser-Doppler-Flowmetry and spectrophotometry in a tissue depth of 2 mm. RESULTS: Tissue oxygen saturation was significantly increased after the first CAP application. The effect amplitude and duration were further increased after the second and third CAP application with a maximum increase by 16,7% (percent change; p = 0,004 vs. baseline) after the third application. There was no significant increase in capillary blood flow until the third CAP application. After the third CAP application, an increase by 22,6% (p = 0,014) was observed. Postcapillary filling pressure was not significantly increased over the measuring period. The repetitive application of CAP further enhances the microcirculation in chronic wounds compared to a single application. CONCLUSION: The repetitive application of CAP boosts and prolongs tissue oxygen saturation and capillary blood flow in chronic wounds compared to a single application. This insight could provide an impetus for new treatment protocols.

Lower Extremity Ulcers.

Lower extremity ulcerations contribute to significant morbidity and economic burden globally. Chronic wounds, or those that do not progress through healing in a timely manner, are estimated to affect 6.5 million people in the United States alone causing, significant morbidity and economic burden of at least an estimated $25 billion annually. Owing to the aging population and increasing rates of obesity and diabetes mellitus globally, chronic lower extremity ulcers are predicted to increase. Here, we explore the pathophysiology, diagnosis, and management of the most (and least) commonly seen lower extremity ulcers.

Development of a core outcome set for venous leg ulceration (CoreVen) research evaluations (protocol).

BACKGROUND: A venous leg ulcer is a chronic leg wound caused by poor venous blood circulation in the lower limbs. It is a recurring condition causing pain, malodour, reduced mobility, and depression. Randomised controlled trials evaluating treatments for venous leg ulcers provide important evidence to inform clinical decision-making. However, for findings to be useful, outcomes need to be clinically meaningful, consistently reported across trials, and fully reported. Research has identified the large number of outcomes reported in venous leg ulcer trials, impacting both synthesis of results, and clinical decision-making. To address this, a core outcome set will be developed. A core outcome set is an agreed standardised set of outcomes which should be, as a minimum, measured and reported in all trials which evaluate treatment effectiveness for a given indication. A core outcome set has the potential to reduce research waste, improve the utility of RCTs, reduce reporting bias, facilitate treatment comparisons across different sources of evidence and expedite the production of systematic reviews, meta-analyses and evidence-based clinical guidelines. AIM: The aim of this project is to develop a core outcome set for research evaluating the effectiveness of interventions for treating venous leg ulceration. METHODS: Through a scoping review of the literature on venous leg ulceration, we will firstly identify a list of candidate outcome domains (broad categories in relation to what is being measured) from randomised controlled trials and qualitative research, and outcomes (specific methods in relation to what is being measured). In two further stages, we will use the resulting lists of outcome domains and outcomes to design two online surveys. A range of stakeholders will be invited to participate in the surveys and they will be asked to indicate which outcome domains and outcomes are most important and should be considered as core in future research reports.

Microcirculatory Flux and Pulsatility in Arterial Leg Ulcers is Increased by Intermittent Neuromuscular Electrostimulation of the Common Peroneal Nerve.

BACKGROUND: Neuromuscular electrical stimulator (NMES) devices increase blood flow to the lower limb by a process of intermittent muscular contraction initiated by a transdermal stimulus to the common peroneal nerve. However, its effects on localized microvascular blood supply to lower limb wounds are unknown. This study is a single-center open label study measuring the effect of neuromuscular stimulation of the common peroneal nerve on the microvascular blood flow within the wound bed of arterial leg ulcers. METHODS: Eights patients with ischemic lower limb wounds had an NMES (geko™) applied to the common peroneal nerve. Baseline and intervention analysis of blood flow to the wound bed and edge was performed using Laser Speckle Contrast Imaging. Mean flow (flux) and pulse amplitude (pulsatility) were measured. RESULTS: Stimulation of the common peroneal nerve with the NMES resulted in a significantly increased flux and pulsatility in both the wound bed and the wound edge in all 8 patients. CONCLUSIONS: Neuromuscular electrical stimulation immediately increases microcirculatory blood flow to the wound bed and edge in patients with ischemic lower limb wounds. These data may provide mechanistic insight into the clinical efficacy of NMES in healing wounds. www.clinicaltrials.gov NCT03186560.

Capillary-venule malformation is a microfistulous variant of arteriovenous malformation.

OBJECTIVE: To describe typical clinical presentation of patients with microfistular, capillary-venule (CV) malformation as a variant form of arteriovenous malformations (AVM). METHODS: A retrospective clinical analysis of 15 patients with CV-AVM confirmed by a computational flow model enrolled in a prospective database of patients with congenital vascular malformation between January 2008 and May 2018. RESULTS: The mean age of the patients at first time of presentation was 30 years with balanced sex ratio. Presentation was dominated by soft tissue hypertrophy (n = 12 [80.0%]) and atypical varicose veins (n = 11 [73.3%]). The anatomic location of enlarged varicose veins gave no uniform pattern and did not correspond with the typical picture of primary varicose vein disease. Most often, symptomatic CV-AVM was found at the lower extremities in this series of unselected patients. The most frequent compartment affected was the subcutis (n = 14 [93.3%]), involvement of muscle was recorded in one-third and cutis in one-fourth of patients. CONCLUSIONS: A high grade of clinical suspicion is needed to recognize CV-AVM and to prevent inadequate therapy owing to missed diagnosis.

The "Double hit": Free tissue transfer is optimal in comorbid population with irradiated wounds for successful limb salvage.

BACKGROUND: Radiation therapy causes histopathologic changes in tissues, including fibrosis, loss of tissue planes, and vascular damage, which can lead to chronic wound formation. Patients with nonhealing, irradiated wounds and comorbidities that affect microvasculature suffer a "double hit", which leads to delayed wound healing. Local wound care and grafts are commonly insufficient. In this study, we evaluated limb salvage outcomes and long-term complications after free tissue transfer (FTT) in patients with chronic, irradiated leg wounds. METHODS: We retrospectively reviewed patients with irradiated lower extremity wounds who underwent FTT from 2012 to 2017. Primary outcomes included limb salvage, ambulation, and overall flap success. Reconstruction involved complete excision of irradiated tissue and coverage with well-vascularized tissue. RESULTS: Seven free flaps in six patients were identified. Average age was 68.4 years and average BMI was 27.8 kg/m2. Comorbid conditions included hypertension (57.1%), peripheral vascular disease (57.1%), underlying hypercoagulability (42.9%), diabetes (14.3%), and tobacco use (14.3%). Wounds were present for an average of 25.5 months prior to FTT. Donor sites included anterolateral thigh (71.4%), vastus lateralis (14.3%), and latissimus dorsi (14.3%). Overall flap success rate was 100% with one patient requiring reoperation for dehiscence. Limb salvage rate was 85.7% with one patient undergoing elective amputation due to pain. All patients could ambulate (one used a prosthesis) at a mean follow-up time of 1.4 years. CONCLUSIONS: Radiation therapy in a comorbid population often leads to the formation of chronic nonhealing wounds. We advocate for earlier consideration of FTT to provide healthy vascularized tissues, thereby avoiding prolonged wound care and patient burden. Successful limb salvage outcomes can be achieved.

Chronic, nonhealing leg ulcer.

When this patient's chronic stasis ulcer failed to respond to the usual treatment of dressings, elevation, and diuretics, our suspicions led us to an unexpected diagnosis.

Ciprofloxacin-Resistant Kerstersia gyiorum Isolated From a Chronic Wound in Brazil: A Case Report.

The presence of Kerstersia gyiorum in lower leg wounds has been reported in case studies from several countries. OBJECTIVE: This study evaluated the antimicrobial susceptibility profile of K gyiorum isolated from a chronic wound. METHODS: An 85-year-old woman with chronic venous insufficiency presented to an intermediate care unit in Niteroi City, Rio de Janeiro, Brazil, with an instep chronic wound of 14 cm² with wound duration of 6 months. K gyiorum was identified by matrix-assisted laser desorption ionization-time of flight, confirmed by 16S rRNA partial sequence analysis, and classified as resistant for ciprofloxacin by reagent strips(minimum inhibitory concentration [MIC] = 32 µg/mL) and the broth macrodilution method (MIC = 8 µg/mL). Intermediate resistance for ciprofloxacin was verified by microscan (MIC = 2 µg/mL). CONCLUSION: The authors identified the first, to their knowledge, lower leg wound with K gyiorum in Brazil and verified that it was ciprofloxacin resistant.

Healing Rates of Venous Leg Ulcers Managed With Compression Therapy: A Secondary Analysis of Data.

PURPOSE: The purpose of this study was to explore average time to heal for patients with venous leg ulcers (VLUs) receiving standard of care that included compression and advanced wound dressings. DESIGN: Secondary analysis of an existing electronic database. SUBJECT AND SETTINGS: A convenience sample consisting of 1323 patients with VLUs from various community care sectors (homecare and clinics) across Canada. METHODS: The Wound Studies database used in the analysis consisted of data from 6 studies conducted prospectively between 1999 and 2009 in which the treatment and delivery of care for all lower leg ulcers (venous, arterial, and mixed) in Canada was examined. From these studies, only patients with VLUs, with an ankle-brachial pressure index of greater than 0.8, and surface area measurements of the ulcers at baseline, 3 months, and 6 months were included. Descriptive statistics were used to determine the proportion of patients who achieved closure at 3 and 6 months and explore the weekly and monthly healing rates for those who did and did not achieve closure. Logistic regression analysis was performed to identify predictive factors for healing. RESULTS: A total of 777 patients (mean age 69 years) met inclusion criteria. The proportion of patients who achieved closure at 3 and 6 months was 42.2% and 48.6%, respectively. Of the participants who achieved wound closure, monthly mean healing rate, measured by percentage of reduction in surface area, was 33.4% (0.56 cm, SD 1.4 [median 0.15 cm]) through month 3, and 31.0% (0.70 cm, SD 1.6 [median 0.08 cm]) through month 6. The overall monthly surface area reduction was 30%. CONCLUSION: Study findings suggest a monthly surface area reduction of 30% provides a baseline healing rate for VLUs managed with compression therapy and advanced dressings. Findings also suggest standard of care is not sufficient for healing in over 50% of the population, as the proportion of those who achieved closure at 3 and 6 months was 42.2% and 48.6%, respectively.

Ultrasound Devices to Treat Chronic Wounds: The Current Level of Evidence.

Chronic wounds cause considerable morbidity and utilize significant health care resources. In addition to addressing wound etiology and treating infection, regular debridement is a key component of wound care with a proven ability to accelerate healing. In this regard, a significant innovation in wound care has been the development of ultrasound debridement technology. The purpose of this review is to evaluate the current evidence behind the technology with an emphasis on noncontact low-frequency (NCLF) ultrasound. A number of studies, especially those evaluating NCLF technology, have demonstrated the potential of ultrasound debridement to effectively remove devitalized tissue, control bioburden, alleviate pain, and expedite healing. However, most of the studies are underpowered, involve heterogeneous ulcer types, and demonstrate significant methodological limitations making comparison between studies difficult; there is a paucity of data on cost-effectiveness. Future clinical trials on ultrasound debridement technology must address the design issues prevalent in current studies, and report on clinically relevant endpoints before adoption into best-practice algorithms can be recommended.

A possible role for inducible arginase isoform (AI) in the pathogenesis of chronic venous leg ulcer.

Chronic venous ulcer (CVU) is a major cause of chronic wounds of lower extremities and presents a significant financial and resource burden to health care systems worldwide. Defects in the vasculature, matrix deposition, and re-epithelialization are the main histopathological changes believed to impede healing. Supplementation of the amino acid arginine that plays a crucial role in the interactions that occur during inflammation and wound healing was proven clinically to improve acute wound healing probably through enhancing activity of inducible arginase (AI) locally in the wounds. However, the possible mechanism of arginine action and the potential beneficial effects of AI/arginine in human chronic wounds remain unclear. In the present study, using biopsies, taken under local anesthesia, from adult patients (n = 12, mean age 55 years old) with CVUs in lower extremities, we investigated the correlation between AI distribution in CVUs and the histopathological changes, mainly proliferative and vascular changes. Our results show a distinct spatial distribution of AI along the ulcer in the epidermis and in the dermis with the highest level of expression being at the ulcer edge and the least expression towards the ulcer base. The AI cellular immunoreactivity, enzymatic activity, and protein levels were significantly increased towards the ulcer edge. Interestingly, a similar pattern of expression was encountered in the proliferative and the vascular changes with strong correlations between AI and the proliferative activity and vascular changes. Furthermore, AI cellular distribution was associated with increased proliferative activity, inflammation, and vascular changes. Our findings of differential expression of AI along the CVU base, edge, and nearby surrounding skin and its associations with increased proliferative activity and vascular changes provide further support to the AI implication in CVU pathogenesis. The presence of high levels of AI in the epidermis of chronic wounds may serve as a molecular marker of impaired healing and may provide future targets for therapeutic intervention.

PredyCLU: A prediction system for chronic leg ulcers based on fuzzy logic; part II-Exploring the arterial side.

Peripheral arterial disease (PAD) and its most severe form, critical limb ischaemia (CLI), are very common clinical conditions related to atherosclerosis and represent the major causes of morbidity, mortality, disability, and reduced quality of life (QoL), especially for the onset of ischaemic chronic leg ulcers (ICLUs) and the subsequent need of amputation in affected patients. Early identification of patients at risk of developing ICLUs may represent the best form of prevention and appropriate management. In this study, we used a Prediction System for Chronic Leg Ulcers (PredyCLU) based on fuzzy logic applied to patients with PAD. The patient population consisted of 80 patients with PAD, of which 40 patients (30 males [75%] and 10 females [25%]; mean age 66.18 years; median age 67.50 years) had ICLUs and represented the case group. Forty patients (100%) (27 males [67.50%] and 13 females [32.50%]; mean age 66.43 years; median age 66.50 years) did not have ICLUs and represented the control group. In patients of the case group, the higher was the risk calculated with the PredyCLU the more severe were the clinical manifestations recorded. In this study, the PredyCLU algorithm was retrospectively applied on a multicentre population of 80 patients with PAD. The PredyCLU algorithm provided a reliable risk score for the risk of ICLUs in patients with PAD.