Chronic Lower Extremity Ulcers Research Articles

Evidence-based management of common chronic lower extremity ulcers

Chronic lower extremity ulcers are a significant burden on patients and health care systems worldwide. Although relatively common, these wounds can be difficult to treat and present a challenge to physicians. Treatment has often been based on anecdotal accounts; however, there is a growing emphasis on using evidence-based conclusions to guide clinical decisions. In this review article, the standard of care and adjuvant therapies of venous leg ulcers and diabetic foot ulcers are presented from an evidence-based perspective.

A retrospective cohort study evaluating efficacy in high‐risk patients with chronic lower extremity ulcers treated with negative pressure wound therapy

The purpose of this study was to evaluate the efficacy of negative pressure wound therapy (NPWT) compared with standard of care on wound healing in high-risk patients with multiple significant comorbidities and chronic lower extremity ulcers (LEUs) across the continuum of care settings. A retrospective cohort study of 'real-world' high-risk patients was conducted using Boston University Medical Center electronic medical records, along with chart abstraction to capture detailed medical history, comorbidities, healing outcomes and ulcer characteristics. A total of 342 patients, 171 NPWT patients with LEUs were matched with 171 non-NPWT patients with respect to age and gender, were included in this cohort from 2002 to 2010. The hazard ratios (HRs) were estimated by COX proportional hazard models after adjusting for potential confounders. The NPWT patients were 2·63 times (95% CI = 1·87-3·70) more likely to achieve wound closure compared with non-NPWT patients. Moreover, incidence of wound closure in NPWT patients were increased in diabetic ulcers (HR = 3·26, 95% CI = 2·21-4·83), arterial ulcers (HR = 2·27, CI = 1·56-3·78) and venous ulcers (HR = 6·31, 95% CI = 1·49-26·6) compared with non-NPWT patients. In addition, wound healing appeared to be positively affected by the timing of NPWT application. Compared with later NPWT users (1 year or later after ulcer onset), early NPWT users (within 3 months after ulcer onset) and intermediate NPWT users (4-12 months after ulcer onset) were 3·38 and 2·18 times more likely to achieve wound healing, respectively. This study showed that despite the greater significant comorbidities, patients receiving NPWT healed faster. Early use of NPWT demonstrated better healing. The longer the interval before intervention is with NPWT, the higher the correlation is with poor outcome.

Comparison of negative pressure wound therapy with an ultraportable mechanically powered device vs. traditional electrically powered device for the treatment of chronic lower extremity ulcers: A multicenter randomized-controlled trial

The purpose of this study was to compare the ultraportable mechanically powered Smart Negative Pressure (SNaP(®)) Wound Care System to the traditional electrically powered Vacuum-Assisted Closure (VAC(®)) Therapy System in the treatment of chronic lower extremity wounds. This 12-center randomized-controlled trial of patients with noninfected, nonischemic, nonplantar lower extremity wounds had enrolled 65 patients, as of January 5, 2010, at the time of a planned interim analysis. Subjects were randomly assigned to treatment with either the SNaP(®) or VAC(®) Systems. The trial evaluated treatment for up to 16 weeks or till complete closure was achieved. Fifty-three patients (N=27 SNaP(®), N=26 VAC(®)) completed at least 4 weeks of therapy. Thirty-three patients (N=18 SNaP(®), N=15 VAC(®)) completed the study with either healing or 16 weeks of therapy. At the time of planned interim analysis, no significant differences (p=0.99) in the proportion of subjects healed between the two devices evaluated were found. In addition, the percent wound size reduction between treatment groups was not significantly different at 4, 8, 12, and 16 weeks, with noninferiority analysis at 4 weeks of treatment reaching the p-value <0.05 significance level (*p=0.019). These interim data suggest no difference in wound closure between the SNaP(®) System and the VAC(®) System in the population studied. We look forward to the final analysis results.

Combining Acoustic Pressure Wound Therapy With Electrical Stimulation for Treatment of Chronic Lower-Extremity Ulcers

Combining Acoustic Pressure Wound Therapy With Electrical Stimulation for Treatment of Chronic Lower-Extremity Ulcers

An Amish boy with recurrent ulcerations of the lower extremities, telangiectases of the hands, and chronic lung disease

A 6-year-old white male of Amish ancestry with chronic lower extremity ulcers was seen inthe Dermatology Clinic at the National Institutes of Health (NIH) Clinical Center inBethesda, MD. Since the age of 2, the patient had experienced numerous deep ulcers on thethighs, legs, and feet that developed without preceding trauma. His wounds typically healedslowly leaving depressed atrophic scars. At the time of presentation, the patient had ulcerslimited to the soles of both feet and difficulty ambulating due to associated pain. The ulcerson the left sole had been present for nine months. His parents reported frequent epistaxis andeasy bruisability. At age 4, the patient underwent splenectomy for thrombocytopenia andwas found to have esophageal varices and cirrhosis. He also suffered from pulmonaryhypertension, recurrent pneumonias with bronchiectasis,, recurrent otitis media, and chronicsinusitis. At the time of evaluation, the patient required three liters per minute of continuousoxygen via nasal canula.The patient’s parents were second cousins. Several family members had had similar medicalproblems: his older brother died at 13 months of age of respiratory failure with history of legulcers and recurrent infections; a paternal cousin also died at 13 months of age withrecurrent infections, chronic lung disease and pulmonary hypertension; and a living maternalcousin had leg ulcers and recurrent infections. The patient had three healthy siblings. Heshared a common ancestry with an Amish kindred several generations earlier who exhibitedsimilar physical findings.

Application of Platelet-Rich Plasma in Plastic Surgery: Clinical andIn VitroEvaluation

The clinical use of platelet-rich plasma (PRP) for a wide variety of application has been reportedly employed most prevalently in problematic wounds, maxillofacial and hemi-facial atrophy, Romberg Syndrome, and diabetic foot ulcers. To our knowledge, PRP has never been described in the enhancement of fat grafting during tissue-engineering application in vivo. The authors describe the preparation of PRP and its use in a series of 43 patients who underwent plastic, reconstructive, and maxillofacial surgery for chronic lower extremity ulcers (n = 18) and multiple facial applications (n = 25). PRP mixed with fat grafting was used in 76% patients affected by multiple facial diseases and in 88.9% patients affected by lower extremity ulcers. PRP injection alone was used in the remaining patients. The authors observed that after a 7.1-week and 9.7-week (average) course of twice-daily wound treatment with PRP suspended on a collagen base, 61.1% and 88.9% of chronic lower extremity ulcers underwent to 100% reepithelization compared with 40% and 60% of controls (n = 10) treated with hyaluronic acid and collagen medication. In patients treated with reconstructing three-dimensional projection of face by fat grafting and PRP, we observed a 70% maintenance of contour restoring and three-dimensional volume after 1 year compared to only 31% of controls (n = 10) treated with fat grafting alone. In vitro, PRP induced a significant increase in the number of adipose-tissue-derived stem cells compared to control cultures. These results documented that PRP accelerates chronic skin ulcer reepithelization and improves maintenance and function of fat graft in patients who underwent plastic reconstructive surgery, possibly by stimulating adipose-tissue-derived stem cell proliferation.

Erythrocytapheresis in Sickle Cell Disease and Multi-Organ Failure in the Intensive Care Unit.

Abstract 4627 IntroductionPatients with sickle cell disease (SCD), including those with homozygosity for hemoglobin (Hb) S (SCD-SS) or compound heterzygosity for sickle and Hb C (SCD-SC), suffer from chronic variable intravascular hemolysis, microvascular ischemia and organ damage. Vaso-occlusion results from a dynamic combination of abnormalities in hemoglobin S structure and function, red blood cell membrane integrity, erythrocyte density, endothelial activation, microvascular tone, inflammatory mediators, and coagulation. HbC enhances, by dehydrating the SC red cell, the pathogenic properties of HbS, resulting in a clinically significant disorder, but somewhat milder sickle cell anemia. The management of SCD continues to be supportive and includes hydration, pain relief, blood transfusion and psychosocial support. However, transfused red cells will significantly increase blood viscosity, potentially reducing blood flow, if the Hb level rises above 10 g/dL. Therefore, if the goal is an acute reduction in the proportion of sickled red cells in addition to an increase in oxygen-carrying capacity, exchange transfusion is the therapy of choice. We report 3 cases of (SCD-SS) and (SCD-SC) disease with multi-organ failure syndrome who were admitted to our intensive care unit (ICU) between January and July 09 where Erythrocyatperesis was effective but somewhat delayed. ReportThe first patient is a 46-year old male with SCD-SC disease who presented with severe leg, back, and chest pain. He was treated with intravenous fluid and nasal oxygen supplementation. Chest pain was sustained with severe hypoxemia, elevated troponins and somnolence developed third day of hospitalization. Fourth day he became more lethargic, breathing at 35/ min. His labs showed acute liver and kidney injury. The patient was transferred to ICU. In spite of respiratory and medical support, his medical status worsened, so hematology team was consulted and red cell exchange transfusion was made with subsequent improvement in mental status. The second patient was a 45 year old patient with SCD-SC disease who was found at home confused, complaining of back, chest and extremities pain, with unsteady gait and labored breathing. In Emergency Department (ED) he was hypotensive with abdominal tenderness and hypoactive bowel movements. His labs showed acute hepatic and renal injury with severe metabolic acidosis. Patient was resuscitated with IV fluids and intubated. CT scan of the abdomen showed diffuse bowel inflammation. On the third day of admission, hematology team was consulted and Erythrocytapheresis was started. His mental status improved slowly but he continued to have a seizure disorder and had to be on hemodialysis. The third patient is a 46 year old with SCD-SS disease and chronic lower extremity ulcers who had recurrent admissions for hyperpigmented gallstones and endoscopic retrograde cholangiopancreatography with stent placements. He presented to ED with nausea, vomiting, diarrhea and fever for 3 days. He was found hypotensive, tachycardic, with respiratory distress and acute liver and kidney abnormalities on labs. He was intubated and started on fluids and antibiotics. Thirty hours post admission he underwent erythrocytapheresis. ConclusionRed cell exchange transfusions remain an effective but possibly underutilized and delayed therapy in acute sickle cell complications, especially acute chest and the multi-organ failure syndromes. It can provide needed oxygen carrying capacity while reducing the overall viscosity of the blood. Although the need for a central line and the requirement for sickle- negative, as-fresh-as-possible blood, matched for minor antigens are major reasons for delay, it seems that it is mostly delayed for clinical reasons, trying to rule out other disorders or contributing factors and when the apheresis starts the patients are in the hospital/ICU for days already. We conclude that in patients with sickle cell disorder (SS or SC) being hypoxic and with chest or multi-organ failure syndrome, red cell exchange transfusion is effective treatment modality and should be initiated as soon as possible. Disclosures:No relevant conflicts of interest to declare.

M.A.I.D.

To evaluate a wound-based prognostic score for chronic lower extremity wounds suitable for daily routine use capable of predicting long-term healing. The main obstacle in the treatment of chronic wounds is to estimate long-term clinical outcome. For diabetic foot ulcers, several ulcer, and nonulcer-related risk factors associated with impaired healing have been described in the past. A new chronic lower extremity ulcer score (M.A.I.D.) was created out of 4 clinically defined parameters, namely palpable pedal pulses (I), wound area (A), ulcer duration (D), and presence of multiple ulcerations (M). Palpable pedal pulses were categorized by the absence (scored as 1) or presence (scored as 0) of pedal pulses, while wounds >4 cm were scored as 1 and wounds < or = 4 cm as 0. Ulcers lasting more than 130 days were categorized as 1 and wounds with a duration of <130 days as 0. Patients with multiple ulcerations were graded as 1 (=1) compared with those with single ulcers (=0). M.A.I.D. was calculated by adding these separate scores to a theoretical maximum of 4. Two thousand nineteen consecutive patients with 4004 wounds were included. When patients were divided into subgroups with the same M.A.I.D., we showed a decreasing probability of healing for ulcers with higher M.A.I.D. scores. An increase in the M.A.I.D. by 1 score-point reduced the chance for healing by 37%. Similarly, the higher the ulcer score, the larger the initial wound area, the longer the wound history, and the more likely the occurrence of soft-tissue infection during follow-up. This new chronic lower extremity ulcer score is capable of anticipating long-term probability of healing by combining 4 clinically assessable parameters. However, adequate and standardized wound care is an indispensable prerequisite for M.A.I.D. to be a valid diagnostic tool in daily clinical routine.

Use of Platelet Gel in Chronic Lower Extremity Ulcers

Use of Platelet Gel in Chronic Lower Extremity Ulcers

Regenerative Surgery: Use of Fat Grafting Combined with Platelet-Rich Plasma for Chronic Lower-Extremity Ulcers

The authors present their experience with reconstructive surgery of the lower extremity for chronic ulcers, evaluating the effects related to the use of a platelet-rich plasma combined with fat tissue. A total of 20 patients, 25 to 50 years of age (median age, 40 years), have been managed with platelet gel in the Plastic and Reconstructive Surgery Department at the "Tor Vergata," University of Rome. The patients were affected by both lower-extremity chronic ulcers and vascular disease. The authors observed that 16 of 20 chronic lower-extremity ulcers reepithelialized during an average of 9.7 weeks, with platelet releasate suspended on a collagen base (platelet-derived wound-healing factor), compared with 2 of 10 similar wounds treated with medication based on hyaluronic acid and collagen. Collectively, these data provide evidence for the clinical use of platelet technology in the healing of both soft and hard tissue wounds. Currently, plastic surgery with autogenous fat grafts can be performed for stabilization of chronic lower-extremity ulcers. The objective of this study was, through the presentation of clinical cases, to suggest a therapeutic plan formed by two sequential treatments: acquisition of platelet gel from a small volume of blood (9-18 ml) followed by the Coleman technique for reconstructing the three-dimensional projection and superficial density of tissues. The results proved the efficacy of combining these two treatments, and the satisfaction of the patients confirmed the quality of the results.

Autologous platelet‐rich fibrin matrix as cell therapy in the healing of chronic lower‐extremity ulcers

A novel autologous platelet-rich fibrin matrix membrane (PRFM) was assessed for the ability to facilitate healing in patients with chronic lower-extremity ulcers. Preliminary data are presented from a prospective trial (n=21). Twelve patients were identified with 17 venous leg ulcers (VLU) and nine bearing 13 nonvenous lower-extremity ulcers. Before enrollment, the patients were evaluated for vascular status and received appropriate surgical intervention to optimize arterial and venous circulatory status. None of the ulcers had responded to a variety of standard treatments from 4 months to 53 years. Initial ulcer size ranged from 0.7 to 65 cm(2) (mean, 11.2 cm(2)). Each PRFM-treated patient received up to three applications of either a 35 or 50 mm fenestrated membrane, depending on initial ulcer size. The primary endpoints were percent and rate of complete closure as measured by digital photography, computerized planimetery, and clinical examination. Patients were followed weekly for 12 weeks with a follow-up visit at 16 weeks. At each 4-week interval, the extent of healing was assessed, and those patients with >50% reduction in wound area were allowed to continue to complete closure. Patients with <50% closure received repeated applications. Complete closure was achieved in 66.7% of the VLU patients (64.7% of treated ulcers) in 7.1 weeks (median, 6 weeks) with an average of two applications per patient. Forty-four percent complete closure was seen with non-VLU patients (31% of treated ulcers). From the results of this small-scale pilot study, PRFM shows significant potential for closing of chronic leg ulcers.

156 Homocysteine Associated with Impaired Wound Healing and Decreased Nitric Oxide Production

Nitric oxide (NO) is a critical mediator of normal tissue repair and is inhibited by homocysteine (Hcy). Following 8 weeks of lower extremity ulcer (LEU) treatment with human fibroblast-derived dermal substitute (Dermagraft®) for 12 (n = 12) patients, a correlation was observed between patients with a poor wound healing response to Dermagraft and elevated serum homocysteine (Hcy). The responders group (R) to Dermagraft treatment (n = 6) was observed with robust granulation tissue, epidermal migration and a 67% rate of healed ulcerations. All R-group patients (6/6) had normal serum Hcy. The nonresponders (NR) group (n = 6) exhibited poor granulation tissue formation and epidermal migration and a complete absence of healed wounds. Five of the NR patients (5/6) were observed with elevated serum Hcy. There was no significant (p < 0.05) difference between the wound areas (cm2 ± SE) of each group [35.43(±28.99)-R vs. 19.90(±7.55)-NR]. After 2 weeks of treatment, the R-group demonstrated significantly greater %Δwound area than the NR-group [62.17 (±7.96)-R group vs. 23.17(±8.82)-NR group; p < 0.05]. Wound fluid nitrate (WFNOx), a surrogate measurement (μM ± SE) for local NO bioactivity, was significantly lower for the NR-group than the R-group [3.17(±1.46)μM-NR group vs. 12.98(±1.73)μM-R group; p < 0.05]. In a large group of LEU patients (n = 138) we observed a 50% incidence of elevated Hcy; 69% for diabetic neuropathic LEU patients and 47% for nondiabetic LEU patients. Hcy inhibits NO production by multiple pathways and may also inhibit wound repair by occupying the fibronectin domain of fibrin during provisional matrix formation. Our study suggests that elevated serum Hcy is a common finding in chronic LEU patients. The high Hcy may contribute to impaired wound healing by decreasing wound NO production and, perhaps, by inhibition of fibronectin-fibrin-mediated wound matrix development.

Prevalence of antithrombin deficiency in patients with chronic leg ulcer.

Antithrombin is one of the main endogenous anticoagulants and its deficiency is associated with deep venous thrombosis. The aim of the present study was to evaluate the prevalence of antithrombin deficiency in patients with chronic lower extremity ulcers. Forty-eight patients with chronic lower limb ulcers for longer than 10 years, evaluated during 1997, were studied: 40 were female (83.3%) and eight were male (16.6%), with ages ranging from 43 to 73 years (mean, 55.2 years). Antithrombin was dosed by the coagulometric method, with evaluation of the functional activity. Measurement was repeated in those cases where deficiency was found to be present. The highest prevalence rate for antithrombin deficiency in the general population was one in every 2000 cases. Data analysis was performed by utilizing the odds ratio with a confidence interval of 95% and P < 0.05. Deficiency in antithrombin levels was recorded in two (4.1%) of the patients with chronic ulcer. These results indicate a higher prevalence rate of antithrombin deficiency in those patients with chronic leg ulcers, suggesting that an association may be present. Further studies with a larger number of patients are required to confirm this hypothesis.

Use of topical recombinant human platelet-derived growth factor-BB (becaplermin) in healing of chronic mixed arteriovenous lower extremity diabetic ulcers

Lower extremity ulcers cause significant morbidity and mortality in patients with diabetes. The primary factors that contribute to the development of this type of ulcer are peripheral neuropathy and peripheral vascular disease, which are often accompanied by infection. Lower extremity diabetic ulcers are chronic and difficult to treat, in part due to underlying pathologic conditions in individuals with diabetes that can contribute to impaired wound healing. This article reports the author's experience with treatment of chronic lower extremity ulcers of mixed etiologies with recombinant human platelet-derived growth factor--BB [rhPDGF-BB, REGRANEX (becaplermin) Gel 0.01%] in a patient with multiple risk factors including long-standing insulin-dependent type 2 diabetes.