Randomized clinical trial of honey-impregnated dressings for venous leg ulcers

Background:

The efficacy of honey as a treatment for venous ulcers has not been evaluated, despite widespread interest. This trial aimed to evaluate the safety and effectiveness of honey as a dressing for venous ulcers.

Methods:

This community‐based open‐label randomized trial allocated people with a venous ulcer to calcium alginate dressings impregnated with manuka honey or usual care. All participants received compression bandaging. The primary outcome was the proportion of ulcers healed after 12 weeks. Secondary outcomes were: time to healing, change in ulcer area, incidence of infection, costs per healed ulcer, adverse events and quality of life. Analysis was by intention to treat.

Results:

Of 368 participants, 187 were randomized to honey and 181 to usual care. At 12 weeks, 104 ulcers (55·6 per cent) in the honey‐treated group and 90 (49·7 per cent) in the usual care group had healed (absolute increase 5·9 (95 per cent confidence interval (c.i.) ? 4·3 to 15·7) per cent; P = 0·258). Treatment with honey was probably more expensive and associated with more adverse events (relative risk 1·3 (95 per cent c.i. 1·1 to 1·6); P = 0·013). There were no significant differences between the groups for other outcomes.

Conclusion:

Honey‐impregnated dressings did not significantly improve venous ulcer healing at 12 weeks compared with usual care. Registration number: ISRCTN 06161544 ( http://www.controlled‐trials.com ). Copyright © 2008 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.     

Doxycycline speeds up healing of chronic venous ulcers

Venous ulcers are common, with an overall prevalence of up to 2% in the general population of western countries, and have significant socioeconomic impact. Matrix metalloproteinases (MMPs) are involved in the alteration of extracellular matrix that could lead to venous ulceration. Sixty‐four patients with venous ulcers were recruited in a 22‐month period. All patients were subjected to the most appropriate treatment considering also the patient's wishes (compression therapy followed or not by vein surgery). Patients were randomised into two groups of 32 persons in each (groups A and B). Patients of group A in addition to the basic treatment, described above, received the administration of oral low doses of doxycycline 20 mg b.i.d. for 3 months, whereas patients of group B received basic treatment only. Healing was assessed by means of direct ulcer tracing with computerised planimetry. Group A showed a higher healing rate compared with group B. In group B, the lower healing rate was related to higher levels of MMP‐9; neutrophil gelatinase‐associated lipocalin and vascular endothelial growth factor, documented in plasma; wound fluid and biopsies executed and compared between both groups. Pharmacological treatments, as doxycycline administration, which by means of its immunomodulatory and anti‐inflammatory actions, through the inhibition of MMP, could improve extracellular matrix functioning and represent a possible solution to support wound healing.     

Micropunch grafting for healing of refractory chronic venous leg ulcers

BackgroundChronic venous ulcers are a serious problem for both patients and physicians. The CEAP classification (clinical manifestations (C), etiologic factors (E), anatomic distribution of disease (A), and underlying pathophysiologic findings (P)) for chronic venous disorders (CVD) was developed in 1994. Published papers on CVD use all or part of the CEAP. Micropunch grafts, which are a variation of skin grafts, have been used with great success in plastic surgery for both esthetic and reconstructive purposes. This study aimed to assess the outcomes of micropunch grafting in the treatment of chronic refractory venous ulcers.MethodsPatients with chronic venous ulcers who did not respond to conservative treatment for more than 6 months were included in the study. All patients underwent ulcer coverage by micropunch skin grafts using a micrometer. The patients were discharged on the same day as the surgery. Micropunch skin grafts were manually counted per square centimeter intraoperatively and during follow-up using Dermlite Dermatoschope? II Pro HR. Patient satisfaction was assessed by using a questionnaire.ResultsTwenty patients underwent the surgery. Most of the patients were middle-aged males. The ulcers were predominantly small- and medium-sized. The mean operation time was 167.00 ?± ?86.01 ?min. After 6 months, the survival rate of the planted micrografts was 84%. Three ulcers had graft loss and two patients had an infection at the ulcer site, which was managed conservatively. The patients were followed-up for 14 months.ConclusionMicropunch grafting is a useful and convenient method for the treatment of difficult venous ulcers and can be performed on an outpatient basis.     

The healing of chronic venous leg ulcers with prepared human amnion

Forty chronic venous leg ulcers were treated, before split skin grafting, with human amnion prepared in one of the four following ways: tissue-culture-maintained, frozen, fresh or lyophilised. Although there was no significant statistical difference in the results obtained with the different preparations of amnion, we found that lyophilised amnion was at least as good as the other preparations in promoting a good take of the skin grafts and was the simplest to store and use. It also produced the shortest healing times. Frozen and fresh amnion were easier to prepare than lyophilised amnion but gave a lower graft take and a longer healing time. Tissue-culture-maintained amnion was the most difficult to prepare and gave the poorest results. Its use was abandoned during the trial because of technical difficulties and a high infection rate.     

Randomized trial of two foam dressings in the management of chronic venous ulceration

A multicenter prospective randomized clinical trial was undertaken to compare two foam dressings (Allevyn Hydrocellular, Smith & Nephew and Mepilex, Molnlycke Health Care AB) in the management of chronic venous leg ulceration. Patients were also randomized to two compression bandage systems (4-layer vs. cohesive short stretch) as a factorial design. Those with causes of ulceration other than venous disease were excluded. In all, 156 patients met the entry criteria and were randomized from the 12 clinical centers with a median (range) ulcer size of 4.33 (0.33-123.10) cm(2). After 24 weeks a total of 100 (64.1%) patients had complete ulcer closure, 46 (29.5%) had withdrawn from the trial, nine (5.8%) remained unhealed and one patient died. Of the patients randomized to Mepilex, 50/75 (66.7%) had complete ulcer healing compared with 50/81 (61.7%) on Allevyn. The hazard ratio for healing after adjustment for bandage type and trial center was 1.48 (95% C.I. 0.87-2.54, p=0.15), which only marginally changed following adjustment for baseline variables, neither of which achieved statistical significance (p=0.16). Withdrawal rates were similar between groups (23, 30.7% Mepilex vs. 23, 28.4% Allevyn). Pain improved following treatment with both dressings (p<0.001), but with no difference between dressings.     

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.     

Second-degree burn healing: the effect of occlusive dressings and a cream

Because occlusive dressings and some creams have been found to speed epithelialization of blade-induced wounds, we studied the effect of two occlusive dressings and a polyglycerylmethacrylate cream containing low concentration of fibronectin on epithelialization in second-degree burn wounds. Cylindrical brass rods were heated in a boiling water bath, removed, wiped dry, and placed (6 sec) on the skin of domestic pigs. The burned epidermis was removed and each burn wound was assigned to one of the following treatment groups: (1) air-exposed, (2) DuoDERM (hydrocolloid dressing; Squibb Co., New Jersey), (3) Opsite (polyurethane dressing; Smith & Nephew, New Jersey), or (4) experimental cream. Several burn wounds were excised from each treatment group on Days 6 to 14 after wounding. The excised burn wounds were incubated in 0.5 M NaBr for 24 hr which allowed separation of the epidermis from the dermis. The epidermis was examined macroscopically for defects in the area of the burn. Specimens were considered healed when a defect was not present. Neither of the occlusive dressings changed the rate of epithelialization as compared to air exposure. Wounds which were treated with the experimental cream epithelialized faster than the air-exposed wounds (P less than 0.025).     

Epidemiology of chronic venous ulcers

A metropolitan population of 238,000 in Perth, Western Australia, was screened for chronic ulceration of the leg. Patients with a chronic leg ulcer and a venous abnormality comprised 57 per cent of all patients with a chronic leg ulcer, giving a prevalence of 0.62 per 1000 population. There was an increasing prevalence with age; 90 per cent of patients were 60 years and older. This group comprised 16.7 per cent of the population, and had a prevalence of 3.3 per 1000. Although chronic venous ulcers were more common in women there was no difference in age related prevalence. In 36 per cent of patients with a venous abnormality, there was at least one other aetiological factor contributing to chronic ulceration of the leg; 96 per cent had either a history of deep venous thrombosis or a condition known to predispose to deep venous thrombosis.     

Measurement of the healing of venous ulcers.

The surface area of 99 leg ulcers was measured from a scaled photograph using a computerized ultrasonic digitizer. This was compared with the area obtained by multiplying the two maximal perpendicular diameters of each ulcer. There was an extremely good correlation between these two methods (r = 0.951). Seventy-four patients were followed up as part of a placebo-controlled double-blind study. In this study, treatment was assessed by the time taken for the ulcerated limb to heal completely. The initial ulcer size was found to be a weak predictor of subsequent ulcer healing (r = 0.49). The healing rates of individual ulcers calculated over 1 month intervals from presentation proved to be a poor predictor of the time required for complete ulcer healing (Spearman rank correlation coefficients ranged from 0.15 to 0.61). The healing curves of individual ulcers showed considerable fluctuations during the process of healing. The product of the maximal dimensions of an ulcer provides an easy and accurate method of monitoring treatment. The reduction in ulcer size within a set time interval, used in many ulcer studies, is a poor predictor of eventual ulcer healing. The percentage of ulcers completely healed within a pre-determined time interval is a better method of assessing new treatments.     

Leg ulcers in chronic venous insufficiency

The incidence of the various types of ulcer is assessed in 180 subjects suffering from chronic ulcer of the legs and various syndrome. It emerges that about 10% of ulcers are not due to chronic venous insufficiency but to other pathologies.     

Epidermal repair in chronic venous ulcers

Certain features of epidermal repair, namely increased mitotic activity, cell migration and cell differentiation, have been investigated in fresh biopsies from 17 patients with chronic venous ulcers, using light and electron microscopy. Increased mitotic activity was present at the edges of most of these lesions whether they were in a grossly recognizable healing or non-healing phase, and some cells with ultrastructural features of migratory cells were invariably seen. The results are discussed in relation to other chronic epithelial lesions and suggest that failure of epithelialization is not due to any lack of epithelial cell production and that some other fundamental defect must be sought.     

Senescence and the healing rates of venous ulcers

OBJECTIVE: Premature cellular senescence has been linked to venous hypertension and may contribute to delayed healing of venous ulcers. We hypothesized that the percentage of senescent cells in in vitro populations of fibroblasts isolated from venous ulcers is directly related to the clinical time-to-healing. METHODS: Biopsy specimens were obtained from ulcer margins and unaffected dermal tissue of the ipsilateral thigh of seven patients with active venous ulcers. Using explant culture techniques, we obtained populations of wound fibroblasts and normal fibroblasts. The percentage of senescence in these cell populations was determined with X-Gal (5-bromo-4-chloro-3-indolyl beta-D-galactoside), which was used as a stain for B-galactosidase, a biomarker for senescent dermal fibroblasts. The X-Gal stain is a peroxidase stain for B-galactosidase. All patients in the study were treated with compression dressings. On a weekly basis, digital images were taken until ulcers healed. Planimetric healing rates were calculated from these images, and an overall time-to-healing was recorded. All cytologic investigations were performed on first passage cells. RESULTS: The average starting ulcer size was 4.2 cm2. Five of the data points represented healed ulcers. The two remaining patients withdrew from the study to pursue other therapies after having been treated with compression dressings for a long time. Linear regression analysis of healed ulcers identified a relationship between percent of senescence and time-to-healing, which was statistically significant (R2 = 0.81, P =.037). High percentages of senescent cells also had a correlation with slowed planimetric healing, which was not statistically significant. CONCLUSIONS: This study demonstrates a clinical correlation between quantitative in vitro senescence and time-to-healing. A percentage of senescence that is greater than 15% in populations of cells isolated from venous ulcers may identify a "difficult to heal" ulcer. There is no good clinical indicator for determining the likelihood of ulcer healing, but these results indicate that senescence percentage may have potential in this regard.     

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.     

Comparative effectiveness of advanced wound dressings for patients with chronic venous leg ulcers: A systematic review

The purpose of this study was to systematically review the literature on the benefits and harms of advanced wound dressings on wound healing, mortality, quality of life, pain, condition of the wound bed, and adverse events for patients with chronic venous leg ulcers as compared with treatment with compression alone. We searched for primary studies in the databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature^® from January 1980 through July 2012. Each study title, abstract, and full article was evaluated by two independent reviewers. Thirty‐seven studies met our specific search criteria, although most evidence was of low or insufficient quality. Cellular dressings, collagen, and some antimicrobial dressings may improve healing rates of chronic venous leg ulcers vs. compression alone or other dressings. Limited data were available on other outcomes. The poor quality of the literature limits conclusions and necessitates future, well‐conducted studies to evaluate the effectiveness of advanced wound dressings on chronic venous ulcers.     

Factors that influence healing in chronic venous ulcers treated with cryopreserved human epidermal cultures.

BACKGROUND: Cryopreserved epidermal cultures (CEC) offer an "off the shelf" treatment for chronic wounds. These cultures are derived from neonatal foreskin and grow rapidly in vitro to form epidermal sheets. They do not require a biopsy from the patient, an advantage compared to autografts. They seem to act as a biological dressing, stimulating epithelialization from the wound edges and adnexae, probably through growth factor release. OBJECTIVE: To summarize our recent experience with the use of CEC in chronic venous leg ulcers and to determine the factors that influence healing in chronic venous ulcers treated with CEC. PATIENTS AND METHODS: A single arm, open label study including a total of 11 patients with documented venous ulcers was performed. The study involved the application of cryopreserved epidermal cultures every other week to nonhealing leg ulcers for a total of 12 weeks or until complete healing of the ulcer. RESULTS: A total of 11 patients with one or more leg ulcers were treated. The average age was similar in healed and unhealed groups. Seven patients completely healed after an average of 4.14 CEC applications. Four patients did not heal after a total of 12 CEC applications. CONCLUSION: Predictors for failure to heal after CEC application in our patients were long wound duration, wound size, presence of lipodermatosclerosis, and history of failed prior split-thickness skin grafts.     

Oxidative stress in chronic venous leg ulcers

Venous leg ulcers are common and cause considerable morbidity in the population. As healing may be slow or may never be achieved, ulcers create persistent and substantial demands on clinical resources. Great efforts have been made to accelerate tissue repair in chronic venous leg ulcers with limited success. This may at least be partly due to the limited knowledge on the microenvironment of chronic wounds. In fact, the tremendous impact of the microenvironmental conditions on the outcome of wound healing has increasingly become apparent. Oxidative stress as a consequence of an imbalance in the prooxidant-antioxidant homeostasis in chronic wounds is thought to drive a deleterious sequence of events finally resulting in the nonhealing state. The majority of reactive oxygen species are most likely released by neutrophils and macrophages and to an unknown extent from resident fibroblasts and endothelial cells. As the inflammatory phase does not resolve in chronic wounds, the load of reactive oxygen species persists over a long period of time with subsequent continuous damage and perpetuation of the inflammation. In this article, we will critically discuss recent findings that support the role of oxidative stress in the pathophysiology of nonhealing chronic venous leg ulcers.