Investigation and treatment of chronic venous ulcer disease.

INTRODUCTION: The investigation and treatment of chronic venous ulceration continues to present many difficulties for the clinician. The uncertainties relate to the appropriate use of different forms of investigation and whether conservative treatment or surgical treatment should be used. METHOD: A comprehensive search was undertaken of published literature on venous ulceration. RESULTS: The extent of investigations is largely determined by the type of treatment that the patient is either fit to undertake or is prepared to undertake. When conservative treatment only is to be used, detailed investigation of the venous system is not required. The role of surgery to the veins remains unproven in improving the healing of venous ulcers. Surgery to prevent ulcer recurrence has been demonstrated to be of benefit only in patients who have normal deep veins. CONCLUSIONS: Investigations performed on the venous system should be determined by the planned treatment. Many of the operations that have been performed on the venous system still remain unproven in providing a benefit to the healing of venous ulcers and in preventing venous ulcer recurrence.

Australian medical patents granted in the United States in 1984-1999.

OBJECTIVE: To describe all medical patents granted in the United States to Australian-resident inventors between 1984 and 1999. DATA SOURCES: All patent data originated from the US Patent and Trademark Office. Data for 1984-1994 were compiled by CHI Research Inc, and data for 1995-1999 were obtained from the Community of Science website. MAIN OUTCOME MEASURES: Number of medical patents granted in the US to Australian-resident inventors; assignees (owners) of these medical patents; proportion of these medical patents related to biotechnology. RESULTS: From 1984 to 1999, 7835 utility patents were granted in the US to Australian-resident inventors. Of these, 1308 patents (17%) were identified as medical patents; 489 (37%) of these were biotechnology patents. Medical patents account for an increasing proportion of all US patents granted to Australian inventors, increasing from 10% in 1984 to 25% in 1999. Biotechnology accounted for an increasing proportion of medical patents, rising from 10% to 55% between 1984 and 1999. More than half the medical patents are owned by commercial interests, and 33% by only 14 organisations, six of which are universities and their affiliated institutions. CONCLUSION: Only a few organisations account for most of the patenting of medical technology. The inventors and their organisations listed on medical patents could be canvassed when developing government policy and targeted for support in commercialising their medical technology.

Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing.

OBJECTIVES: to assess the effect of topical autologous platelet lysate on the healing of chronic venous ulcers. DESIGN: a randomised placebo controlled double-blind trial. MATERIALS: all patients had blood taken for preparation of autologous platelet lysate. METHODS: patients with proven chronic venous ulceration were randomised to the trial. Autologous platelet lysate or placebo buffer solution were applied twice per week for up to 9 months in combination with standardised compression bandaging. RESULTS: a total of 86 patients (36 males and 50 females, median age 70 years) were entered into the study. The patient and treatment groups were equivalent for ulcer size, ulcer duration and other characteristics. Cox regression analysis of the time to ulcer healing did not show any difference in healing between platelet lysate and placebo application. CONCLUSIONS: platelet lysate prepared and delivered by the method used in this study had no influence on the healing of chronic venous ulceration.

Pericapillary fibrin deposits and skin hypoxia precede the changes of lipodermatosclerosis in limbs at increased risk of developing a venous ulcer.

This study investigated the possibility that pericapillary fibrin deposition, found in the calf skin of patients with venous ulceration and lipodermatosclerosis, might already be present in the dermis of the gaiter area of apparently healthy limbs before any skin changes were visible. The apparently healthy limbs of 19 consecutive patients with a healed venous ulcer on one leg and no history of ulceration or clinical evidence of lipodermatosclerosis in the opposite calf, were studied. Bipedal ascending phlebography and foot volume plethysmography were performed, and systemic fibrinolytic activity and fibrinogen levels were calculated. Transcutaneous oxygen measurements were expressed as a ratio of levels from a fixed position in the gaiter skin over a control site on the arm. Biopsies of a standard site in the gaiter skin and the thigh were assessed for the presence of laminin, fibrinogen and fibronectin using immunofluorescent microscopy. The extent of pericapillary fluorescence was expressed as a ratio of the number of capillaries with deposits divided by the total number of capillaries staining with laminin (fibrin and fibronectin scores). Pericapillary fibrin deposits were observed in the dermis in 16 of the biopsies of the gaiter region (median score 0.20), and in eight of the biopsies from the thigh (median score 0.0). This difference was highly significant (P<0.01, Wilcoxon signed rank test). The transcutaneous oxygen ratio correlated negatively with the fibrin score (Spearman rank correlation coefficient -0.62, P<0.01), and there was a weak negative correlation between the half volume refilling time on foot volume plethysmography (an indicator of venous reflux) and the fibrin score (Speraman rank correlation coefficient -0.47, P<0.05). No such correlation could be shown between the fibrin score and the indicators of calf pump function, the euglobulin clot lysis time or the plasma fibrinogen. The presence of significant numbers of pericapillary fibrin deposits within the dermis of the gaiter skin has been demonstrated in 84% of this cohort of 'at risk' limbs before there is any evidence of clinical lipodermatosclerosis.

Lower levels of PAI-2 may contribute to impaired healing in venous ulcers - a preliminary study.

Plasminogen activators may potentially influence the wound healing processes of cell migration, matrix degradation and cellular adhesion in venous ulcers by their regulation of protease activity. The aim of this study was to assess the levels of plasminogen activators in venous ulcers and to gain preliminary data from healing wounds. The concentrations of u-PA, t-PA, PAI-1 and PAI-2 antigen as well as functional u-PA were assessed in tissue homogenates from 20 chronic venous ulcers, six actively healing venous ulcers and five traumatic wounds. The concentrations of functional u-PA, u-PA antigen and PAI-1 were significantly greater and PAI-2 was significantly lower in the edge and base of chronic venous ulcers compared to adjacent intact skin (P<0.01). Healing wounds had significantly higher functional u-PA at the ulcer edge and higher u-PA antigen concentration in intact skin (P<0.05). PAI-2 levels were significantly higher in the ulcer edge and base in the healing wounds than in chronic venous ulcers (P<0.05). These findings suggest that regulation of protease activity by u-PA and PAI-2 may play a role in the impaired healing of chronic venous ulcers.

Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers.

The cause of impaired healing in chronic leg ulcers is not known. However, recent attempts to modify the healing process have focused on adding growth factors to stimulate healing and have failed to produce dramatic improvements in healing. This study used a unique model of chronic wound healing in humans to obtain wound fluid samples from chronic venous leg ulcers that had changed from a nonhealing to a healing phase. These samples were used to assess cytokine and growth factor levels, and mitogenic activity in these nonhealing and healing chronic wounds. The pro-inflammatory cytokines interleukin-1, interleukin-6 and tumor necrosis factor-alphawere found to be present in significantly higher concentrations in wound fluid from nonhealing compared to healing leg ulcers. There were detectable levels but, no significant change in the levels of platelet derived growth factor, epidermal growth factor, basic fibroblast growth factor or transforming growth factor-betaas ulcers healed. Wound fluid was added to fibroblasts in vitro to assess mitogenic activity. There was a significantly greater proliferative response to healing wound fluid samples compared to nonhealing samples. These results suggest that healing may be impaired by inflammatory mediators rather than inhibited by a deficiency of growth factors in these chronic wounds.

Changes in calf muscle function in chronic venous disease.

The aim of this study was to assess calf muscle function in patients with chronic venous disease and recently healed venous ulcers. Forty-nine consecutive patients with recently healed proven venous leg ulcers and 20 age- and sex-matched control subjects were entered into this study. Both patients and control subjects underwent duplex scan evaluation of their leg veins and isokinetic measurement for calf muscle strength and endurance. Calf muscle function was significantly impaired in patients with chronic venous disease compared with control subjects. Both peak torque/body weight (strength), P = 0.049 (CI 0.3-18.4%) and total work (endurance), P = 0.05 (Cl 6.01-97.6 Nm) were reduced. This study has shown that patients with chronic venous disease have a significant impairment of calf muscle function compared with healthy control subjects. This study suggests that there is a need to evaluate whether a programme to improve muscle strength may be of benefit in both healing and preventing the recurrence of chronic venous ulcers.

Effect of exercise on calf muscle pump function in patients with chronic venous disease.

BACKGROUND: Musculoskeletal dysfunction may be associated with poor calf muscle pump function in patients with chronic venous ulceration. The aim of this study was to evaluate the effects of physical exercise on calf muscle pump function. METHODS: Twenty patients were recruited into a 6-week intensive exercise programme. Calf muscle function and calf muscle pump function were assessed using an isokinetic device and air plethysmography respectively, before and after the exercise programme. RESULTS: There was significant improvement in calf muscle pump function, measured as increased ejection fraction and decreased residual fraction (P < 0.05); however, venous reflux was not altered (P > 0.05). Calf muscle strength and endurance parameters all increased, but not significantly (P > 0.05). CONCLUSION: Poor calf muscle pump function in patients with chronic venous ulceration can be improved by physical exercise.

Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors.

To assess the differences in proteolytic activity of acute and chronic wound environments, wound fluids were collected from acute surgical wounds (22 samples) and chronic wounds (25 samples) of various etiologies, including mixed vessel disease ulcers, decubiti and diabetic foot ulcers. Matrix metalloproteinase (MMP) activity measured using the Azocoll assay was significantly elevated by 30 fold in chronic wounds (median 22.8 microg MMP Eq/ml) compared to acute wounds (median 0.76 microg MMP Eq/ml) (p < 0.001). The addition of the matrix metalloproteinase inhibitor Illomostat decreased the matrix metalloproteinase activity by approximately 90% in all samples, confirming that the majority of the activity measured was due to matrix metalloproteinases. Gelatin zymograms indicated predominantly elevated matrix metalloproteinase-9 with smaller elevations of matrix metalloproteinase-2. In addition tissue inhibitor of metalloproteinase-1 levels were analyzed in a small subset of acute and chronic wounds. When tissue inhibitor of metalloproteinase-1 levels were compared to protease levels there was an inverse correlation (p = 0.02, r = - 0.78). In vitro degradation of epidermal growth factor was measured by addition of 125I labelled epidermal growth factor to acute and chronic wound fluid samples. There was significantly higher degradation of epidermal growth factor in chronic wound fluid samples (mean 28.1%) compared to acute samples (mean 0.6%). This also correlated to the epidermal growth factor activity of these wound fluid samples (p < 0. 001, r = 0.64). Additionally, the levels of proteases were assayed in wound fluid collected from 15 venous leg ulcers during a nonhealing and healing phase using a unique model of chronic wound healing in humans. Patients with nonhealing venous leg ulcers were admitted to the hospital for bed rest and wound fluid samples were collected on admission (nonhealing phase) and after 2 weeks (healing phase) when the ulcers had begun to heal as evidenced by a reduction in size (median 12%). These data showed that the elevated levels of matrix metalloproteinase activity decreased significantly as healing occurs in chronic leg ulcers (p < 0.01). This parallels the processes observed in normally healing acute wounds. This data also supports the case for the addition of protease inhibitors in chronic wounds in conjunction with any treatments using growth factors.

Levels of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors in chronic venous leg ulcers--correlations to healing status.

This study tested the hypothesis that excessive tumor necrosis factor-alpha (TNF-alpha) levels in chronic venous leg ulcers are associated with impaired healing. TNF-alpha was measured by two enzyme-linked immunosorbent assays and a bioassay (KYM-1D4) in paired wound fluid samples collected during the nonhealing and healing phases from 21 human patients with venous leg ulcers. Soluble TNF receptor levels (p55 and p75) were also measured. The levels of immunoreactive TNF-alpha were significantly higher in wound fluid from nonhealing ulcers than in wound fluid from healing ulcers (p < 0.005), whereas the levels of bioactive TNF-alpha were not. Statistical analysis confirmed that TNF-alpha bioactivity relative to the amount of immunoreactive TNF-alpha was downregulated in wound fluid from nonhealing ulcers compared with healing ulcers. The levels of soluble p55 and p75 receptors in wound fluid showed a significant linear correlation (p < 0.001), suggesting a partially coordinated or common regulatory mechanism for the cleavage of transmembrane TNF receptors in chronic venous ulcers in vivo. Although the levels of soluble p75 receptors were significantly higher in nonhealing wound fluid compared with healing wound fluid (p < 0.025), these levels were theoretically inadequate to substantially neutralize the bioactivity of the accompanying TNF-alpha levels on their own. The bioactivity accompanying the elevated levels of immunoreactive TNF-alpha in wound fluid from nonhealing ulcers may have been further down-modulated by an additional mechanism. Because healing was initiated without a significant decline in the level of bioactive TNF-alpha, TNF-alpha-mediated events may not be the key events contributing to the impaired healing seen in chronic venous ulcers.

Variability and reliability of air plethysmographic measurements for the evaluation of chronic venous disease.

PURPOSE: Air plethysmography (APG) has the potential to help evaluate different treatments for the prevention of recurrence of venous ulcers; however, there are little reported data on the variation and reliability of the different parameters. This study aimed to assess the variation in different APG parameters in patients with chronic venous disease and to evaluate the reliability of APG in test-retest situations. METHOD: Seventeen patients (18 limbs) with chronic venous disease were recruited into this study. Subjects were asked to undergo tests on two occasions, 1 to 6 weeks apart. Three tests were performed at each visit, and three patients had 10 tests performed at one visit. The coefficients of variation were calculated for repeated measurements and test-retest reliability, and the differences between the means of three tests and the 10 tests were also analyzed. RESULTS: The coefficients of variation for the repeated measurements ranged from 7.5% to 27% for the majority of parameters of APG. The differences between the means of three tests and the means of 10 tests were less than 10% in this study. The coefficients of variation of method error were approximately 10% in test-retest measures. CONCLUSIONS: This study has shown that evaluations of calf pump function and venous reflux using APG display variations in repeated measurements and in the test-retest measures. The variations found within patients and on retesting patients on different days suggest that APG is very unlikely to be able to detect small changes in the parameters of venous reflux and calf pump function. It is essential to understand the inherent variation of APG measurements when they are used to assess treatments that are designed to improve venous function.

The influence of dressings on venous ulcer healing--a randomised trial.

OBJECTIVE: To assess the effect of different dressings on venous ulcer healing. DESIGN: A randomised clinical trial. MATERIALS: Patients were randomised to treatment with one of three dressings: a zinc oxide impregnated bandage, a zinc oxide impregnated stockingette, or an alginate dressing. All patients were treated as outpatients and had compression bandaging with two minimal stretch bandages (Elastocrepe) and a stockingette (Tubigrip) to keep the bandages in place. METHODS: One hundred and thirteen patients (133 ulcerated limbs) with chronic ulceration of the leg due to venous disease alone, and attending Fremantle Hospital Leg Ulcer Clinic, Western Australia were entered into the study. Healing was measured as complete healing of the ulcerated limb or failure of the limb to heal within 9 months. RESULTS: There was no significant difference between the three groups in ulcer size, duration, and other parameters compared. Healing was affected significantly by ulcer size and which leg was ulcerated. There was significantly faster healing with the paste bandage. CONCLUSION: The use of a paste bandage significantly improved the healing of chronic venous ulcers when used in combination with compression bandaging, and compared to an alginate dressing and a zinc oxide impregnated stockingette.

Incisional hernias are more common in aneurysmal arterial disease.

OBJECTIVE: To test the hypothesis that incisional hernia was a more frequent complication following aortic reconstructive surgery in patients with aneurysmal as opposed to occlusive aortic disease. DESIGN: A retrospective review. MATERIALS AND METHODS: All patients having aortic reconstructive surgery at a teaching hospital between 1988 and 1992 were identified and recalled to be examined for evidence of an incisional hernia. RESULTS: Of the 134 patients having aortic reconstructive surgery, 87 were available to be examined by an independent clinician. The overall incisional hernia rate was 28%. Patients with aneurysmal disease were significantly more likely to develop an incisional hernia after elective surgery than patients with occlusive disease (p = 0.04). None of the other variables investigated, including age, chronic obstructive airways disease, diabetes, smoking, wound infection, obesity, length of intensive care unit stay and number of units of blood transfused, were significantly related to the complication of incisional hernia. CONCLUSION: Incisional hernia is a common complication of aortic reconstructive surgery, especially in patients with aneurysmal disease.

Malignancy in chronic leg ulcers.

OBJECTIVE: To evaluate the frequency of malignant ulcers in patients presenting with leg ulcers. DESIGN: A descriptive study from data collected between July 1988 and June 1995 from 981 patients (2448 ulcers) attending a leg ulcer clinic. SETTING: A specialised leg ulcer clinic at a tertiary teaching hospital. SUBJECTS: 43 patients with 55 malignant skin lesions. OUTCOME MEASURES: Tissue biopsies in ulcerated lesions that suggested malignancy or were not responding to appropriate treatment. RESULTS: Forty-three patients were found to have malignant lesions on the legs, giving a frequency of malignant ulcers of 4.4 per 100 leg ulcer patients, or 2.2 per 100 leg ulcers. Seventy-five per cent of the malignant ulcers were basal cell carcinoma and 25% were squamous cell carcinoma. CONCLUSIONS: Malignant skin changes are common in chronic leg ulcers. A biopsy should be taken from all suspicious ulcers or ulcers that do not respond to appropriate treatment.

Influence of arterial disease, age and active ulceration on venous refilling time measured by photoplethysmography.

This study investigated the influence of arterial disease, patient age and the presence of a venous ulcer on venous refilling time as measured by photoplethysmography. Refilling time was evaluated in 157 control limbs, in 133 limbs with venous disease, in 17 limbs with arterial disease and in 20 limbs with mixed disease (arterial and venous disease) as the cause of ulceration. Refilling time reduced progressively with age in control subjects and was significantly shorter over the age of 50 years. Limbs with venous disease alone had a significantly shorter refilling time when compared with controls (Mann-Whitney U test, P < 0.01); however, there was no alteration in refilling time with age. Limbs with arterial disease, without clinical evidence of venous insufficiency, had a shorter refilling time when compared with controls but a longer refilling time compared with those with venous disease (P < 0.01). The refilling time in patients with mixed ulcers did not differ from those with venous ulcers (P < 0.265). Refilling time measured when an ulcer was present was not significantly different to that measured after the ulcer had healed (P = 0.59). Venous refilling time normally reduces with age but is not affected by arterial disease or the presence of an ulcer.

Qualitative bacteriology and leg ulcer healing.

This study investigated the bacterial profile of leg ulcers in 52 patients attending the Fremantle Hospital leg ulcer clinic. The aim was to identify whether the presence of specific bacterial groups delays healing, whether the bacterial flora changes as ulcers heal and, if so, whether these changes influence healing. The results show that the presence of any one specific bacterial group did not appear to delay healing, although the presence of four or more bacterial groups was associated with delayed healing. This was found to be statistically significant. It was noted that the bacterial flora does change as ulcers heal and that these changes were not related to changes in healing, with the exception of skin flora.

Biochemical analysis of wound fluid from nonhealing and healing chronic leg ulcers.

The purpose of this study was to determine the biochemical composition of fluid taken from chronic wounds, to compare these values with that of serum, and therefore to assess whether the wound fluid is representative of the extracellular environment of the wound. Paired wound fluid and blood samples were collected from eight patients with chronic leg ulcers in a nonhealing and healing phase. Wound fluid and serum samples were screened for a profile of general biochemical analyses, including electrolytes, lactate, glucose, and protein analyses. Electrolyte levels were essentially identical in wound fluid and serum samples. Lactate and lactate dehydrogenase levels were significantly greater and glucose and bicarbonate levels were significantly lower in wound fluid when compared with the paired serum samples. Albumin and total protein levels in wound fluid were on average half those of serum levels. In this small sample of eight patients, wound fluid collected from chronic leg ulcers is an exudate with the biochemical composition expected in extracellular fluid. In addition, bicarbonate and glucose levels increase and C-reactive protein levels decrease in wound fluid, but remain unchanged in serum, during healing. These results suggest changes in the state of hypoxia and the inflammatory process in the healing wound.

Growth factors, tissue and urokinase-type plasminogen activators in venous ulcers.

Bioimmunoassays for tissue and urokinase-type plasminogen activators (t-pA and u-pA), and enzyme-linked immunosorbent assays (ELISA) for t-pA were performed on biopsies from the edge and base of 15 venous ulcers. TGF-beta 1, bFGF and PDGF were assessed by ELISA in the edge and base of 19 further venous ulcers and 7 biopsies of normal skin. The presence of all three growth factors and u-pA was confirmed immunohistochemically. T-pA was detected using the ELISA and the bioimmunoassay, but was quantified in 3/15 ulcer bases and 4/15 ulcer edges using the bioimmunoassay only. U-pA was measured in all ulcer samples except one. TGF-beta 1 was measured in 13/19 ulcer bases and 9/19 edges, while free TGF-beta 1 was measured in only 2/19 bases and 4/19 edges. Venous ulcer bases contain significantly greater quantities of u-pA, TGF-beta 1, and bFGF than ulcer edges. TGF-beta 1 was never detected in normal skin. There is significantly less bFGF in normal skin than in venous ulcer bases, but not edges (p = 0.013, p = 0.31 respectively, Mann Whitney U-test). There was a good correlation between ulcer edge TGF-beta 1 and time to healing in ten ulcers that healed within six months from the date of biopsy (r = -0.56, p = 0.065, Spearman Rank Correlation). There was a significantly greater amount of ulcer edge bFGF in the ulcers that healed within six months than those that remained unhealed (p = 0.036, Mann-Whitney U-test).(ABSTRACT TRUNCATED AT 250 WORDS)

The Australian polidocanol (aethoxysklerol) study. Results at 2 years.

BACKGROUND: An ongoing study of the safety and effectiveness of polidocanol by 98 investigators in Australia infecting 16,804 limbs over 2 years. OBJECTIVE: To evaluate the complications of polidocanol and compare its effectiveness and complications with sodium tetradecyl sulphate (STD) and hypertonic saline. METHODS: A single-arm prospective study of polidocanol complications and its effectiveness as a sclerosant was performed. This was compared with each investigator's previous experience with other sclerosing agents. Patients had either varicose veins or venule ectasias and/or spider veins (telangiectasia). A total of 16,804 limbs were injected by 98 investigators. Sclerotherapy was performed with 0.5% or 1% polidocanol for telangiectasias or spider veins, and with 3% polidocanol for varicose veins. The effectiveness of the sclerotherapy and any complications were reported during a 2-year period. RESULTS: There were very few complications reported with polidocanol. There were no reported deaths or anaphylaxis. The investigators with previous experience of other sclerosants considered that the effectiveness of polidocanol was superior to STD (85%) and hypertonic saline (84%). Ninety percent of investigators considered that polidocanol had less frequent complications than STD, and 80% considered that these were less severe. Seventy-four percent considered that polidocanol had fewer side effects than hypertonic saline, and 74% considered that these were less severe. CONCLUSIONS: Polidocanol is an effective sclerosant that has few complications.