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Objectives: The real mechanism for the development of the later stages of chronic venous insufficiency still remains unclear. Venous hypervolemia and microvascular ischemia have been reported to be the consequences of venous insufficiency. The aim of this study was to investigate the effects of induced venous hypovolemia by dorsiflexion exercise in patients with venous leg ulcers., Methods: Thirty-six participants, all of whom had an ankle brachial pressure index between 0.8 and 1.2 mmHg, were chosen for this study. The participants were divided into two groups: Group A, a non-exercise group and Group B which performed regular exercise in the form of dorsiflexion. The basic assessment, including the history and examination, ankle-brachial pressure index (ABPI), Duplex scan and tcPO 2 measurements, was performed on two occasions at the beginning of the trial and after three months., Results: The tcPO 2 level was low in the beginning in all the subjects, but the picture was different at the end of the trial. There was a significant increase in the tcPO 2 level (p<0.001) in the patients who performed exercise while there was no difference in the measurements (p>0.05) in the non-exercise group., Conclusions: Induced venous hypovolemia through regular evacuation of the peripheral venous system improved tissue oxygenation at skin level. Venous hypervolemia may be the main contributing factor for the development of venous hypoxia and microvascular ischemia.

Introduction: A venous leg ulcer (VLU) has a major impact on the quality of life and functional ability of individuals, but no single treatment is yet effective. This study investigates the changes induced by dorsiflexion exercise on skin perfusion in VLU patients to achieve a better understanding of venous ulcer pathophysiology., Methods: Seventy-eight venous leg ulcer patients were randomised into four groups. The non-exercise groups included a control group (n = 18) and a compression therapy group (n = 20) and the exercise groups included an exercise-only group (n = 20) and a compression and exercise group (n = 20). The exercise groups were expected to perform exercise for three months. Measurements included transcutaneous oximetry (tcPO 2 ) and laser Doppler flowmetry (LDF). Skin perfusion measurements for all groups were taken twice: at the beginning and end of the three-month period., Results: Initially, all participants showed a low level of tcPO 2 . The exercise groups showed a significant increase after three months of exercise (p<0.001), the tcPO 2 level remained the same in the non-exercise groups. The LDF parameters decreased significantly (p<0.001) in the compression and exercise group and decreased to a lesser extent in the exercise-only group. There were no LDF changes in the non-exercise groups., Conclusions: Perfusion measurements showed significant changes after three months of regular exercise. We conclude that exercise has a significant effect on tissue perfusion parameters in venous leg ulcer and this effect may play a role in understanding the pathophysiology of VLU.

This trial compared skin blood flow, temperature and incidence of venous leg ulcers in patients with chronic venous disease using compression wraps and elevation pillows. Patients with CEAP C4 skin damage and C5 history of ulcers were randomly assigned to a cryotherapy intervention (n = 138) or placebo cuff control (n = 138) applied to the lower legs over 9 months. The time the ulcers healed prior to enrollment in the study for the cryotherapy group ranged from 1 to 2218 days (n = 8, median = 32 days); for the control group, the range was 24 to 489 days (n = 6, median = 390 days). There were no statistically significant blood flow changes measured in perfusion units with a laser Doppler flowmetre within or between the groups; mean difference between the groups was 0·62, P = 0·619. No differences were noted in skin temperature measured with an infrared thermometer within and between the groups; mean difference between the groups was -0·17°C, P = 0·540. Cryotherapy did not improve skin blood flow or temperature and did not show efficacy in preventing ulcers. However, at least 30% of intervention and 50% of control participants were anticipated to develop an ulcer during the study; only ∼7% occurred. These findings suggest that strict adherence to standard of care decreases the incidence of leg ulcers and remains a best practice for leg ulcer prevention., (© 2016 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Background: Venous ulcers, also known as stasis ulcers, are skin wounds often found at the medial surface of the lower leg. These wounds are related to chronic venous insufficiencies and affect almost 2.5 million patients every year in the United States., Method: Eighteen participants with venous stasis ulcers on at least one leg and twenty healthy participants were tested. Normal and combined normal and shear loadings were applied to each lower leg and local blood perfusion was monitored. Basal perfusion, post-occlusive reactive hyperemia as well as changes in perfusion due to different loadings were compared., Findings: Legs with existing venous stasis ulcers ("wounded legs") had the highest reactive hyperemia and basal perfusion values. Legs without ulcers but from participants with venous stasis ulcers ("non-wounded legs") had intermediate reactive hyperemia, and healthy legs exhibited the lowest values. Wounded legs also exhibited the largest decrease in blood perfusion under both normal and combined loadings. Non-wounded legs decreased perfusion similarly to healthy legs under normal loadings; however, non-wounded legs exhibited larger decreases in blood flow than healthy legs in response to shear and normal loading together., Interpretation: These results suggest that patients with venous stasis disease have abnormal responses to tissue loading and raise the possibility that this technique may have the potential to identify patients at risk for developing a venous stasis ulcer. Moreover, they emphasize the importance of studying shear loading in addition to normal loading in attempting to understand the pathophysiology of this disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: To determine the effect of topically applied amelogenin extracellular matrix protein(AEMP) in patients with non-healing venous leg ulcers combined with atrophie blanche., Method: This retrospective case series of patients with non-healing venous leg ulcers with atrophie blanche of the distal proportion of their lower legs, where non-healing was defined as no progress toward healing for 3 months previously, under standard therapy. Patient records were reviewed for associated diseases, wound diagnoses, distal blood pressure, previous treatments and changes in wound area. Patients were treated with AEMP once a week, for a period of 12 weeks, or until full healing., Results: Eleven patient records were reviewed retrospectively. The median age of the patients was 81 years (range 40-95 years), with a mean wound size of 4.7 ± 3.Scm2 and median wound duration of 6 months (range 3-444 months).AII patients had venous or combined arterial/venous insufficiency. After 12 weeks' treatment with AEMP, complete healing, defined as I 00% re-epithelialisation, was documented in four patients (36%), marked improvement(> SO% epithelialisation) in three patients (54%, 55% and 83% wound closure, respectively), slight improvement in one patient (9.4% wound closure), no change for two patients and worsening in one.AEMP was well tolerated, and no patients reported side effects., Conclusion: The results of this retrospective study suggest that AEMP improves healing in chronic venous leg ulcers combined with atrophie blanche.

Background: Chronic venous insufficiency (CVI) ulcers represent a major medical problem worldwide. Current theories concerning the pathogenesis of CVI ulcers focus on abnormalities in the blood vascular system. Other abnormalities, such as chronic leg edema, may also play pathogenic roles in CVI ulcer development and further understanding of such alterations may lead to better treatments., Objective: To gain insight into lymphatic abnormalities occurring in CVI, we compared dermal lymphatics in histologic sections from CVI ulcers and normal controls., Methods: We compared global and architectural features of dermal lymphatics in D2-40-stained histologic sections from CVI ulcer tissue and from normal controls. D2-40 recognizes podoplanin, a transmembrane glycoprotein that is constitutively expressed in lymphatic endothelial cells, allowing us to distinguish dermal blood vessels from lymphatic vessels., Results: Our analyses reveal that CVI ulcer specimens have more dermal lymphatic vessels per unit area than controls (5.71 vs 4.08 per mm(2), respectively; P = .0281); a higher percentage of lymphatic vessels with collapsed lumina compared with controls (30.5% vs 8.1%, respectively; P < .0001); and a higher percentage of competent lymphatic vessels displaying open inter-endothelial junctions compared with controls (5.7% vs 2.9%, respectively; P < .0369)., Limitations: Our study is limited by its retrospective nature and relatively small sample size., Conclusions: Lymphatic vessels in CVI ulcer specimens display global and architectural differences compared with lymphatic vessels in control specimens. These findings further implicate lymphatic dysfunction in the pathogenesis of CVI ulcers and allow for the formulation of a hypothesis concerning lymphatic changes that may be tested in future studies., (Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Microcirculation of 15 ischemic and 15 venous ulcers, their scars, and intact surrounding skin were examined in order to demonstrate their similarities in the development and healing process. Subpapillary and nutritive perfusion of four areas were investigated by a laser Doppler perfusion imager (arbitrary units) and capillary microscopy (capillaries/mm2): one ulcer area without granulation tissue (no wound healing) and one with granulation tissue (ulcer healing); one skin area adjacent to the ulcer (1-8 mm) (scar developed from ulcer areas) and one distant (12-25 mm; intact skin). Areas without granulation tissue in ischemic and venous ulcers were similar, demonstrating a lack of capillaries (0.13 +/- 0.52; 0.93 +/- 2.09) and low laser Doppler flux (0.81 +/- 0.69; 1.47 +/- 1.17; P > 0.05 for each). In granulation tissue of both ulcers there was a tendency to a higher capillary density (0.67 +/- 1.40; 5.60 +/- 2.32; P < 0.0001 for venous ulcers) and a higher laser Doppler flux (1.15 +/- 0.67; 4.04 +/- 1.62; P < 0.0001 for venous ulcers) than in areas without granulation tissue. In scars of ischemic and venous ulcers capillary density (8.18 +/- 8.84; 13.60 +/- 5.45) and laser Doppler flux (1.72 +/- 1.00; 1.94 +/- 1.45) were similar (P > 0.05). In skin distant from ischemic ulcers very high capillary density (24.63 +/- 1.89) was associated with low laser Doppler flux (0.99 +/- 0.59); distant from venous ulcer capillary density was moderate (10.47 +/- 3.42) while laser Doppler flux was high (3.77 +/- 1.62; P < 0.0001 between both groups). The development and healing process of ischemic and venous ulcers is similar. Nutritive and subpapillary perfusion are involved in ulcer healing. In intact skin surrounding ischemic and venous ulcers, microcirculation is different due to the underlying pathophysiology., (Copyright 2001 Academic Press.)

Incompetence of venous valves do not lead per se to trophic skin changes of the lower limb. In severely concerned patients suffering from dermatoliposclerosis or venous leg ulcers retrograde pressure waves were detected in the nutritive capillaries of the skin by the "servo nulling" pressure measurement during simulated calf muscle contraction. Between the degree of trophic skin change and the capillary density and cutaneous oxygen partial pressure a close correlation was found. Healing of venous ulcers occurred only if the cutaneous microangiopathy in the ulcer area improved. Capillary density and transcutaneous oxygen partial pressure were of prognostic impact as to healing of venous ulcers.

Purpose: We have previously shown that fibroblasts cultured from venous ulcers display characteristics of senescence and have reduced growth rates. Susceptibility of young fibroblasts to the microcirculatory changes associated with venous ulcers, such as macrophage trapping and activation, could explain the prevalence of senescent fibroblasts in these wounds., Methods: We tested the in vitro effect of venous ulcer wound fluid (VUWF), as well as pro-inflammatory cytokines known to be present in VUWF (TNF-alpha, IL-1beta, and TGF-beta1), on neonatal foreskin fibroblasts (NFFs). NFF growth rates, cellular morphology, and senescence-associated beta-galactosidase (SA-beta-Gal) activity were determined in the presence or absence of VUWF and the above cytokines. VUWF TNF-alpha concentration and the effect of anti-TNF-alpha antibody on VUWF inhibitory activity were determined in samples obtained from four patients with venous ulcers., Results: NFF growth rates were significantly reduced by VUWF (42,727 +/- 6301 vs 3902 +/- 2191 P =. 006). TNF-alpha also significantly reduced NFF growth rates in a dose-dependent manner (P =.01). No significant growth-inhibitory activity was seen for IL-1alpha or TGF-beta. Incubation with VUWF significantly increased the percentage of SA-beta-Gal-positive fibroblasts in vitro on culture day 12 (P =.02). TNF-alpha and TGF-beta1 had similar effects. TNF-alpha was detected in all VUWF tested, with a mean of 254 +/- 19 pg/mL., Conclusion: These data suggest that the venous ulcer microenvironment adversely affects young, rapidly proliferating fibroblasts such as NFFs and induces fibroblast senescence. Pro-inflammatory cytokines such as TNF-alpha and TGF-beta1 might be involved in this process. The role of other unknown inhibitory mediators, as well as pro-inflammatory cytokines, in venous ulcer development and impaired healing must be considered.

Background: To obtain more information about microcirculatory disturbances in venous ulcers, we studied their laser Doppler flux images and capillary densities., Materials and Methods: On photographs of venous ulcers and the adjacent skin of 17 patients, four regions of interest were marked: one non-granulation tissue area (NGTA) within the venous ulcer, one granulation tissue area (GTA) within the ulcer, one adjacent skin area (ASA) and one distant skin area (DSA). Within these four regions the average laser Doppler area fluxes and capillary densities were determined for each patient using a laser Doppler imager and capillary microscopy respectively., Results: The laser Doppler area flux (mean +/- SD in AU) was significantly lower in NGTA (1.39 +/- 1.12) than in GTA (4.06 +/- 1. 52) or DSA (3.86 +/- 1.54) (P < 0.00001). In addition, the ASA flux (1.95 +/- 1.39) was significantly lower than the GTA or DSA flux (P < 0.0001). Capillary density (capillaries per mm2) in NGTA (0.82 +/- 1.98) was significantly lower than that in GTA (6.00 +/- 2.55), ASA (13.88 +/- 5.16) or DSA (10.29 +/- 3.41) (P < 0.0001). In addition, the capillary density of ASA was significantly higher than that of GTA or DSA (P < 0.05)., Conclusion: The four areas showed the following characteristics: NGTA, low laser Doppler area flux and lowest capillary density (possible sign of ulcer area without healing tendency); GTA, high laser Doppler area flux and second lowest capillary density (possible sign of wound healing); ASA, low laser Doppler area flux and highest capillary density (possible sign of healing process nearly completed; scar); DSA, high laser Doppler area flux and second highest number of capillaries (sign of microcirculation of chronic venous disorder).

In an attempt to clarify the pathophysiology of haemodynamics in legs with venous ulcer we investigated the effect of a single intermittent pneumatic compression treatment on the peripheral resistance of leg arteries and the cutaneous laser Doppler flux in the leg. Eight patients with venous leg ulcers and 10 subjects with healthy legs were investigated. Doppler waveforms of the leg arteries and laser Doppler flux of the leg skin were recorded before and after a single intermittent pneumatic compression treatment with the subjects in a recumbent position. In the legs with venous ulcer, the peripheral resistance of the arteries was lower and the laser Doppler flux was greater, compared with healthy legs (p = 0.003 and p = 0.002, respectively). A single intermittent pneumatic compression treatment raised the peripheral resistance in the arteries of legs with ulcer and laser Doppler flux of the skin more in ulcer legs than in healthy legs (p = 0.046 and p = 0.034, respectively). These findings suggest that removal of oedema causes redistribution of skin blood flow in the legs with venous ulcer favouring the superficial capillary perfusion. This could explain why compression treatment promotes the healing of venous leg ulcers.

Background: In patients with chronic venous insufficiency erythematous areas in indurated skin (hypodermitis) and non erythematous areas of lipodermatosclerosis were examined., Methods: In 13 patients with venous ulcers a total of 32 localizations in more or less erythematous and indurated ulcer edges were measured. The amount of erythema was taken as an indicator for the extent of hypodermitis. The parameters examined were erythema (a-value), skin temperature (t), laser Doppler flow (LDF), transcutaneous (tcpO2) and intracutaneous oxygen tension (icpO2). According to the amount of erythema the different localizations were separated into two groups: areas with a-values lower than 14,2 were classified as lipodermatosclerosis without or with little erythema, are-as with a-values higher than 14,2 were classified as areas of lipodermatosclerosis with extensive erythema. Identical measurements were also performed in healthy looking skin below the knee., Results: Skin temperature and LDF were higher in areas with much erythema compared to those with little or no erythema. TcpO2, measured with an electrode temperature of 44 degrees C, was lower in areas with inflammation; tcpO2-values at 37 degrees C and icpO2-values showed no differences in ulcer edges with different amounts of inflammation., Conclusion: The results show differences of microcirculation between areas of lipodermatosclerosis with and without hypodermitis. These differences did not influence the actual tissue oxygenation in deeper parts in the dermis.

Skin-derived antileukoproteinase (SKALP), also known as elafin, is a proteinase inhibitor with specificity for polymorphonuclear leucocyte (PMN)- derived elastase and proteinase-3. SKALP is absent in normal human epidermis, but is strongly induced in inflammatory dermatoses such as psoriasis. SKALP is putatively involved in the regulation of cutaneous inflammation by inhibiting PMN derived proteinases. The aim of this study was to investigate SKALP expression and PMN infiltration during wound healing in human skin. This was examined in healing excisional wounds in normal skin and in impaired healing in various types of chronic venous ulcers. Tissues were analysed using immunohistochemistry and Northern blot analysis. Healing of excisional wounds was studied from day 0 to day 14. An influx of PMN was seen rapidly after wounding and was maximal between day 2 and 4 and then subsided. SKALP was induced within 48 h and was expressed in the suprabasal keratinocytes of the wound edge and the migrating epidermal sheet. SKALP expression was maximal on day 4 and was downregulated at the time of complete reepithelialization (7-14 days). In venous ulcers, PMN were abundant in the wound bed and scarce under the wound edge. SKALP was strongly expressed in the keratinocytes of the wound edge in all types of ulcers studied. In the wound bed, SKALP was not detectable. Our results suggest that SKALP plays a role in the acute, inflammatory phase of wound healing. From the kinetics and topology of SKALP expression we surmise that it negatively regulates PMN infiltration.

Background: Chronic venous insufficiency may be associated with lipodermatosclerosis or atrophie blanche. Coagulation abnormalities may be related to these cutaneous disorders., Objective: Our purpose was to determine whether fibrinolytic abnormalities exist in patients with lipodermatosclerosis or atrophie blanche., Methods: A case control study of patients with venous disease and atrophie blanche or lipodermatosclerosis was performed. Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in a resting and venous occluded state were measured., Results: Plasma levels of PAI-1 were different between the two groups of patients. The lipodermatosclerosis group had significantly higher levels of PAI-1 in both the resting and venous occluded states (p < 0.001). Patients with atrophie blanche had milder elevations of PAI-1 in the resting and venous occluded state (p = 0.06)., Conclusion: Fibrinolytic abnormalities are present in patients with venous disease. These abnormalities are different between patients with lipodermatosclerosis and patients with atrophie blanche.

Cutaneous blood flow regulation is disturbed in severe chronic venous insufficiency (CVI). The feedback system between the transmural pressure in the postcapillary venules and the precapillary resistance regulating arterioles has gone awry. The upregulated control system causes "luxus"-hyperperfusion. In this study laser Doppler fluxmetry was performed in 6 patients' florid venous ulcers (U) and later in the former ulcer area after healing (H) and in the inner ankle area of 12 healthy volunteers (C). Laser Doppler flux (LDF) changes were measured with the leg elevated and lowered as well as after arterial and during venous occlusion. The results proved a diminished (p < 0.01) flux increase with the leg elevated (U: LDF = -9%, H: LDF = 3.1%, C: LDF = 80%) and after arterial occlusion (U: LDF = 1.3%, H: LDF = 0%; C: 189.6%) in severe CVI both in florid ulcers and after healing. The ability to reduce flux when transmural pressures were increased remained. Leg lowering reduced flux by 46.4% in ulcers and by 36.8% after healing. This postural response to high transmural pressures, however, seemed weakened compared to controls, where LDF decreased by 65.8%. Our findings suggest that the postural feedback system remains disturbed and upregulated even after a venous ulcer has healed.

Data obtained from transcutaneously measured PO2 (tcPO2) were taken as an indication for a decreased oxygen supply to the skin in patients with chronic venous insufficiency III. Direct (invasive) measurements in LDS have not yet been performed. We therefore measured the intracutaneous PO2 (icPO2) in healthy skin and LDS (8 healthy volunteers and 18 patients with CVI III) with needle probes (250 microns tip diameter). The icPO2 values were compared with data of tcPO2 (37 degrees C and 44 degrees C electrode temperature). In healthy skin the mean icPO2 was about 50 mmHg and no steep PO2 gradients were found. In LDS (ulcer edge) mean PO2 values were lower than in healthy skin, however, no hypoxia or anoxia was observed. At the same site most tcPO2 (44 degrees C) values were between 0 and 5 mmHg. The mean icPO2 values from ulcer edges of different patients ranged from 6 mmHg to 42 mmHg (mean 22 mmHg). In LDS very different PO2 profiles were seen. There was no correlation between tcPO2 and icPO2 data. Our present results may suggest that skin damage in patients with CVI is not necessary associated with hypoxia.

Chronic venous ulceration has an estimated prevalence of from 0.06 to 1.3% with about 57 to 80% of patients with leg ulcers having demonstrable venous disease. The sequence of events whereby chronic venous insufficiency leads to leg skin ulceration is not yet worked out. Venous hypertension may set the stage for subsequent ulcer development via linkages to observed changes in skin microvessel metrics, morphology, rheology, permeability, hemodynamics, and the interstitium. Periulcer measurements show decreased transcutaneous oxygen and elevated carbon dioxide tensions, yet the skin blood perfusion measured with laser Doppler fluxometry (LDF) is reported to be elevated. This elevated perfusion, (Q), could be due to independent changes in blood velocity (U), and volume (V), with different mechanistic implications depending on the mode. Thus, we sought to determine the relative contributions of these two components with the aim of clarifying the mechanism responsible for the reported skin flow changes. Patients studied (n = 16) had unilateral venous ulcers, an ankle/brachial BP index > 0.8, and venous pathology demonstrated by duplex imaging. Ulcer areas ranged from 0.6 to 76.9 cm2 (mean = 13.7 cm2) and were present for 2 to 144 months, mean = 32. With the patient supine, Q (ml/min/100 g), V (%), and U (mm/sec) were measured by LDF (Vasamedics, BPM403A) at two to three sites on periulcer skin and compared with measurements at corresponding sites on the nonulcerated limb at local skin temperatures of 35 and 44. Results confirm an elevation in basal periulcer flow (7.0 vs 1.8 ml/min/100 g, P = 0.001) and show this to be due to elevations in both circulating blood volume (1.24 vs 0.62%, P < 0.001) and velocity (1.23 vs 0.65 mm/sec, P = .004). Maximal Q, V, and U were also higher on the ulcer leg, being for Q, 11.2 vs 6.42 ml/min/100 g, P = 0.03; for V, 1.49 vs 1.13%, P = .002; and for U, 1.76 vs 1.33 mm/sec, P = 0.020. Expressing each leg's basal values as a percentage of its own maximal response shows the ulcerated leg to have higher values for Q, V, and U, with (ulcer leg/control leg) ratios being 2.5, 1.8, and 1.4, respectively. These findings show that the LDF perfusion increase is due to roughly equal increases in microvessel circulating blood volume and velocity.(ABSTRACT TRUNCATED AT 400 WORDS)

The author discusses three factors involved in venous ulceration: skin hypoxia, white-cell trapping, abnormalities in regulation of the microcirculation, eg, neuropathy. Leukocytes remain the most likely initiating factor.

Chronic venous insufficiency is a common disease with skin changes, varicosity and leg ulceration. Several theories have been proposed to explain all the changes that occur. We recently saw several patients with Klinefelter's syndrome complicated by leg ulceration and all the typical skin changes of venous insufficiency. The underlying disease was however lacking. They all showed disturbances in their fibrinolytic parameters. In this article we discuss (local) fibrinolytic disturbances as a possible factor in the pathogenesis of the skin changes in chronic venous insufficiency.

Skin damage due to chronic venous insufficiency is preceded by severe microangiopathy of skin. With increasing clinical symptoms like edema, hyperpigmentation, induration, ulcer and atrophy blanche number of nutritive capillaries and transcutaneous oxygen-tension decreases, transcapillary, and interstitial leakage increases and cutaneous vascular reserve disappears. These congruent results were found by means of capillaroscopy, fluorescence-videomicroscopy, transcutaneously measured oxygen partial pressure and Laser Doppler Fluxmetry. Most of capillaries are elongated and tortuous, especially in ulcer stage they look glomerular. Compared to pin-shaped capillaries glomerular capillaries contribute less to nutrition because of functional AV-shunts. As dilated capillaries are already seen in skin areas without any trophic skin changes, cutaneous microangiopathy seems to be first consequence of venous hemodynamic disturbances which then is followed by skin disease. As severe microangiopathy still remains after healing of ulcer, it explains frequent recurrencies.

Abnormalities of vasomotion, impairment of the venoarteriolar reflex and increased skin blood flow reported in the liposclerotic skin of patients with chronic venous insufficiency (CVI) suggest altered nervous control of the skin microcirculation. The aim of this study was to determine whether patients with CVI have a peripheral neuropathy. Forty patients with CVI and lipodermatosclerosis (LDS) and 35 age and sex-matched controls were examined for neuropathy using three modalities of testing. Threshold to warming was used to assess unmyelinated fibres, and threshold to cooling and vibration to assess myelinated fibres. Warming and cooling thresholds were measured on the sole of the foot by a purpose built, computer controlled instrument. The threshold to vibration was measured on the big toe using the Ohio Bio-thesiometer. A significantly raised threshold to warming and vibration was found in the CVI group compared to the normal controls [median threshold to warming (interquartile range) in CVI group = 5.3 (0.1-9.1) median threshold to warming (interquartile range) in controls = 1.21 (0.17-3.5), p = 0.005 and median threshold to vibration (interquartile range) in CVI group = 22 (13-31) median threshold to vibration (interquartile range) in controls = 12 (8.5-27.5), p = 0.024]. The thresholds to cooling was not statistically different in the two groups. This study demonstrates the presence of a peripheral neuropathy in patients with chronic venous insufficiency, and this may be important in the pathogenesis of venous ulceration.

Chronic venous insufficiency (CVI) leads to morphological and functional changes in nutritive capillaries resulting in disturbances of the nutrition of the skin. Up to now, data obtained from transcutaneous measured pO2 were taken as an indication for a decreased oxygen supply to the skin. With the aim of obtaining direct information on the tissue oxygenation of dermis and subcutis we have measured the distribution of tissue pO2 values with needle probes (300 microns tip diameter, Eppendorf-Netheler-Hinz-GmbH, Hamburg). 12 patients with CVI III and 8 healthy volunteers were included in this study. The needle probes were inserted into the skin of the proximal third of the lower leg and, in patients, in the areas with mild and with severe sclerosis (ulcer edge). The pO2 data from the needle probes were compared with pO2 data obtained from transcutaneous surface probes (tcpO2) and with data from laser doppler flux measurements LDF). In clinically healthy skin the intracutaneously measured pO2 (icpO2) was 51 +/- 7 mmHg (mean +/- S.D.) and the subcutaneously measured pO2 (scpO2) was 47 +/- 8 mmHg. In lipodermatosclerosis invasively determined pO2-values were lower than in healthy skin, however, no hypoxic or anoxic values were found. Compared with tcpO2-values there was no considerable difference between icpO2-values measured in mild sclerosis and severe sclerosis (icpO2 28 mmHg as compared to 25 mmHg; scpO2 31 mmHg as compared to 27 mmHg). The icpO2 values obtained from the edge of the ulcer showed a large variation from patient to patient (6 mmHg to 42 mmHg). There was no correlation between the pO2 data and the LDF-values.

There are instances when chronic disease states manifest as microvascular disturbances of the skin. Objective assessment of these disturbances would permit a better understanding of the causative factors and, in certain circumstances, influence decisions of clinical management. Recent advances in technology that permit such assessment non-invasively are evaluated in this review.

The function of cutaneous primary afferent unmyelinated nerves (C-fibres) was assessed by measuring axon reflex vasodilatation in the skin over the arms and feet of 15 elderly patients with chronic venous ulcers using a laser Doppler flowmeter. Dilatation of skin microvasculature in response to nerve-independent stimuli was also assessed. Results were compared with those of control subjects matched for age and sex. The chronic venous ulcer group showed reduced axon reflex vasodilatation in the feet but not the arms. Response to nerve-independent vasodilators was similar in both ulcer patients and controls in arms and feet. Local impairment of C-fibre function may partly explain the increased incidence and resistance to healing of leg ulcers in old people.

White blood cells have recently been implicated in the development of venous ulceration. Fifty subjects (14 normal controls, 21 with superficial venous insufficiency (SVI), and 15 with deep venous insufficiency (DVI] have been studied in the supine and dependent positions in a constant environment using video capillary microscopy, laser Doppler flowmetry and transcutaneous oxygen measurements to the gaiter skin. All three groups had an increase in visible capillary loops and a reduction in blood flux in the gaiter region when the leg was placed in the dependent position. There was a decrease in the leg/chest transcutaneous oxygen ratio in all three groups on dependency. These results suggest that the 'oedema protection reflex' (as measured by the laser Doppler probe) is present not only in normal and SVI limbs but also in DVI limbs. The increase in visible capillary loops suggests that intraluminal capillary occlusion is not occurring within the period of this study. The exact microvascular defecit of venous ulceration remains to be explained.

We examined the levels of oxygen on the skin of the gaiter areas of limbs with venous disease using a Roche Transcutaneous pO2 Monitor to determine whether hypoxia contributes to the skin changes and ulceration associated with severe venous disease. We studied patients with superficial varicose veins and no skin changes (Group 1: n = 25), patients with skin changes and healed ulcers (Group 2: n = 15), and an age matched normal control group (controls: n = 25). TcpO2 measurements were taken 5 cm above the medial malleolus with the limb both horizontal and vertical using a Roche Transcutaneous pO2 Monitor. A standard heel-raising test using a Medisonics Photoplethysmograph indicated the degree of venous insufficiency present. Results show that Group 1 patients and controls have similar skin oxygen levels (Group 1: TcpO2 66.48 + 14.12 mmHg; controls: TcpO2 61.60 +/- 11.02 mmHg) whereas those with skin changes and ulceration have significantly lower oxygen levels (Group 2: TcpO2 46.57 +/- 9.70 mmHg, t = 4.29, P less than 0.001). Group 2 patients did not show a significant rise in TcpO2 levels in the standing position whereas Group 1 patients and controls did (t = 2.6, P less than 0.02). PPG post-exercise recovery times confirmed differences between the three groups. These findings show that significant skin hypoxia occurs on the gaiter area of limbs with severe venous disease and support the concept of an oxygen diffusion block.

The changes in foot vein pressure during exercise have been measured in 30 normal legs and 109 legs with varicose veins or postphlebitic changes and correlated with the number of capillaries visible in a histological section of skin from the ulcer-bearing area. There was a significant correlation between the inability of the calf pump to reduce foot vein pressure during exercise and the number of capillaries in the skin. It is suggested that the increased number of capillaries secondary to venous hypertension during exercise may be the prime cause of the nutritional abnormalities that eventually cause a venous ulcer.

It was with ochre dermatitis that the clinical notion of "capillaritis" was first put forward, but in what sense is it still possible today to speak of "capillaritic ulcer"? Although some special characteristics have been ascribed to it, this ulcer is derived from a microvascular and tissue reaction to venous stasis, whether the latter is primary due to varicose veins or secondary due to "post-thrombotic syndrome" or obliterative arteriopathy of the supplying trunks and especially the nutritional branches of the dermohypodermic network. This type of ulcer involves the Circulatory Unit and is expressed by an imbalance in irrigation, the result of a whole sequence of capillary closures and anastomotic openings, of which the "mosaic" appearance on infra-red thermography is evidence. It is a stasis ulcer in which the mode of distribution of the capillaries is involved just as much as the thickness of the skin of the groove of Bisgaard, but it is the result of the majority of the angiopathic states of the lower limb.

The aetiology of lower limb ulcers is often the result of intricate vascular pathology and the quality of the peri-ulcer microcirculation is a major factor in the prognosis of the disease. We measured the skin perfusion pressure (S.P.P.) using an infra-red photoplethysmograph of the PPG type (ESM, Mauguio, France). The study included 30 healthy subjects, 25 patients with leg ulcers of varied etiology (venous: 14, arterial: 11), and 15 patients with uncomplicated varicose veins. Measurements were undertaken in dorsal decubitus position after a 15 minute rest. The S.P.P. was expressed as the percentage of humeral blood pressure. The results showed an important decrease of S.P.P. in patients with arterial ulcers when compared to patients with healthy legs (39.9 +/- 16.4% and 82.8 +/- 10.0% respectively). The S.P.P. values were intermediate (54.4 +/- 19.3%) in patients with venous ulcers while they were normal in the patients with uncomplicated varicose veins (87.3 +/- 12.3%). Among this population, 18 patients (11 with uncomplicated varicose veins and 7 with venous ulcers) were investigated before and after a one month treatment with a flavonoid (Daflon 500 mg, 2 tablets per day). An increase of S.P.P. to normal values after treatment was found in patients with venous ulcers though not in patients with varicose veins. This non invasive procedure appreciating the microcirculation status in peri-ulcerous skin could be of predictive value for the healing potential. It could be a good method to assess the efficacy of vasculotropic agents.