Rationale and current evidence of aquatic exercise therapy in venous disease: A narrative review.

Chronic venous disorders (CVD) of the lower limbs can be treated with different strategies. Typically, conservative management is based on compression therapy, anticoagulants and venoactive drugs. Endovenous treatments remain the gold standard to treat saphenous insufficiency, with sclerotherapy and surgery maintaining a role in selected cases. In addition, several 'unconventional' approaches have been proposed to prevent CVD progression and complications, minimize symptoms and improve the quality of life and postoperative outcomes. Among these, balneotherapy and aquatic exercises are proving as valid and effective supporting treatments, as mentioned in a growing number of scientific publications. Moreover, aquatic protocols have been studied for both venous and lymphatic insufficiency. For these reasons, they were mentioned in the last CVD guidelines provided by the European Society for Vascular Surgery. The aim of this narrative review is to overview and summarize current literature evidences on the role and effectiveness of aquatic rehabilitative protocols in CVD, reviewing old and current literature. Furthermore, the physical basis of the effects of water immersion on lower limb venous and tissues modifications are also described.

Compression Stocking With 100% Donning and Doffing Success: An Open Label Randomised Controlled Trial.

OBJECTIVE: The aim of this study was to test whether an investigational two layer stocking exerting 27-29 mmHg pressure at the medial supramalleolar level, but without compression in the foot and heel, is easier to put on and take off than a standard stocking of the same compression class (23-32 mmHg), and also to assess the prevention of diurnal oedema with both types of stocking. METHODS: This was an open label randomised controlled trial, which included 47 patients. All participants were at least 65 years of age and suffered from chronic venous disease class C3 - C6 in one leg. The primary end point was donning success; secondary endpoints were doffing success, prevention of diurnal oedema over one day, and the comfort of wearing the stocking. Patients were randomly allocated to one of two groups. Both types of compression stocking were compared in each group for ease of donning and doffing in the manner of a crossover study. Subsequently, patients wore the stocking type assigned to their group for a whole day to evaluate comfort and the effect on diurnal leg volume. RESULTS: All participants were able to don the investigational stocking unaided, compared with 75% for the standard stocking (p < .001). Unaided removal success was 100% with the investigational stocking vs. 66% for the standard stocking (p < .001). There was no significant difference in leg volume reduction between the study groups after a day of wear. The investigational stocking was also rated as being more comfortable than the standard stocking (p < .001). CONCLUSION: The investigational stocking, which has no compression in the foot or heel area, is significantly easier to don and doff, with no inferiority in oedema prevention, compared with a standard stocking of the same compression class.

Cadaveric Skin Grafts May Greatly Increase the Healing Rate of Recalcitrant Ulcers When Used Both Alone and in Combination With Split-Thickness Skin Grafts.

BACKGROUND: Leg ulcers that do not heal despite appropriate treatment are defined as recalcitrant ulcers. Large surface area, depth, and long duration represent some of most important factors impeding ulcer healing. After sharp debridement, dermal substitutes including skin from cadaver donors may increase the healing rate of recalcitrant ulcers reducing the risk of scar formation and recurrence. OBJECTIVE: Assessing if, after sharp debridement, dermal substitutes including skin from cadaver donors may increase the healing rate of recalcitrant ulcers reducing the risk of scar formation and recurrence. PATIENTS AND METHODS: Among patients admitted to our hospital for all types of chronic leg ulcers, we retrospectively reviewed the records of patients affected by recalcitrant ulcers (surface greater than 100 cm, tissue loss involving epidermis, dermis, and subcutaneous tissue, duration longer than 1 year, and showing no healing tendency). After sharp debridement, the ulcers were covered by allografts with strict follow-up after discharge. Multiple allografts were performed when necessary, and a final autograft was applied in case of incomplete healing. RESULTS: The records of 414 patients were analyzed. Forty-three patients were lost at follow-up, and the remaining 371 healed after 765 grafting procedures. In 163 patients, the ulcers healed by means of a final autograft. In all the remaining cases, allograft led to ulcer healing. CONCLUSION: Allografts represent an effective treatment option in case of recalcitrant, large, deep and long-lasting leg ulcers.

A Wearable Compression Device to Normalise Calf Muscle Pump Function in Chronic Venous Insufficiency for Each Postural Position.

BACKGROUND: For the currently used compression therapy, the applied compression pressure is usually inadequate to exert an effective impact on the veins in different body positions. The aim was to assess the venous ejection fraction achieved by a new compression device which automatically adjusts the interface pressure to body position in an acute experimental setting. METHODS: A new portable, battery driven compression device providing pressure adjusted to allow for body position, and connected to a less or very stiff calf cuff wrap was tested. In patients with superficial venous incompetence, the ejection fraction (EF) of the calf pump was measured by strain gauge plethysmography. Applied in a random sequence, values achieved without compression, with the two cuffs, and with compression stockings exerting 23-32 mmHg, were compared. The applied compression pressures were simultaneously recorded in the supine and standing positions, and during walking. Comfort was assessed by a visual analogue scale (VAS) with 0 corresponding to very low comfort and 10 to very comfortable. RESULTS: In 16 patients with CEAP clinical stage C3-C6, EF without compression was 37%, increasing to 46.9% with stockings, to 64.8% (p < .001) by less stiff and to 75.5% (p < .001) by stiffer wraps. The median interface pressure (supine/standing) was 31/56 mmHg for the less stiff device, 32/68 mmHg for the stiffer device, and 23/26 mmHg for the stockings. The static stiffness index and the walking pressure amplitudes were significantly higher than those generated by the stocking, and the highest values were found with the stiffer wrap material. The device comfort was high both in the supine and standing positions (VAS 8 ± 2). CONCLUSIONS: The tested devices were comfortable at rest and haemodynamically effective during walking by automatically adjusting compression pressures to body position. They are significantly more effective than elastic stockings in improving EF. The system is able to overcome the problems of fast pressure loss by continuously re-adjusting the compression pressure.

A New Two Component Compression System Turning an Elastic Bandage into an Inelastic Compression Device: Interface Pressure, Stiffness, and Haemodynamic Effectiveness.

INTRODUCTION: Bandage application does not exert consistent compression pressure, leading to extremely variable compression when applied to patients. A new elastic bandage can exert a predefined pressure independently of healthcare providers and the size of the wrapped limb. The bandage system includes a series of non-stretchable patches that when applied to the bandage make it stiff. The aim of this work was to assess, in an experimental setting, the venous ejection fraction (EF) from the lower leg and the tolerability of this new bandage in a group of patients affected by superficial venous incompetence. METHODS: EF was measured using strain gauge plethysmography under baseline conditions and the bandage was applied with a supine pressure of 20 and 30 mmHg, with and without the stiff patches, in 25 patients with severe venous reflux in the great saphenous vein. The interface pressure of the bandages was measured simultaneously in the medial gaiter area. RESULTS: All patients showed EF values that were significantly reduced compared with normal individuals. Elastic bandages with an average pressure of 20 and 30 mmHg in the supine position achieved a slight improvement in EF, and, after applying non-stretchable patches on the same bandage with similar resting pressure, EF was restored to its normal range (p < .001). Improvement in EF correlates with the pressure differences between standing and lying pressure and between muscle systole and diastole during exercise. CONCLUSION: This study confirms that inelastic is much more effective than elastic compression for improving impaired venous haemodynamics. The test material can be applied with a predetermined pressure, which considerably enhances the consistency of application, and it is easily transformed into an inelastic system just by applying stiff patches without any stretch and without significantly increasing the comfortable supine pressure.

Photodynamic therapy in infected venous and mixed leg ulcers: a pilot experience.

OBJECTIVE: To assess the tolerability and efficacy of photodynamic therapy (PDT) with RLP068, a novel phthalocyanine-derived photosensitiser, in controlling the bacterial load in different leg ulcers, due to vascular pathophysiology. METHOD: An observational study of patients with infected leg ulcers of different pathophysiology, admitted to the hospital for a skin grafting procedure, were included. All patients underwent two sessions of PDT at time zero and after 72 hours. A semi-quantitative swab was taken before and 30 minutes after both sessions of PTD. During the time interval between the two treatments the ulcer was covered with foam dressing and compression therapy was applied to all patients. No systemic or topical antibiotics were administered. Statistical analysis of results was performed. RESULTS: A total of 36 patients (13 males, 23 females; aged 72.4±8.6 years, range: 55-85 years) were recruited; two had ulcers on both legs. PDT was shown to be effective in reducing bacterial load after the first treatment. Before the second PDT treatment (72 hours after first PDT treatment), a slight increase of the bacterial load was observed in all ulcers. However, after the second PDT session, bacterial swab results were negative in all but two ulcers. The procedure was well tolerated in all but four patients, who reported a very severe pain at baseline, which increased during treatment. CONCLUSION: In this study, PDT was effective in reducing bacterial load in patients with infected vascular leg ulcers, and allowed successful skin grafting to take place in all patients. The treatment was generally well tolerated. Studies with a greater number of patients and a control group are planned to confirm these results.

Chronic venous disease - Part II: Proteolytic biomarkers in wound healing.

Venous leg ulcers (VLU) are characterized by sustained proteolytic microenvironment impairing the healing process. Wound fluid (WF) reflect the biomolecular activities occurring within the wound area; however, it is unclear if WF from different healing phases have different proteolytic profiles and how VLU microenvironment affects the wound healing mechanisms. We investigated the proteolytic network of WF from distinct VLU phases, and in WF- and LPS-stimulated THP-1 monocytes treated with glycosaminoglycan sulodexide, a well known therapeutic approach for VLU healing. WF were collected from patients with VLU during inflammatory (Infl) and granulating (Gran) phases. WF and THP-1 supernatants were analyzed for nine matrix metalloproteinases (MMP) and four tissue inhibitors of metalloproteinases (TIMP) by multiplex immunoassays. Our results demonstrated that: 1) WF from Infl VLU contained significantly increased concentrations of MMP-2, MMP-9, MMP-12, TIMP-1, and TIMP-2 compared to Gran WF; 2) WF from Gran VLU showed significantly increased levels of MMP-1, MMP-7, MMP-13, and TIMP-4 compared to Infl WF; 3) LPS- and WF-stimulation of THP-1 cells significantly increased the expression of several MMP compared to untreated cells; 4) Sulodexide treatment of both LPS- and WF-stimulated THP-1 significantly down-regulated the release of several MMPs. Our study provides evidence-based medicine during treatment of patients with VLU. WF from Infl and Gran VLU have different MMP and TIMP signatures, consistent with their clinical state. The modulation of proteolytic pathways in wound microenvironment by glycosaminoglycan sulodexide, provide insights for translating research into clinical practice during VLU therapy.

Chronic venous disease - Part I: Inflammatory biomarkers in wound healing.

Venous leg ulcers (VLUs) produce wound fluid (WF), as a result of inflammatory processes within the wound. It is unclear if WF from different healing phases of VLU has a peculiar biochemical profile and how VLU microenvironment affects the wound healing mechanisms. This study was conducted to evaluate the cytokine/chemokine profiles in WF from distinct VLU phases, in WF- and LPS-stimulated monocytes and treated with glycosaminoglycan Sulodexide, a therapeutic option for VLU healing. WF and plasma were collected from patients with VLU during active inflammatory (Infl) and granulating (Gran) phases. Demographics, clinical characteristics and pain measurements were evaluated. WF, plasma, and THP-1 supernatants were analyzed for 27 inflammatory mediators by multiplex immunoassay. Our results demonstrated that: 1) pain was significantly increased in patients with Infl compared to Gran VLU; 2) cytokine profile of Infl WF was found to be statistically different from that Gran WF, as well significantly increased respect to plasma; 3) LPS- and WF-stimulation of THP-1 cells significantly increased the expression of several cytokines compared to untreated cells; 4) Sulodexide treatment of both LPS- and WF-stimulated THP-1 monocytes was able to significantly down-regulate the release of peculiar inflammatory mediators. Our study highlighted the importance to understand biomolecular processes underlying CVI when providing treatment for chronic VLU. Identification of inflammatory biomarkers in leg ulcer microenvironment, may provide useful tools for predicting healing outcome and developing targeted therapies.

Catheter Foam Sclerotherapy of the Great Saphenous Vein, with Perisaphenous Tumescence Infiltration and Saphenous Irrigation.

OBJECTIVES: This was a prospective observational study to assess the short- to mid-term efficacy and safety of catheter foam sclerotherapy (CFS) of the great saphenous vein (GSV), including peri-saphenous tumescence infiltration (PST) and intra-saphenous saline irrigation (ISI), in combination with phlebectomy of the varicose tributaries. METHODS: Eighty-eight limbs in 82 patients (19 male, 63 female, mean age 55.7 years) affected by varices related to GSV incompetence were submitted to CFS of the refluxing GSV segment after PST and ISI, combined with phlebectomy of the varicose tributaries. Sodium tetradecylsulfate (STS) 3% + CO2/O2 sclerosant foam (SF) (median 7 mL) was injected in the GSV trunk (median caliber 7.1 mm) by means of a 4F catheter. Clinical and colour duplex ultrasound (CDU) investigation was performed pre-operatively, and 40 days, 6, 12, and 36 months post-operatively. A visual analogue scale (VAS) was used to assess procedure related symptoms and venous symptoms before and 40 days after the treatment. RESULTS: Clinical recurrence (visible varices) at 40 days, 6 and 12 months was 0%, whereas at 36 months it was 4.7%; VAS pre-operative score of heaviness, pain, and cramps/paraesthesiae decreased from 6 (IQR 6-8) to 1 (IQR 0-3), from 3 (IQR 0-7) to 0 (IQR 0-1), and from 3 (IQR 0-7) to 0 (IQR 0-1) respectively at 40 days. The CDU based occlusion rate at 40 days, 6, 12, and 36 months was 100% (88/88), 100% (88/88), 94.3% (83/88), and 89.4% (76/85) respectively. Six of the nine patent saphenous veins (average diameter 1.4 mm) had anterograde flow (overall 96.5% reflux free GSVs). One superficial venous thrombosis was recorded without any further relevant complication. CONCLUSIONS: GSV treatment by means of CFS and adjuvant PST + ISI, combined with phlebectomy of varicose tributaries, proved to be safe and effective in terms of clinical and duplex based outcomes at short/mid-term follow-up.

Chronic Venous Insufficiency: Transforming Growth Factor-ß Isoforms and Soluble Endoglin Concentration in Different States of Wound Healing.

Venous leg ulcer (VLU) is a huge healthcare problem with poorly understood pathophysiology. Transforming growth factor-ß (TGF-ß) and endoglin (Eng), are inflammatory and wound healing mediators. Eng, co-receptor for TGF-ß type-II receptors, may be cleaved forming soluble Eng (sEng), antagonizing TGF-ß signaling, a crucial process in vascular pathologies. We evaluated the accumulation in wound fluid (WF) of TGF-ß isoforms and sEng in healing stages, showing the effects of sulodexide treatments, a glycosaminoglycan with clinical efficacy in VLU healing. Patients with inflammatory (Infl) and granulating (Gran) VLU were recruited. WFs and THP-1 monocytes exposed to Infl and Gran WF (treated/untreated with sulodexide) were analyzed for TGF-ß isoforms and sEng by multiplex immunoassay. In both Infl and Gran WF, TGF-ß1 and ß2 were similar; TGF-ß3 was significantly increased in Infl compared to Gran WFs (p = 0.033). sEng was significantly elevated in Gran compared to Infl WFs (p = 0.002). In THP-1 monocytes there was a significant increase in sEng after co-treatment of WF and sulodexide. The increase in TGF-ß3 found in Infl WF highlights its negative effect on wound healing, while the increased levels of sEng in Gran WF affects the leukocyte adhesion/transmigration through the endothelium, reducing the inflammatory response and favoring the wound healing. Glycosaminoglycan sulodexide potentiates the effects of sEng release from monocyte, representing an important therapeutic option for wound healing.

Management of Patients With Venous Leg Ulcers: Challenges and Current Best Practice.

Introduction It is well documented that the prevalence of venous leg ulcers (VLUs) is increasing, coinciding with an ageing population. Accurate global prevalence of VLUs is difficult to estimate due to the range of methodologies used in studies and accuracy of reporting. (1) Venous ulceration is the most common type of leg ulceration and a significant clinical problem, affecting approximately 1% of the population and 3% of people over 80 years of age (2) in westernised countries. Moreover, the global prevalence of VLUs is predicted to escalate dramatically, as people are living longer, often with multiple comorbidities. Recent figures on the prevalence of VLUs are based on a small number of studies, conducted in Western countries, and the evidence is weak. However, it is estimated that 93% of VLUs will heal in 12 months, and 7% remain unhealed after five years. (3) Furthermore, the recurrence rate within 3 months after wound closure is as high as 70%. (4) (-6) Thus, cost-effective adjunct evidence-based treatment strategies and services are needed to help prevent these ulcers, facilitate healing when they occur and prevent recurrence. The impact of a VLU represents social, personal, financial and psychological costs on the individual and further economic drain on the health-care system. This brings the challenge of providing a standardised leg ulcer service which delivers evidence-based treatment for the patient and their ulcer. It is recognised there are variations in practice and barriers preventing the implementation of best practice. There are patients not receiving appropriate and timely treatment in the initial development of VLUs, effective management of their VLU and preventing recurrence once the VLU has healed. Health-care professionals (HCPs) and organisations must have confidence in the development process of clinical practice guidelines and have ownership of these guidelines to ensure those of the highest quality guide their practice. These systematic judgments can assist in policy development, and decision making, improve communication, reduce errors and improve patient outcomes. There is an abundance of studies and guidelines that are available and regularly updated, however, there is still variation in the quality of the services offered to patients with a VLU. There are also variations in the evidence and some recommendations contradict each other, which can cause confusion and be a barrier to implementation. (7) The difference in health-care organisational structures, management support and the responsibility of VLU management can vary in different countries, often causing confusion and a barrier to seeking treatment. These factors further complicate the guideline implementation process, which is generally known to be a challenge with many diseases. (8).

A large Italian observational multicentre study on vascular ulcers of the lower limbs (Studio Ulcere Vascolari).

An observational study of 2 years was promoted by the Italian Association for Cutaneous Ulcers (AIUC) in order to monitor the epidemiology of leg ulcers, the trend of healing and the more frequent therapeutic approaches in lower limb ulcers. Fifty-nine sites in 14 different Italian regions involved in the study, with 1333 enrolled patients (1163 patients fully evaluated and followed up for 9 months). A prevalence of females (62%) was observed with a mean age of 70 years and a high rate of hypertension (62%), diabetes (38%) and obesity (29%). Venous ulcer was most frequent (55%), followed by mixed (25%) and diabetic (8·3%) ulcers. Basically, all patients received a local therapy (LT) (compression and advanced local therapies), while 63% of patients have an associated systemic pharmaceutical treatment. Ulcer healing rates progressively increased throughout the study and despite the type of observational study does not allow conclusions on the treatment, it was observed that the patients receiving additional systemic drugs were associated with a more rapid acceleration of healing rates of ulcers compared to LT alone (3 months: 39·7% versus 29·2%; 6 months: 62·0% versus 47·0%; 9 months: 74·7% versus 63·8%). In particular, the Studio Ulcere Vascolari (SUV) study showed that a combination treatment with sulodexide and compression therapy allows for a greater increase in the healing rates in venous ulcers.

Black holes in compression therapy: A quest for data.

OBJECTIVE: Although compression therapy (CT) is considered a crucial conservative treatment in chronic venous disease, strong evidence is missing for many clinical indications. This literature review aims to point out what strong evidence we have for CT and all the clinical scenarios where strong evidence still needs to be included. METHODS: The research was conducted on MEDLINE with PubMed, Scopus and Web of Science. The time range was set between January 1980 and October 2022. Only articles in English were included. RESULTS: The main problem with CT is the low scientific quality of many studies on compression. Consequently, we have robust data on the effectiveness of CT only for advanced venous insufficiency (C3-C6), deep vein thrombosis and lymphedema. We have data on the efficacy of compression for venous symptoms control and in sports recovery, but the low quality of studies cannot result in a strong recommendation. For compression in postvenous procedures, superficial venous thrombosis, thromboprophylaxis, post-thrombotic syndrome prevention and treatment, and sports performance, we have either no data or very debated data not allowing any recommendation. CONCLUSIONS: We need high-level scientific studies to assess if CT can be effective or definitely ineffective in the clinical indications where we still have a paucity of or contrasting data.

Segmental differences in daytime changes of leg volume.

BACKGROUND: The aim of our study was to comparatively assess volume changes related to daily occupation of the whole leg (WLv), of the lower leg (LLv) and of the upper leg (ULv) in subject with no venous and lymphatic disorders. METHOD: WLv, LLv, and Ulv were evaluated by water displacement volumetry (WDV) in the morning and in the evening in 20 healthy subjects. RESULTS: In the legs with occupational edema (OE), WLv increased by 7.07%, LLv by 5.25%, and ULv by 9.80%. In legs without clear OE, WLv increased by 2.41%, LLv by 1.35, and ULv by 3.38%. CONCLUSIONS: Surprisingly, the increase of ULv was greater than that of LLv. An evening increase in the leg volume also occurred in legs with no clear OE. In our series, a clinically evident OE was related to an increase of the WLv, LLv, and ULv greater than 5.83%, 8.68%, and 1.88%, respectively.

Pressure and stiffness of a new air-inflated compression wrap.

OBJECTIVE: To report pressure and stiffness, in healthy volunteers, of a new compression device with an air bladder inflated by a pump to regulate pressure. METHODS: The device was applied to 60 legs of 30 volunteers and set to exert different pressures of 20-50 mmHg. The exerted pressure was measured in supine and standing positions and during simple physical exercises; static stiffness index, dynamic stiffness index, and walking pressure amplitudes were calculated. RESULTS: The exerted pressure showed a good correlation with the expected pressure at each pressure range. The stiffness indices were >10 mmHg in the range of inelastic materials. The device was considered very easy to apply and use by the testing researchers. CONCLUSIONS: The device stiffness is in the same range as the inelastic bandages. Consequently, similar hemodynamic effectiveness could be expected but must be proved. Unlike inelastic bandages, this device was easy to apply and use.