Mechanisms in experimental venous valve failure and their modification by Daflon 500 mg.

OBJECTIVES: To characterize the acute response of the vein wall to venous hypertension and associated altered fluid shear stress and to test the effect of micronized purified flavonoid fraction (MPFF, Daflon 500), on this response. MATERIAL AND METHODS: A femoral arteriovenous fistula was created in Wistar rats (n=48). A cohort of 24 rats received oral treatment with MPFF (100 mg/kg/day body weight), 24 rats underwent the arteriovenous fistula procedure and received no treatment. At days 1, 7 and 21 the animals (n=8 at each time point) were killed. Experimental parameters measured included limb circumference, blood flow at the sapheno-femoral junction, leukocyte infiltration and gelatinase activity (matrix metalloproteinase, MMP). RESULTS: The acute rise in venous hypertension was accompanied by limb edema and venous reflux together with an eventual loss of valve leaflets in the saphenous vein. There was an increase in granulocyte and macrophage infiltration into the venous wall and the surrounding tissue, and a lesser increase in T- and B-lymphocyte infiltration. These changes were accompanied by a local increase in the proteolytic enzymes, MMP-2 and MMP-9. Administration of MPFF reduced the edema and lessened the venous reflux produced by the acute arteriovenous fistula. Decreased levels of granulocyte and macrophage infiltration into the valves were also observed compared with untreated animals. CONCLUSIONS: Venous hypertension caused by an arteriovenous fistula resulted in the development of venous reflux and an inflammatory reaction in venous valves culminating in their destruction. MPFF was able to delay the development of reflux and suppress damage to the valve structures in this rat model of venous hypertension.

New clinical and laboratory staging systems to improve management of chronic lymphedema.

We have developed new clinical (C) and laboratory (L) staging systems to improve the clinical management of chronic lymphedema. These systems were retrospectively assessed in 220 chronic lymphedema patients followed up for 4 years. Clinical evaluation of the treatment response/disease progression was performed at 6 month intervals and laboratory evaluation at a yearly interval except for recurrent sepsis cases. The reliability of C-stage and L-stage for the progression of disease were analyzed separately. The C-staging was based on the subjective and objective findings of local and systemic conditions, while L-staging was based on lymphoscintigraphicfindings. Clinical implementation of this new staging system facilitated interpretation of the progress/deterioration of the clinical response to CDT treatment, and it was found to be a useful guideline for the decision/selection of further surgical treatment. We propose that these two separate staging systems could now become a new guideline for improved management of lymphedema with a better prediction of treatment outcome and decision point for additional medical/surgical therapy. Further clinical implementation and evaluation is necessary to demonstrate clinical usefulness especially to guide surgical therapy and L-staging in followup.

Venous hypertension, inflammation and valve remodeling.

OBJECTIVES: To identify possible mechanisms for destruction of valves in chronic venous hypertension and the results of treatment with an anti-inflammatory micronized purified flavonoid fraction. MATERIAL AND METHODS: The saphenous vein valves in a rat model of venous hypertension caused by a femoral arterial-venous fistula were studied. Studies included femoral venous pressure, valve morphology, femoral venous reflux and selected molecular inflammatory markers as examined by immunohistochemistry. The effects of treatment with the anti-inflammatory micronized purified flavonoid fraction (S 5628, Servier, 50 and 100 mg/kg/day) were investigated. RESULTS: The femoral venous pressure was elevated close to arterial values for a period of 3 weeks. We then examined the morphology of the veins and selected molecular inflammatory markers were assessed. The results show that in this model venous reflux develops in response to venous hypertension. This can be inhibited by the administration of the anti-inflammatory micronized purified flavonoid fraction (S 5628, Servier, 50 and 100 mg/kg/day). The valve becomes incompetent by a combination of venous dilation and shortening of the valve leaflets. This is not inhibited by treatment with S 5628. The valve leaflets are infiltrated with granulocytes, monocytes and T-lymphocytes, and the endothelial cells express enhanced levels of P-selectin and ICAM-1. Cells in the valves are subject to extensive apoptosis although no enhancement of MMP 2,9 expression could be detected at the three-week time point examined in this study. CONCLUSIONS: These results indicate that in this model chronic elevation of venous pressure is associated with an inflammatory reaction in venous valves, a process that may lead to their dysfunction, reflux, and upstream elevation of venous pressure. These effects are mitigated by the anti-inflammatory micronized purified flavonoid fraction in a dose dependent manner.

Treatment of varicose veins: proximal saphenofemoral ligation comparing adjunctive varicose phlebectomy with sclerotherapy at a military medical center.

There is no consensus as to the single best approach to the treatment of varicose veins. There has been a trend toward less invasive procedures to reduce the number of incisions and provide more selective ablation of varicosities. Ultimately, therapeutic decisions have depended on surgeon preference and the patient population. The active duty military population presents a unique challenge in the treatment of varicose veins. This mobile and active population requires a treatment method that provides maximum relief with the lowest possible morbidity and rapid recovery. The authors previously reported their experience with 104 patients who underwent saphenofemoral ligation combined with perforator point ligation and staged sclerotherapy. This group was compared to 103 patients who underwent saphenofemoral ligation, point perforator ligation, and stab avulsion phlebectomy as a single procedure. Follow-up for the sclerotherapy group included patient satisfaction surveys and documentation of recurrent varicosities. All ambulatory phlebectomy patients responded positively with respect to symptomatic and cosmetic results. Overall satisfaction was favorable and there was no significant difference in patient satisfaction between the ambulatory phlebectomy and sclerotherapy groups. Twelve per cent of the sclerotherapy patients developed true recurrences or new varicosities compared to 11% in the ambulatory phlebectomy group. The most common complication was superficial thrombophlebitis (20% ambulatory phlebectomy, 16% sclerotherapy) which was mild in all cases. All but three patients in the ambulatory phlebectomy group returned to work within 7 days and 75% returned to full duty within 72 hours. Completion of therapy was accomplished in a much shorter period for the ambulatory phlebectomy group. Overall patient satisfaction was achieved for both ambulatory phlebectomy and sclerotherapy patients. Completion of therapy was achieved in a shorter period with fewer clinic visits in the ambulatory phlebectomy group and this has become our procedure of choice for active duty military patients.

New advances in the understanding of the pathophysiology of chronic venous insufficiency.

Chronic venous insufficiency (CVI) is inseparably linked to elevated venous pressure and is accompanied by vascular, dermal, and subcutaneous tissue damage and restructuring. Abundant evidence exists both in humans and in experimental models to suggest that the tissue damage may be initiated by generation of an inflammatory reaction. Inflammatory indicators include elevation of endothelial permeability; attachment of circulating leukocytes to the endothelium; infiltration of monocytes, lymphocytes, and mast cells into the connective tissue; and development of fibrotic tissue infiltrates and several molecular markers, such as growth factor or membrane adhesion molecule generation. Indicators of an inflammatory reaction are already detectable at early stages of CVI and may be involved in the development of primary venous valve dysfunction. One of the important questions is to identify trigger mechanisms for the inflammatory reaction in CVI. Current evidence suggests that, among several possible mechanisms (hypoxia, humoral stimulation), a shift in fluid shear stress from normal physiological levels and endothelial distension under the influence of elevated venous pressure may serve as trigger mechanisms for inflammation.

Therapeutic approach to chronic venous insufficiency and its complications: place of Daflon 500 mg.

Early manifestations of chronic venous insufficiency (CVI) are edema, hyperpigmentation, and lipodermatosclerosis. Late complications are cutaneous ulceration and delayed healing. The specific hallmarks of this inflammation include CD68-positive infiltration into the dermal tissue, monocytes, and lymphocytes and enhanced endothelial permeability. This may lead to "fibrin cuff" formation. In addition, membrane adhesion molecules are present and cytokine expression is seen. In one experimental model of mesenteric venous hypertension, the inflammatory process was detected in its earliest stages. This was evident in the form of neutrophilic leukocyte adhesion to venular endothelium as well as migration of cells across the endothelium and basement membrane into the interstitial space. Simultaneously, parenchymal cell death was detected. This suggests that the mechanism that triggers the inflammatory reaction is venous hypertension. This may cause venous distension and a shift in fluid shear stress. Our observations suggest that patients with venous insufficiency demonstrate circulatory humoral stimulators for leukocyte activation. Otherwise, there is evidence that the inflammatory reaction is limited to the region of the venous ulceration or at least to the skin areas with severe microangiopathy. It may be that activated leukocytes traverse perivascular cuffs and release active transforming growth factor-beta1 (TGF-beta1) which has been found to be elevated exclusively in areas of clinically active CVI. Surgical intervention markedly decreases the number of dysfunctional vein segments and allows pharmacologic agents to protect normal structures from continuing damage. Daflon 500 mg, the purified micronized flavonoid fraction containing 90% diosmin and 10% hesperidin, acts favorably in venous ulcer treatment by inhibiting the synthesis of prostaglandins and free radicals. It decreases bradykinin-induced microvascular leakage and may act favorably to inhibit leukocyte activation, trapping, and migration. Clinically, edema is reduced, ulcer healing is accelerated, and leukocyte trapping diminished. The action of micronized purified flavonoid fraction is beginning to be better understood, and as further knowledge is gained, better pharmacologic control of CVI is a tantalizing promise.

Growing the vascular surgical practice: venous disorders.

For the 48th meeting of the International Society for Cardiovascular Surgery, North American Chapter in June 2000, we were asked to organize a presentation with the title displayed above. We welcomed this opportunity because the phrase 'growing the practice' literally means giving greater service to underserved patients with vascular disorders. Underserved individuals with vascular disorders include those with nonatherosclerotic arterial disorders, patients with lymphedema, and individuals with a variety of venous disorders including venous insufficiency. The majority of these conditions are not surgical, but venous insufficiency commands attention because its treatments are interventional. Therefore, this presentation will discuss prevalence of venous insufficiency, a unifying concept of its pathophysiology, how treatment may be selected, what the new technology provides, and then a description of coding issues and whether or not interventions are actually worthwhile from the point of view of the patient.

Internal to external carotid artery transposition to repair recurrent stenosis after carotid artery stenting.

Recently, carotid artery stenting (CAS) has emerged as a treatment option for carotid artery stenosis. Since the procedure is new, management of its complications is not standardized. This case report describes one method of arterial reconstruction after failed CAS. A 64-year-old male underwent CAS of his right internal carotid artery (ICA) for an asymptomatic 65% stenosis. Seven months later the stented area had narrowed to 95%. Arteriography revealed that the common and external carotid arteries (ECA) were free of disease so we elected to perform a transposition of the distal ICA onto the proximal ECA. The ECA and its branches were completely mobilized and the ascending pharyngeal and lingual arteries divided. The ICA was divided distal to the stent. Transection of the occipital artery provided an arteriotomy for an end ICA to side ECA anastamosis, thus preserving ECA flow. Postoperative surveillance after 8 months has revealed no recurrent stenosis. Operative repair of restenosis after CAS may be challenging if standard endarterectomy is not possible. Other options for reconstruction are feasible but if the common and external carotid arteries are disease-free, an ICA to ECA transposition provides a simple all-arterial repair that avoids bypass and prosthetic material.

Defining the role of extended saphenofemoral junction ligation: a prospective comparative study.

OBJECTIVE: This study explores the added effect of extended saphenofemoral junction (SFJ) ligation when the greater saphenous vein (GSV) has been eliminated from participating in thigh reflux by means of endovenous obliteration. GSV obliteration, unlike surgical stripping, can be done with or without SFJ ligation to isolate and study SFJ ligation's specific contribution to treatment results. METHODS: Sixty limbs treated with SFJ ligation and 120 limbs treated without high ligation were selected from an ongoing, multicenter, endovenous obliteration trial on the basis of their having primary varicose veins, GSV reflux, and early treatment dates. RESULTS: Five (8%) high-ligation limbs and seven (6%) limbs without high ligation with patent veins at 6 weeks or less were excluded as unsuccessful obliterations. Treatment significantly reduced symptoms and CEAP clinical class in both groups (P =.0001). Recurrent reflux developed in one (2%) of 49 high-ligation limbs and eight (8%) of 97 limbs without high ligation by 6 months (P =.273). New instances of reflux did not appear thereafter in 57 limbs followed to 12 months. Recurrent varicose veins occurred in three high-ligation limbs and four limbs without high ligation by 6 months and in one additional high-ligation limb and two additional limbs without high ligation by 12 months. Actuarial recurrence curves were not statistically different with or without SFJ ligation (P >.156), predicting greater than 90% freedom from recurrent reflux and varicosities at 1 year for both groups. CONCLUSION: These early results suggest that extended SFJ ligation may add little to effective GSV obliteration, but our findings are not sufficiently robust to warrant abandonment of SFJ ligation as currently practiced in the management of primary varicose veins associated with GSV vein reflux.

Expression of adhesion molecules and cytokines on saphenous veins in chronic venous insufficiency.

The objective of this study was to assess the relationship of signaling molecules to monocyte/ macrophages as a precursor to venous valve and venous wall dysfunction in patients with varicose veins. One of the hallmarks of venous dysfunction is destruction of venous valves with subsequent reflux and elevation of distal venous pressure. We recently observed that monocytes/macrophages migrate into the venous walls and valves of patients with venous insufficiency. There, they may play a role in the pathogenesis of primary venous insufficiency. If so, an important element in their performance would be the interaction between the monocytes and the endothelium as a precursor of damage to venous valves and the venous wall. To explore this interaction, immunohistochemistry was carried out to detect adhesion molecules and cytokines in surgical specimens removed during surgical therapy. Twenty-four surgical specimens consisting of proximal saphenous vein and subterminal valve were obtained using minimally traumatic technique in 6 males and 18 females who ranged in age from 31 to 79 years. Reflux was confirmed preoperatively by duplex technique, and severity was classified by the CEAP classification of the American Venous Forum. Ten patient limbs were class 2, eight were class 3, four were class 4, and two were class 6. The venous specimens were labeled using monoclonal antibody against ICAM-1, E-selectin, IL-1alpha, and TNF-alpha. CD68 was used for detection of monocytes/macrophages. Our results indicate that not only luminal venous endothelium but also endothelium in the vasa vasora of refluxing saphenous veins is activated, as indicated by the up-regulation of ICAM-1. However, IL-1alpha and TNF-alpha were increased in only selected specimens and are mainly detected in the vein wall. The factors that serve as trigger mechanisms to activate cells in the pathogenesis of primary venous dysfunction remain to be explored.

Left iliac vein occlusion: its clinical spectrum.

The cases reported here demonstrate the variability of the clinical manifestations of left common iliac venous occlusive disease. In each instance, therapy must be adjusted to meet the symptomatic needs of the individual patient. The experience reported here should reinforce the fact that occlusions even 25 months or longer in duration may be reopened. Continuing patency can be enhanced by stent placement.

Extensive tissue necrosis following high-concentration sclerotherapy for varicose veins.

BACKGROUND: Tissue necrosis after sclerotherapy has been observed, but is unexplained. OBJECTIVE: To present the complication of extensive tissue necrosis following high-concentration sclerotherapy for varicose veins. METHODS: Cases coming to the attention of the authors are presented briefly with commentary and discussion to explain the mechanisms of tissue destruction. RESULTS: Although the complication of extensive tissue necrosis has been ascribed to intra-arterial injection, in fact, careful study of the cases described here shows that intravenous injection was present in each case. A theory of distribution of the sclerosant into the arterial arborization is proposed. This theory would explain the distribution of sclerosant into the arterial tree and would also explain the causation of extensive tissue necrosis. Mention is made of experimental work in which intra-arterial injection was not the mechanism of causation of tissue necrosis. CONCLUSION: Extensive tissue necrosis following high-concentration sclerotherapy may be rare, but its occurrence is serious and its treatment may be incomplete.

Failure of nonoperative management of isolated superior mesenteric artery dissection.

A case of isolated dissection of the superior mesenteric artery is presented here. This rare condition was confirmed angiographically in a 46-year-old man with persistent abdominal pain. He was treated initially with anticoagulation alone. One year later, he developed recurrent symptoms and had radiologic documentation of progression of the condition. Operative repair was performed and recovery was uneventful. This case demonstrates a failure of the nonoperative approach to this rare condition and suggests that disease progression may be inevitable. Early surgical correction may ease operative management.

Arterial injury in uncomplicated upper extremity dislocations.

The purpose of this study is to analyze causes and consequences of arterial injury complicating simple dislocations of the upper extremity. This is a multicenter, 5-year, retrospective analysis of vascular injury in patients sustaining shoulder or elbow dislocations without associated fractures. Foci of the study were mechanisms of injury, preoperative imaging, incidence of closed reductions, types of arterial injury, methods of surgical repair, and ultimate outcome. Arterial injury in this patient cohort occurred in 0.74% of patients. Axillary artery injury occurred in 0. 97% and brachial in 0.47%. Both elbow and shoulder dislocations may cause severe arterial damage and strenuously test surgical expertise to achieve successful repair.

Surgical treatment of Takayasu's arteritis: case report and literature review.

Surgical intervention during the early stages of Takayasu's arteritis is rarely necessary. In the chronic stages of this disease, however, surgeons may be faced with difficult decisions regarding the timing of complex arterial reconstructions. These issues can be especially challenging in the pediatric population. We report the case of an 8-year-old girl with chronic Takayasu's arteritis complicated by malignant hypertension. Despite aggressive medical therapy, her blood pressure remained uncontrolled. Imaging studies demonstrated infrarenal aortic and right common iliac artery aneurysms with concomitant segmental stenosis of the right common iliac artery. Since her transplant kidney was based off the right external iliac artery, it was felt that this high-grade stenosis was responsible for her severe hypertension. Immediate surgical reconstruction was therefore recommended. Intraoperatively, the aneurysmal aorta and iliac arteries were found to be densely calcified. The transplant kidney was perfused during aortic clamping by placement of a suprarenal aorta to the right external iliac artery shunt. Endoaneurysmorrhaphy was then performed to reconstruct the aorta after extensive endarterectomy. In the early postoperative period, antihypertensive medications were decreased to two oral agents. She was discharged on the seventh postoperative day and placed on two agents. At a 1-year follow-up visit, she is on one antihypertensive medication. Her right leg complaints have resolved. Ultrasound surveillance revealed no evidence of recurrent aneurysmal or occlusive disease. A brief review of complications related to Takayasu's arteritis in the children and indications for surgical intervention completes this report.

Non-elastic compression: an alternative in management of chronic venous insufficiency.

Non-elastic compression has been used to treat venous insufficiency of the lower extremities for more than 150 years. The best and most recognized example is the Unna boot. When compared with other dressings, the Unna boot has performed as well as or better than other forms of compression. While the Unna boot is used worldwide, a 3- or 4-layer dressing has emerged as the dressing of choice in treating severe chronic venous insufficiency in the United States and English-speaking European countries. In the United States, non-elastic compression can also be applied as a CircAid legging. This semirigid support has been compared with heavyweight class 3 below-knee medical stockings. At 2 and 6 hours after application, inelastic compression maintained limb size and reduced venous volume better than did stockings. At 6 hours, the ejection fraction of the calf muscle pump was increased and venous filling index significantly improved with inelastic compression compared with stockings. Comparison of elastic stockings with short-stretch bandages has also been completed. The short-stretch bandage was found to be similar but not identical to the semirigid inelastic support device. The studies have shown that venous filling index improved by short-stretch bandaging and that venous reflux time was prolonged more by the short-stretch bandages than by stockings. The findings of these studies demonstrate that the inelastic support dressing mimics the action of the Unna boot in providing counter-pressure to perforating vein outflow. This may improve cutaneous and subcutaneous microcirculation in a manner similar to perforating vein surgery, which has been shown to accelerate leg ulcer healing.

The inflammatory reaction during venous hypertension in the rat.

OBJECTIVE: Numerous studies have examined arterial occlusion followed by reperfusion but few studies have reported about venular occlusion which, in contrast to arterial occlusion, is associated with elevation of the capillary blood pressure. Here we examine leukocytes infiltration and tissue injury in rat mesentery during local venular occlusion and venous hypertension followed by reperfusion, and determine the level of protection offered by pretreatment with micronized, purified flavonoid fraction (MPFF). METHODS: Leukocyte rolling, adhesion, migration, and parenchymal cell death as detected by propidium iodide labeling were determined during venular occlusion using a micropipette followed by reperfusion in the rat mesenteric microcirculation pretreated with 0, 50, or 100 mg/kg MPFF for 7 days. Spontaneous leukocyte activation by nitroblue tetrazolium reduction and expression of CD18 and CD62L on naive donor neutrophils incubated with plasma from each treatment group were determined. RESULTS: Venous occlusion led to elevated levels of leukocyte rolling, adhesion, and migration as well as parenchymal cell death. These injurious processes were significantly inhibited by MPFF in a those-dependent fashion. MPFF reduced spontaneous leukocyte NBT reduction and the neutropil expression of CD62L, even though CD18 was not affected. CONCLUSION: These results suggested that microvascular occlusion in venules with elevation of the micropressure followed by reperfusion is a highly cytotoxic process in the rat mesentery which can be attenuated by MPFF pretreatment.