Peter J. Pappas

The care of patients with varicose veins and associated chronic venous diseases: Clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum

The Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) have developed clinical practice guidelines for the care of patients with varicose veins of the lower limbs and pelvis. The document also includes recommendations on the management of superficial and perforating vein incompetence in patients with associated, more advanced chronic venous diseases (CVDs), including edema, skin changes, or venous ulcers. Recommendations of the Venous Guideline Committee are based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system as strong (GRADE 1) if the benefits clearly outweigh the risks, burden, and costs. The suggestions are weak (GRADE 2) if the benefits are closely balanced with risks and burden. The level of available evidence to support the evaluation or treatment can be of high (A), medium (B), or low or very low (C) quality. The key recommendations of these guidelines are: We recommend that in patients with varicose veins or more severe CVD, a complete history and detailed physical examination are complemented by duplex ultrasound scanning of the deep and superficial veins (GRADE 1A). We recommend that the CEAP classification is used for patients with CVD (GRADE 1A) and that the revised Venous Clinical Severity Score is used to assess treatment outcome (GRADE 1B). We suggest compression therapy for patients with symptomatic varicose veins (GRADE 2C) but recommend against compression therapy as the primary treatment if the patient is a candidate for saphenous vein ablation (GRADE 1B). We recommend compression therapy as the primary treatment to aid healing of venous ulceration (GRADE 1B). To decrease the recurrence of venous ulcers, we recommend ablation of the incompetent superficial veins in addition to compression therapy (GRADE 1A). For treatment of the incompetent great saphenous vein (GSV), we recommend endovenous thermal ablation (radiofrequency or laser) rather than high ligation and inversion stripping of the saphenous vein to the level of the knee (GRADE 1B). We recommend phlebectomy or sclerotherapy to treat varicose tributaries (GRADE 1B) and suggest foam sclerotherapy as an option for the treatment of the incompetent saphenous vein (GRADE 2C). We recommend against selective treatment of perforating vein incompetence in patients with simple varicose veins (CEAP class C(2); GRADE 1B), but we suggest treatment of pathologic perforating veins (outward flow duration ≥500 ms, vein diameter ≥3.5 mm) located underneath healed or active ulcers (CEAP class C(5)-C(6); GRADE 2B). We suggest treatment of pelvic congestion syndrome and pelvic varices with coil embolization, plugs, or transcatheter sclerotherapy, used alone or together (GRADE 2B).

A strategy for increasing use of autogenous hemodialysis access procedures: Impact of preoperative noninvasive evaluation

PURPOSE We studied the efficacy of preoperative noninvasive assessment of the upper extremity to identify arteries and veins suitable for hemodialysis access to increase our use of autogenous fistulas (AF). METHODS From Sep. 1, 1994, to Apr. 1, 1997, 172 patients who required chronic hemodialysis underwent segmental upper extremity Doppler pressures and duplex ultrasound with mapping of arteries and veins. The following criteria were necessary for satisfactory arterial inflow: absence of a pressure gradient between arms, patent palmar arch, and arterial lumen diameter 2.0 mm or more. The criteria necessary for satisfactory venous outflow were venous luminal diameter greater than or equal to 2.5 mm for AF and greater than or equal to 4.0 mm for synthetic bridging grafts (BG) and continuity with distal superficial veins in the arm. Intraoperative and duplex ultrasound measurements were compared. Contemporary experience was compared with the 2-year period (1992 to 1994) before implementation of the protocol. RESULTS During the period from Sep. 1, 1994, to Apr. 1, 1997, 108 patients (63%) had AF, 52 (30%) had prosthetic BG, and 12 (7%) had permanent catheters (PC) placed. Early failure was seen in 8.3% of AFs. Primary cumulative patency rates were 83% for AF and 74% for BG at 1 year (p < 0.05), with a mean clinical follow-up of 15.2 months. No postoperative infections were observed with AF, whereas six infections (12%) were observed with BG and two (17%) with PC insertion. During the period from June 1, 1992, to Aug. 31, 1994, 183 procedures were performed with a distribution of 14% AF, 62% BG, and 24% PC. In this earlier period the AF early failure rate was 36%, and the patency rates were 48%, 63%, and 48% for AF, BG, and PC, respectively (mean follow-up, 13.8 months). CONCLUSION A protocol of noninvasive assessment increased use of AFs. The cumulative patency rate of AFs was improved, and early failure rates were reduced when compared with the preceding institutional experience. Routine noninvasive assessment is recommended to document adequacy of arterial inflow and delineate venous outflow to maximize opportunities for AF.

Carotid restenosis: Operative and endovascular management

PURPOSE Surgical management of carotid restenosis (CR) after carotid endarterectomy (CEA) has been associated with a higher perioperative complication rate than that of primary CEA. We recently used carotid angioplasty-stenting (CAS) as an alternative to operative management in patients who had undergone CEA within three years, and we retrospectively compared these results with those of operative management of CR and the overall results of CEA. METHODS CEA was performed on 1065 adult patients (58% symptomatic, 42% asymptomatic), 62% of whom were men (n = 660) and 38% of whom were women (n = 405), from 1989 to 1997. Before our initiation of a program of CAS, 16 operative procedures (1.9% of CEAs) were performed for CR in 14 adult patients (7 women and 7 men). During the last 20 months, CAS was used in the management of 17 CRs (16 patients; 9 women and 7 men). RESULTS The 30-day stroke morbidity-death rate for all CEAs (n = 1065) was 1.4%; 11 strokes (1. 0%) occurred (4 major strokes with disability and 7 strokes with minor or no disability), and 4 deaths (0.4%) occurred (2 deaths caused by myocardial infarction, 1 caused by intracranial hemorrhage, and 1 caused by stroke). Operative management of CR (n = 16) included patch angioplasty in 12 cases (autologous vein patches in 10 cases and synthetic patches in 2 cases), whereas interposition grafting was used in 4 cases (saphenous vein in 3 instances and synthetic [polytetrafluoroethylene] in one case). No strokes or deaths were observed. One recurrent laryngeal nerve palsy occurred (6.2%). Among the 16 patients undergoing 17 CAS procedures, the technical procedures were accomplished in all patients. No strokes or deaths occurred. No recurrent restenoses (50% or greater) have been identified within or adjacent to the CAS procedures. CONCLUSION CR caused by myointimal hyperplasia can be managed by operative techniques or CAS with comparable periprocedural complications. Although long-term follow-up will be required to determine the incidence of recurrent restenosis, CAS may become the preferred procedure in these cases. A randomized clinical trial ultimately will be necessary to determine the role of CAS, as compared with that of operative management.

Primary chronic venous disorders

Primary chronic venous disorders, which according to the CEAP classification are those not associated with an identifiable mechanism of venous dysfunction, are among the most common in Western populations. Varicose veins without skin changes are present in about 20% of the population while active ulcers may be present in as many as 0.5%. Primary venous disorders are thought to arise from intrinsic structural and biochemical abnormalities of the vein wall. Advanced cases may be associated with skin changes and ulceration arising from extravasation of macromolecules and red blood cells leading to endothelial cell activation, leukocyte diapedesis, and altered tissue remodeling with intense collagen deposition. Laboratory evaluation of patients with primary venous disorders includes venous duplex ultrasonography performed in the upright position, occasionally supplemented with plethysmography and, when deep venous reconstruction is contemplated, ascending and descending venography. Primary venous disease is most often associated with truncal saphenous insufficiency. Although historically treated with stripping of the saphenous vein and interruption and removal of major tributary and perforating veins, a variety of endovenous techniques are now available to ablate the saphenous veins and have generally been demonstrated to be safe and less morbid than traditional procedures. Sclerotherapy also has an important role in the management of telangiectasias; primary, residual, or recurrent varicosities without connection to incompetent venous trunks; and congenital venous malformations. The introduction of ultrasound guided foam sclerotherapy has broadened potential indications to include treatment of the main saphenous trunks, varicose tributaries, and perforating veins. Surgical repair of incompetent deep venous valves has been reported to be an effective procedure in nonrandomized series, but appropriate case selection is critical to successful outcomes.

Vein transposition in the forearm for autogenous hemodialysis access.

PURPOSE We describe a technique of superficial venous transposition in the forearm used for the formation of an arteriovenous fistula for hemodialysis access. These modifications of the single-incision radiocephalic fistula are designed to increase options for arteriovenous fistulas by using veins and arteries that are suitable for use but are not in immediate proximity. METHODS Arteries and veins suitable for a primary arteriovenous fistula were identified and mapped using duplex ultrasound in 89 patients. Separate incisions were used in the majority of cases, and the selected forearm vein was mobilized, angiodilated, and transposed into a subcutaneous tunnel on the volar aspect of the forearm. Before initiation of hemodialysis, duplex ultrasound scanning was performed, and the location that was most suitable for cannulation was identified. Repeat scans were performed at 3-month intervals for analysis of patency. RESULTS Superficial venous transpositions were performed using a single incision in 13 instances in which the vein was in immediate proximity to the radial artery (type A). Dorsal-to-volar forearm transposition (type B) was performed in 30 veins with anastomoses to the radial (n = 26), ulnar (n = 2), or brachial (n = 2) arteries. Volar-to-volar forearm transposition (type C) was performed in the remaining 46 veins, with anastomoses to the radial (n = 42), ulnar (n = 2), or brachial arteries (n = 2). Successful hemodialysis was accomplished in 81 of 89 patients (91%). The primary cumulative patency rate was 84% at 1 year and 69% at 2 years. The mean duration of follow-up was 14.3 months. CONCLUSIONS The use of superficial venous transposition for the formation of autogenous hemoaccess was associated with ease of cannulation by dialysis personnel, high maturation rates, reduced early failure rates, and enhanced patency rates. We recommended the use of these technical modifications to increase the use of autogenous fistulas in the forearm.

Endothelial nitric oxide synthase regulates microvascular hyperpermeability in vivo

Nitric oxide (NO) is an important regulator of blood flow, but its role in permeability is still challenged. We tested in vivo the hypotheses that: (a) endothelial nitric oxide synthase (eNOS) is not essential for regulation of baseline permeability; (b) eNOS is essential for hyperpermeability responses in inflammation; and (c) molecular inhibition of eNOS with caveolin‐1 scaffolding domain (AP‐Cav) reduces eNOS‐regulated hyperpermeability. We used eNOS‐deficient (eNOS−/−) mice and their wild‐type control as experimental animals, platelet‐activating factor (PAF) at 10−7m as the test pro‐inflammatory agent, and integrated optical intensity (IOI) as an index of microvascular permeability. PAF increased permeability in wild‐type cremaster muscle from a baseline of 2.4 ± 2.2 to a peak net value of 84.4 ± 2.7 units, while the corresponding values in cremaster muscle of eNOS−/− mice were 1.0 ± 0.3 and 15.6 ± 7.7 units (P < 0.05). Similarly, PAF increased IOI in the mesentery of wild‐type mice but much less in the mesentery of eNOS−/− mice. PAF increased IOI to comparable values in the mesenteries of wild‐type mice and those lacking the gene for inducible NOS (iNOS). Administration of AP‐Cav blocked the microvascular hyperpermeability responses to 10−7m PAF. We conclude that: (1) baseline permeability does not depend on eNOS; (2) eNOS and NO are integral elements of the signalling pathway for the hyperpermeability response to PAF; (3) iNOS does not affect either baseline permeability or hyperpermeability responses to PAF; and (4) caveolin‐1 inhibits eNOS regulation of microvascular permeability in vivo. Our results establish eNOS as an important regulator of microvascular permeability in inflammation.

Carotid artery stenting: analysis of data for 105 patients at high risk.

OBJECTIVES Carotid artery stenting (CAS) has been recommended as an alternative to carotid endarterectomy (CEA) by some clinicians. However, recently published clinical trials have reported 30-day stroke and death rates of 10% to 12%. This prompted review of our experience with CAS in patients at high risk, to document our results and guide further use of CAS. METHODS From September 1996 to the present, we performed 114 consecutive CAS procedures in 105 patients. Sixty-three patients were men (60%) and 42 patients were women (40%), with mean age of 70 years (range, 45-93 years). Indications for CAS included recurrent stenosis after previous CEA in 74 patients (65%), primary lesions in 32 patients at high risk (28%), and carotid stenosis with previous ipsilateral radiation therapy in 8 patients (7%). Asymptomatic stenosis (>80%) was managed in 70 patients (61%), and symptomatic lesions (>50%) were treated in 44 patients (39%). RESULTS CAS was technically successful in all patients. Mean severity of stenosis before CAS was 87% +/- 6%, compared with 9% +/- 4% after CAS. Two patients (1.9%) died, 1 of reperfusion-intracerebral hemorrhage and 1 of myocardial infarction 10 days after discharge; and 1 patient (0.95%) had a stroke (retinal infarction), for a 30-day stroke and death rate of 2.85%. Two patients (1.9%) had transient neurologic events. No cranial nerve deficits were noted. No neurologic complications have been noted in the last 27 patients (26%). CONCLUSIONS A 30-day stroke and death rate of 2.85% in our experience demonstrates acceptability of CAS as an alternative to repeat operation or primary CEA in patients at high risk or in patients with radiation-induced stenosis. We recommend further clinical investigation of CAS and participation in clinical trials by vascular surgeons.

Dermal tissue fibrosis in patients with chronic venous insufficiency is associated with increased transforming growth factor-β1 gene expression and protein production

PURPOSE Pathologic dermal degeneration in patients with chronic venous insufficiency (CVI) is characterized by aberrant tissue remodeling that results in stasis dermatitis, tissue fibrosis, and ulcer formation. The cytochemical processes that regulate these events are unclear. Because transforming growth factor-beta(1) (TGF-beta(1)) is a known fibrogenic cytokine, we hypothesized that the increased production of TGF-beta(1) would be associated with CVI disease progression. METHODS Seventy-eight punch biopsy specimens of the lower calf (LC) and the lower thigh (LT) of 52 patients were snap frozen in liquid nitrogen and stratified into four groups according to the Society for Vascular Surgery/International Society for Cardiovascular Surgery CEAP classification (C, clinical; E, etiologic; A, anatomic distribution; and P, pathophysiology). One set of LC biopsy specimens were analyzed for TGF-beta(1) gene expression with quantitative reverse transcriptase-polymerase chain reaction: healthy skin, n = 6; class 4, n = 6; class 5, n = 5; and class 6, n = 7. A second set of biopsy specimens from the LC and LT were analyzed for the amount of bioactive TGF-beta(1) with a certified cell line 64 mink lung epithelial bioassay: healthy skin, n = 8; class 4, n = 23; class 5, n = 13; and class 6, n = 10. The location of TGF-beta(1) was determined at the light and electron microscopy level with immunocytochemistry and immunogold (IMG) labeling. Multiple comparisons were analyzed with a one-way analysis of variance and the Student-Newman-Keuls post hoc tests. The LC and LT comparisons were analyzed with a two-tailed unpaired t test. RESULTS The TGF-beta(1) gene transcripts for control subjects and patients in classes 4, 5, and 6 were 7.02 +/- 7.33, 43.33 +/- 9.0, 16.13 +/- 7.67, and 7.22 +/- 0.56 x 10(-14) mol/microg total RNA, respectively. The transcripts were significantly elevated in class 4 patients only (P </=.05). The amount of active TGF-beta(1) in picograms/gram of tissue from LC and LT biopsy specimens as compared with healthy skin biopsy specimens were as follows: healthy skin, <1. 0 pc/g; class 4: LC, 5061 +/- 1827 pc/g; LT, 317.3 +/- 277 pc/g; class 5: LC, 8327 +/- 3690 pc/g; LT, 193 +/- 164 pc/g; and class 6: LC, 5392 +/- 1800 pc/g; LT, 117 +/- 61 pc/g. Differences between healthy skin and the skin of the patients in classes 4 and 6 were significant (P </=.05 and P </=.01, respectively). Differences between the LC and LT biopsy specimens within each CVI group were also significant: class 4, P </=.003; class 5, P </=.008; and class 6, P </=.02. Immunocytochemistry results of healthy skin showed TGF-beta(1) staining of epidermal basal cells only. CVI dermal biopsy results demonstrated positive staining in epidermal basal cells, fibroblasts, and leukocytes. Many leukocytes had positive staining of intracellular granules, which appeared morphologically similar to mast cells. IMG labeling results demonstrated gold particles in the leukocytes and collagen fibrils of the extracellular matrix. CONCLUSION Our study indicated that activated leukocytes traverse perivascular cuffs and release active TGF-beta(1). Positive TGF-beta(1) staining results of dermal fibroblasts were observed and suggest that fibroblasts are the targets of activated interstitial leukocytes. Increased protein production, despite normal levels of gene transcripts in patients in classes 5 and 6, suggests that alternate mechanisms other than gene transcription regulate protein production. A potential mechanism for quick access and release is storage of TGF-beta(1) in the extracellular matrix. IMG labeling to collagen fibrils support this possibility. Furthermore, TGF-beta(1) was exclusively elevated in areas of clinically active disease, indicating a regionalized response to injury. These data suggest that alterations in tissue remodeling occur in patients with CVI and that dermal tissue fibrosis in CVI is regulated by TGF-beta(1).

Morphometric assessment of the dermal microcirculation in patients with chronic venous insufficiency

PURPOSE Ultrastructural assessments of the dermal microcirculation in patients with chronic venous insufficiency have been limited to qualitative morphologic descriptions of venous ulcer edges or venous stasis dermatitis. The purpose of this investigation was to quantify differences in endothelial cell structure and local cell type with emphasis on leukocytes and their relationship to arterioles, capillaries, and postcapillary venules (PCVs). METHODS Two 4.0 mm punch biopsies were obtained from areas of dermal stasis skin changes in the gaiter region of the leg, as well as from noninvolved areas of skin in the ipsilateral thigh, from 35 patients: CEAP class 4 (11 patients), class 5 (9 patients), class 6 (10 patients), and five normal skin biopsies from patients without chronic venous insufficiency. Electron microscopy was performed on sections at 6700x and 23,800x magnification. At 6700x endothelial cell thickness was determined, and the number of fibroblasts, leukocytes, and mast cells were recorded relative to their proximity to arterioles, capillaries, and PCVs. Similarly, at 23,800x endothelial cell vesicle density, interendothelial junctional widths, and basal lamina thickness (cuff width) were measured. Preliminary evaluation for the presence of transforming growth factor-beta 1 (TGF-beta 1) was performed on three patients using reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS Quantitative measurements demonstrated increased mast cell content for class 4 and 5 patients around arterioles and PCVs and increased macrophage numbers for class 6 patients around PCVs (p < 0.05). Fibroblasts were the most common cells observed; however, no differences were demonstrated between groups. No differences were observed in interendothelial junctional widths or vesicle densities in arterioles, capillaries, or PCVs. Basal lamina thickness was increased only at the capillary level (p < 0.05). The results of RT-PCR for TGF-beta 1 messenger RNA were positive in the three patients studied. CONCLUSIONS Our data suggest that (1) mast cells play a role in the pathogenesis of chronic venous insufficiency; (2) the effects of mast cells, macrophages, or both may be mediated in part by TGF-beta 1; and (3) capillary cuff formation is not associated with widened interendothelial gap junctions, but may be a result of enhanced vesicular transport rate or conformational changes in the interendothelial glycocalyx.

The effect of venous thrombus location and extent on the development of post-thrombotic signs and symptoms

OBJECTIVE This prospective study determined the incidence of signs and symptoms of chronic venous disease and recurrent venous thrombotic events (VTE) in relation to the location and extent of the initial venous thrombus. METHODS A first episode of acute deep vein thrombosis (DVT) occurred in 120 lower extremities of 105 patients (59 men; mean age, 54 years [range, 23-82 years]). Patients who presented with pain, swelling, or signs and symptoms of pulmonary embolism of <10 days were included. The DVT was diagnosed with duplex ultrasound (DUS) imaging. Patients were grouped by those having thrombosis in one venous segment (group A) or multiple levels (group B). Patients were treated with heparin and warfarin. Patients with at least 1-year of follow-up with clinical and DUS were included. RESULTS No difference was found in the duration of signs and symptoms at presentation. The median follow-up was 3.4 years (range, 1.2-7 years). More symptomatic limbs were seen in group B (71 of 79) compared with group A (21 of 41; P < .001). Post-thrombotic syndrome (PTS) was more advanced in group B vs group A, including the prevalence of skin damage and ulceration (61 of 79 vs 26 of 41, P < .001; 29 of 79 vs 6 of 41, P = .019, respectively). Limbs with calf DVT that had focal thrombosis were most often asymptomatic. Calf thrombosis in patients with proximal DVT produced the highest prevalence of PTS. Venous claudication was exclusively found in group B and was present only when iliac veins were involved. Recurrent thrombosis had a trend for a higher prevalence in group B (5 of 41 vs 16 of 79, P = .39). Reflux, obstruction, or a combination of the two were more common in group B (61 of 79) vs group A (15 of 41; P < .0001). Limbs with both reflux and obstruction were more likely to develop skin damage (group A, 5 of 6 vs 1 of 35, P < .0001; group B, 24 of 29 vs 5 of 50, P < .0001). CONCLUSIONS Recurrent thrombosis and skin damage is more likely to develop in patients with multiple sites of thrombosis than in those with thrombosis in a single vein segment. Patients with reflux and obstruction presented more skin damage than those with reflux or obstruction alone. Involvement of the calf veins in the presence of proximal vein thrombosis increased the likelihood for PTS.