Duplex assessment of venous reflux and chronic venous insufficiency: The significance of deep venous reflux

AbstractPurpose: This study was undertaken to examine the role of superficial and deep venous reflux, as defined by duplex-derived valve closure times (VCTs), in the pathogenesis of chronic venous insufficiency.Methods: Between January 1992 and November 1995, 320 patients and 500 legs were evaluated with clinical examinations and duplex scans for potential venous reflux. VCTs were obtained with the cuff deflation technique with the patient in the upright position. Imaging was performed at the saphenofemoral junction, the middle segment of the greater saphenous vein, the lesser saphenous vein, the superficial femoral vein, the profunda femoris vein, and the popliteal vein. Not all patients had all segments examined because tests early in the series did not examine the profunda femoris or lesser saphenous vein and because some patients had previous ligation and stripping or venous thrombosis. VCTs were examined for individual segment reflux, grouped into superficial and deep systems, and then correlated with the clinical stage as defined by the SVS/ISCVS original reporting standards in venous disease. Segment reflux was considered present if the VCT was greater than 0.5 seconds, and system reflux was considered present if the sum of the segments was greater than 1.5 seconds. Between-group differences were analyzed with analysis of variance and post hoc tests where appropriate.Results: Sixty-nine limbs studied were in class 0, 149 limbs were in class 1, 168 limbs were in class 2, and 114 limbs were in class 3. VCTs in the superficial veins were significantly lower in class 0 than in the other clinical classes. There was no difference in superficial reflux in the symptomatic limbs (classes 1 to 3). Reflux VCTs in the superficial femoral and popliteal veins increased as the clinical symptoms progressed, with a significant increase in class 3 ulcerated limbs when compared with nonulcerated limbs. The incidence of deep venous reflux was 60% in class 3 limbs, compared with 29% in class 2 limbs, whereas the incidence of superficial venous reflux did not differ among the symptomatic limbs. Isolated superficial femoral and popliteal vein reflux was uncommon, even in class 3 limbs, but combined superficial femoral and popliteal vein reflux was found in 53% of class 3 limbs, compared with 18.5% of class 2 limbs.Conclusions: Reflux in the deep venous system plays a significant role in the progression of chronic venous insufficiency. Deep system reflux increases as clinical changes become more severe, with significant axial reflux contributing to ulcer formation. (J Vasc Surg 1996;24:755-62.

Early results and lessons learned from a multicenter, randomized, double-blind trial of bone marrow aspirate concentrate in critical limb ischemia

ObjectivesDespite advances in endovascular therapies, critical limb ischemia (CLI) continues to be associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. We sought to explore the feasibility of conducting a definitive trial of a bone marrow-derived cellular therapy for CLI in this “no option” population.MethodsA pilot, multicenter, prospective, randomized, double-blind, placebo-controlled trial for “no option” CLI patients was performed. The therapy consisted of bone marrow aspirate concentrate (BMAC), prepared using a point of service centrifugation technique and injected percutaneously in 40 injections to the affected limb. Patients were randomized to BMAC or sham injections (dilute blood). We are reporting the 12-week data.ResultsForty-eight patients were enrolled. The mean age was 69.5 years (range, 42-93 years). Males predominated (68%). Diabetes was present in 50%. Tissue loss (Rutherford 5) was present in 30 patients (62.5%), and 18 (37.5%) had rest pain without tissue loss (Rutherford 4). Patients were deemed unsuitable for conventional revascularization based on multiple prior failed revascularization efforts (24 [50%]), poor distal targets (43 [89.6%]), and medical risk (six [12.5%]). Thirty-four patients were treated with BMAC and 14 with sham injections. There were no adverse events attributed to the injections. Renal function was not affected. Effective blinding was confirmed; blinding index of 61% to 85%. Subjective and objective outcome measures were effectively obtained with the exception of treadmill walking times, which could only be obtained at baseline and follow-up in 15 of 48 subjects. This pilot study was not powered to demonstrate statistical significance but did demonstrate favorable trends for BMAC versus control in major amputations (17.6% vs 28.6%), improved pain (44% vs 25%), improved ankle brachial index (ABI; 32.4% vs 7.1%), improved Rutherford classification (35.3% vs 14.3%), and quality-of-life scoring better for BMAC in six of eight domains.ConclusionsIn this multicenter, randomized, double-blind, placebo-controlled trial of autologous bone marrow cell therapy for CLI, the therapy was well tolerated without significant adverse events. The BMAC group demonstrated trends toward improvement in amputation, pain, quality of life, Rutherford classification, and ABI when compared with controls. This pilot allowed us to identify several areas for improvement for future trials and CLI studies. These recommendations include elimination of treadmill testing, stratification by Rutherford class, and more liberal inclusion of patients with renal insufficiency. Our strongest recommendation is that CLI studies that include Rutherford 4 patients should incorporate a composite endpoint reflecting pain and quality of life

The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design

<p>Abstract</p> <p>Background</p> <p>Autologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI). One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP), which is usually combined with mortality for AMP-free survival (AFS). Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control) of 48 patients treated with site of service obtained bone marrow cells (BMAC) as well as a systematic review of the literature.</p> <p>Methods</p> <p>Cells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood). Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss.</p> <p>Results</p> <p>Fifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6%) and those with tissue loss (46.7%), irrespective of treatment group, was significant (p = 0.0029). In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337). The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067). Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain.</p> <p>Conclusions</p> <p>BMAC shows promise in improving AMP-free survival if the trends in this pilot study are validated in a larger pivotal trial. The difference in amp rate between Rutherford 4 & 5 patients suggests that these patients should be stratified in future RCTs.</p

Three-dimensional steep wave impact on a vertical cylinder

In the present study we investigate the 3-D hydrodynamic slamming problem on a vertical cylinder due to the impact of a steep wave that is moving with a steady velocity. The linear theory of the velocity potential is employed by assuming inviscid, incompressible fluid and irrotational flow. As the problem is set in 3-D space, the employment of the Wagner condition is essential. The set of equations we pose, is presented as a mixed boundary value problem for Laplace's equation in 3-D. Apart from the mixed-type of boundary conditions, the problem is complicated by considering that the region of wetted surface of the cylinder is a set whose boundary depends on the vertical coordinate on the cylinder up to the free-surface. We make some simple assumptions at the start but otherwise we proceed analytically. We find closed-form relations for the hydrodynamic variables, namely the time dependent potential, the pressure impulse, the shape of the wave front (from the contact point to beyond the cylinder) and the slamming force