A novel native collagen dressing with advantageous properties to promote physiological wound healing.

OBJECTIVE: Chronic hard-to-heal wounds generate high costs and resource use in western health systems and are the focus of intense efforts to improve healing outcomes. Here, we introduce a novel native collagen (90 %):alginate (10 %) wound dressing and compare it with the established oxidised dressings Method: Matrices were analysed by atomic force microscopy (AMF), scanning electron microscopy (SEM), and immunoelectron microscopy for collagen types I, III and V. Viability assays were performed with NIH-3T3 fibroblasts. Matrix metalloproteinase (MMP) binding was analysed, and the effect of the wound dressings on platelet-derived growth factor B homodimer (PDGF-BB) was investigated. RESULTS: Unlike oxidised regenerated cellulose (ORC)/collagen matrix and ovine forestomach matrix (OFM), the three-dimensional structure of the native collagen matrix (NCM) was found to be analogous to intact, native, dermal collagen. Fibroblasts seeded on the NCM showed exponential growth whereas in ORC/collagen matrix or OFM, very low rates of proliferation were observed after 7 days. MMP sequestration was effective and significant in the NCM. In addition, the NCM was able to significantly stabilise PDGF-BB in vitro. CONCLUSION: We hypothesise that the observed microstructure of the NCM allows for an effective binding of MMPs and a stabilisation and protection of growth factors and also promotes the ingrowth of dermal fibroblasts, potentially supporting the re commencement of healing in previously recalcitrant wounds. DECLARATION OF INTEREST: This work was supported by BSN Medical, Hamburg, Germany.

Variability of interface pressure produced by ready-to-wear compression stockings.

PURPOSE: To assess the variability of interface pressure and changes in this pressure over one month time interval under ready-to-use compression stockings. METHODS: Fifteen healthy volunteers with a broad range of sizes and shapes of the calves were included in final analysis. Each volunteer sequentially used six pairs of stockings daily for one month each. The six pair set consisted of stockings of three compression classes (class 1: 20-30 mmHg, class 2: 30-40 mmHg and class 3: 40-50 mmHg), made of two materials with different stiffnesses. Interface pressure measurements were performed at B1 point using SIGaT(®) tester (Ganzoni-Sigvaris, St Gallen, Switzerland). Interface pressure was measured in supine and standing positions, and during performing 10 tiptoes. Pressure measurements were performed twice (in the morning and after using stockings for eight hours) on the first day of using each pair of stockings, and repeated on the 30th day. RESULTS: At the time of the first use the interface pressure was within the range specified by the manufacturer for 160 out of 180 individual stockings. Twenty stockings (11.1%) produced interface pressure which was 5 mmHg or more outside the range of specified compression class. In 16 of these cases it was only one of the pair of stockings from the same box that produced lower than specified pressure. The pressure under stockings did not change significantly during the day. After one month the interface pressure under the class 1 stockings decreased on average by 1.4 ± 4.3 mmHg (P = 0.013). Class 2 and 3 stockings showed minimal pressure changes which were not statistically significant. CONCLUSIONS: In vivo measurements of interface pressure should be a requirement for clinical studies of compression stockings, and may be reasonable for ensuring appropriate pressure level in clinical practice.

The relative position of paired valves at venous junctions suggests their role in modulating three-dimensional flow pattern in veins.

PURPOSE: The aim of the study is to investigate the relative position of orifices of two valves within the most proximal segments of the great saphenous vein (GSV), and the femoral vein (FV). METHODS: A total of 15 volunteers with no signs or symptoms of venous disease and 13 unaffected limbs of patients with unilateral primary chronic venous disease (CVD) were included. Two most proximal valves of the GSV and the FV were identified. The angle between the two valves, and the distance between the valves were measured. RESULTS: The mean distance between the two valves in the GSV was 3.8 ± 0.4 cm, and in the FV was 4.6 ± 0.3 cm. In one limb, the distance between the FV valves was 1 cm less than GSV valves, and in two limbs the distances were equal. In the remaining 12 limbs available for comparison, the valves in the FV were 1-2 cm further apart compared to the GSV (P = 0.002, paired t-test). All studied pairs of valves were positioned at a minimum 60° angle to each other. The mean angle between the two valves was 84.3 ± 8.4° in the GSV, and 88.3 ± 6.7° in the FV (P = 0.24). The angle between the two valves correlated with the distance between the valves (r = 0.68, P = 0.000005). No significant relations were found between the diameter of the studied vein, and the angle between the two valves. There was no difference in valve orientation between volunteers and unaffected limbs of the patients with CVD. CONCLUSION: When two valves are present in the areas of venous junctions, they consistently positioned at a significant angle to each other. A hypothesis that venous valves at the junctions increase efficiency of venous return by creating a helical flow pattern can be postulated and deserves further investigation.

Reprinted article "Prospective randomised study of endovenous radiofrequency obliteration (closure) versus ligation and vein stripping (EVOLVeS): two-year follow-up".

PURPOSE: To study intermediate clinical outcomes, rates of recurrent varicosities and neovascularisation, ultrasound changes of the GSV, and the quality of life changes in patients from EVOLVeS trial. METHODS: Forty five patients were re-examined 1 year and 65 two years after treatment. Follow-up visits included clinical examination with CEAP classification and calculation of venous clinical severity score (VCSS), ultrasound examination, and a quality of life questionnaire. RESULTS: The clinical course of the disease (CEAP, VCSS) was similar in the two treatment groups. 51% of the GSV trunks occluded by RFO underwent progressive shrinkage with the external diameter decreased from 6.3 SD 1.4 mm at 72 h after treatment to 2.9 SD 1.5 mm at 2 years. An additional 41% of the GSV became undetectable by ultrasound at 2-year follow up. In two patients we observed re-opening of an initially closed GSV lumen. Neovascularisation was found in one RFO case and in four S and L cases. Cumulative rates of recurrent varicose veins at combined 1 and 2 years follow-up were 14% for RFO and 21% for S and L (NS). The difference in global QOL score in favour of RFO re-appeared at 1 year and remained significant at 2 years after treatment. CONCLUSION: The 2-year clinical results of radiofrequency obliteration are at least equal to those after high ligation and stripping of the GSV. In the vast majority of RFO patients the GSV remained permanently closed, and underwent progressive shrinkage to eventual sonographic disappearance. Recurrence and neovascularisation rates were similar in the two groups although limited patient numbers prevent reliable statistical analysis. Improved quality of life scores persisted through the 2-year observations in the RFO group compared to the S and L group.

Duplex ultrasound investigation of the veins of the lower limbs after treatment for varicose veins - UIP consensus document.

OBJECTIVES: Duplex ultrasound has become the reference standard in assessing the morphology and haemodynamics of the lower limb veins. The project described in this article was an initiative of the Union Internationale de Phlébologie (UIP). The aim was to obtain a consensus of international experts on the methodology and terminology to be used for assessment after treatment of incompetent superficial and perforating veins in the lower limb by ultrasound imaging. DESIGN: The study design was consensus meetings leading to a consensus document. METHODS: The UIP invited group submitted relevant literature references and written contributions concerning the methodology, terminology and value of duplex imaging after treatment. The authors prepared a draft document that was circulated to a larger group of experts and revised according to the comments received. Eventually, all participants agreed upon the final version of the article. RESULTS: Formal analysis of the results of interventions for varicose veins relies on adequate preoperative assessment and a careful description of the procedure employed. The timing of investigations of outcome should be classified as immediate (1-4 weeks), short-term (1 year), midterm (2-3 years) and long-term (5 years or more). The examination should employ standard methodology and formally described variables, which can be tailored to the intervention that was undertaken. The experts have made detailed recommendations concerning the methods to be used for duplex ultrasound examination and reporting after various treatments for varicose veins, including novel treatments under scientific study. CONCLUSIONS: Duplex ultrasonography is a fundamental component of the investigation of the lower limb venous system after treatment for varicose veins.

Invasive treatment of deep venous disease. A UIP consensus.

Deep venous disease includes primary and/or secondary pathological changes in the deep venous system. These may consist of valve insufficiency, complete or incomplete vein obliteration and/or functional impairment.

Venous haemodynamics: what we know and don't know.

The presence of haemodynamic abnormalities in chronic venous disease (CVD) has been well established. The relationships between these abnormalities and clinical manifestations, or natural history of CVD, are complex and remain to be investigated. Flow-mediated processes and mechanisms unrelated to blood flow may play an important role in the pathophysiology of CVD. Current state of knowledge makes questionable a possibility of building treatment strategies based on a single simplified model of the disease. As an example of such simplified approach, CHIVA introduces an opportunity to critically assess the gaps in knowledge in venous pathophysiology.

Effects of isovolemic resuscitation with hemoglobin-based oxygen carrier Hemoglobin glutamer-200 (bovine) on systemic and mesenteric perfusion and oxygenation in a canine model of hemorrhagic shock: a comparison with 6% hetastarch solution and shed blood.

OBJECTIVE: To study Hemoglobin glutamer-200 bovine (Hb-200), 6% hetastarch (HES) and shed whole blood (WB) resuscitation in canine hemorrhagic shock. STUDY DESIGN: Prospective laboratory investigation. Animals Twelve adult dogs [29 +/- 1 kg (mean +/- SD)]. METHODS: Anesthetized dogs were instrumented for recording systemic and mesenteric hemodynamic parameters and withdrawal of arterial, mixed and mesenteric venous blood, in which hematological, oxygenation, blood gas and acid-bases variables were determined. Recordings were made before [baseline (BL)], after 1 hour of hypovolemia and immediately and 3 hours post-resuscitation with 30 mL kg(-1) of either Hb-200, HES, or WB. RESULTS: Blood withdrawal (average 34 +/- 2 mL kg(-1)) caused significant hemodynamic changes, metabolic acidosis and hyperlactatemia characteristic for hemorrhagic shock. Only WB transfusion restored all variables. Hemoglobin glutamer-200 bovine infusion returned most hemodynamic parameters including cardiac output and mesenteric arterial blood flow to BL but increased mean arterial pressure above BL (p < 0.05). However, Hb-200 failed to restore total Hb and arterial oxygen content (CaO2), leaving systemic (DO2I) and mesenteric O2 delivery (DO2Im) below BL (p < 0.05). Nevertheless, acid-base variables recovered completely after Hb-200 resuscitation, and met-hemoglobin (Met-Hb) levels increased (p < 0.05). Hetastarch resuscitation returned hemodynamic variables to or above BL but further decreased total Hb and CaO2, preventing recovery of sDO2I and mDO2I (p < 0.05). Thus, systemic and mesenteric O2 extraction stayed above BL (p < 0.05) while acid-base variables recovered to BL, although slower than in Hb-200 and WB groups (p < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Resuscitation with Hb-200 seemed to resolve metabolic acidosis and lactatemia more rapidly than HES, but not WB; yet it is not superior to HES in improving DO2I and DO2Im. The hyperoncotic property of solutions like Hb-200 that results in rapid volume expansion with more homogenous microvascular perfusion and the ability to facilitate diffusive O2 transfer accelerating metabolic recovery may be the key mechanisms underlying their beneficial effects as resuscitants.

Prospective randomised study of endovenous radiofrequency obliteration (closure) versus ligation and vein stripping (EVOLVeS): two-year follow-up.

PURPOSE: To study intermediate clinical outcomes, rates of recurrent varicosities and neovascularisation, ultrasound changes of the GSV, and the quality of life changes in patients from EVOLVeS trial. METHODS: Forty five patients were re-examined 1 year and 65 two years after treatment. Follow-up visits included clinical examination with CEAP classification and calculation of venous clinical severity score (VCSS), ultrasound examination, and a quality of life questionnaire. RESULTS: The clinical course of the disease (CEAP, VCSS) was similar in the two treatment groups. 51% of the GSV trunks occluded by RFO underwent progressive shrinkage with the external diameter decreased from 6.3 SD 1.4 mm at 72 h after treatment to 2.9 SD 1.5 mm at 2 years. An additional 41% of the GSV became undetectable by ultrasound at 2-year follow up. In two patients we observed re-opening of an initially closed GSV lumen. Neovascularisation was found in one RFO case and in four S and L cases. Cumulative rates of recurrent varicose veins at combined 1 and 2 years follow-up were 14% for RFO and 21% for S and L (NS). The difference in global QOL score in favour of RFO re-appeared at 1 year and remained significant at 2 years after treatment. CONCLUSION: The 2-year clinical results of radiofrequency obliteration are at least equal to those after high ligation and stripping of the GSV. In the vast majority of RFO patients the GSV remained permanently closed, and underwent progressive shrinkage to eventual sonographic disappearance. Recurrence and neovascularisation rates were similar in the two groups although limited patient numbers prevent reliable statistical analysis. Improved quality of life scores persisted through the 2-year observations in the RFO group compared to the S and L group.

Prospective randomized study of endovenous radiofrequency obliteration (closure procedure) versus ligation and stripping in a selected patient population (EVOLVeS Study).

PURPOSE: This study was designed as a prospective multicenter randomized comparison of procedure-related complications, patient recuperation, and quality-of-life outcomes between patients undergoing vein stripping with high ligation and patients undergoing great saphenous vein (GSV) obliteration with temperature-controlled radiofrequency ablation without adjunctive high ligation (Closure procedure). METHODS: Eighty-five patients (86 limbs) from five sites (France, 2; Austria, 1; United States, 2) were randomly allocated to undergo radiofrequency obliteration (RFO) or stripping and high ligation (S&L). Final analysis included data for 44 limbs in the RFO group and 36 limbs in the S&L group. Follow-up examinations were performed at 72 hours, 1 week, 3 weeks, and 4 months. All patients completed the CIVIQ2 quality-of-life (QOL) questionnaire and underwent clinical and ultrasound examinations at each follow-up visit. RESULTS: Immediate success on the day of treatment was reported for 95% (42 of 44) of limbs in the RFO group and 100% (36 of 36) of limbs in the S&L group. In seven RFO limbs (16.3%) a scan obtained 72 hours after the procedure showed flow in the proximal GSV. Five of these segments had reflux in the open segment. At 1 week two of these closed, and an additional segment closed at 3 weeks. In no cases did flow reappear after complete occlusion of the GSV. Time to return to normal activities was significantly less in the RFO group (mean, 1.15 days; 95% confidence interval [CI], 0.05-2.34) compared with the S&L group (mean, 3.89 days; CI, 2.67-5.12; P =.02). In the RFO group, 80.5% of patients returned to routine activities of daily living within 1 day, compared with 46.9% of patients in the S&L group (P <.01). Patients in the RFO group were able to return to work in 4.7 days (CI, 1.16-8.17), compared with 12.4 days (CI, 8.66-16.23) for the S&L group (P <.05). Analysis of the QOL surveys showed statistically significant differences in favor of the RFO group for global score and pain score during follow-up. The magnitude of the difference, however, progressively decreased between 1 week and 4 months. CONCLUSIONS: In the absence of significant complications, such as deep vein thrombosis and pulmonary embolism, severe neuritic sequelae, and skin burns, there are significant early advantages to endovascular obliteration of the GSV compared with conventional vein stripping.

Effects of haemoglobin-based oxygen carrier hemoglobin glutamer-200 (bovine) on intestinal perfusion and oxygenation in a canine hypovolaemia model.

The objective of this investigation was to study the effects of the first marketed haemoglobin-based oxygen carrier, Hemoglobin glutamer-200 (bovine) (Hb-200) (Oxyglobin) on splanchnic perfusion and oxygenation in a canine model of acute hypovolaemia. Twelve anaesthetized dogs [mean weight 30.8 (S.D. 1.4) kg] were instrumented for recordings of heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), cardiac output and cranial mesenteric arterial (CMA) and venous blood flows (CMV). Total and plasma haemoglobin (Hb), oxygen content and saturation, lactate concentration, pH and blood gases were analysed in arterial, mixed venous and mesenteric venous blood samples. Measurements were made before (baseline) and after 1 h of haemorrhage, after which animals were resuscitated with either shed blood (controls) or Hb-200 until HR, MAP and CVP returned to prehaemorrhage levels. Recordings were repeated immediately and 3 h after termination of fluid resuscitation, after which organ specimens were obtained for microscopic examination. Haemorrhage (average 32 ml kg(-1)) reduced MAP to 50 mm Hg, increased HR and systemic vascular resistance (SVR), and was accompanied in both the systemic and the splanchnic circulation by significant decreases in blood flow, Hb content and oxygen delivery (DO2), and lactic acidosis. In controls, all variables recovered to baseline after isovolaemic resuscitation with shed blood. In dogs resuscitated with a small volume of Hb-200 (10 ml kg(-1)), HR, MAP, CVP and CMA and CMV blood flows returned to baseline. However, cardiac output, total Hb, oxygen content and systemic and mesenteric DO2 remained depressed while SVR increased further. Mesenteric and systemic acid-base status recovered in both groups, and there was no difference in microscopic tissue damage between groups. Thus, Hb-200 reconstituted splanchnic perfusion and oxidative metabolism in spite of pronounced systemic vasoconstriction and insufficient restoration of CO and DO2; it may improve diffusive oxygen transport in the microvasculature by virtue of haemodilution and its high efficiency in the uptake and release of oxygen.

The effects of hemoglobin glutamer-200 (bovine) on the microcirculation in a canine hypovolemia model: a noninvasive computer-assisted intravital microscopy study.

UNLABELLED: We sought to correlate in vivo microvascular, systemic function, hemodynamic, and oxygenation changes in autologous shed blood (n = 4) and hemoglobin glutamer-200 (Hb-200) (n = 4) resuscitations in hypovolemic dogs. Hemorrhage (approximately 40% blood loss) reduced mean arterial pressure to approximately 50 mm Hg and caused significant (P < 0.01) decreases in hematocrit, total hemoglobin, mean pulmonary arterial pressure, cardiac output, and oxygen delivery and significant (P < 0.01) increases in heart rate, systemic vascular resistance, and lactic acidosis. Significant (P < 0.01) changes in conjunctival microvascular variables also occurred, including a 19% decrease in venular diameter and 79% increase in average blood flow velocity. Shed blood resuscitation returned microvascular, systemic function, hemodynamic, and oxygenation variables to prehemorrhagic baseline values. In contrast, Hb-200 failed to restore hematocrit, total hemoglobin, cardiac output, oxygen delivery index, and systemic venous resistance to baseline, but it restored other systemic functions and all hemodynamic and microvascular changes. In addition, Hb-200 resuscitation in hypovolemic dogs (approximately 40% blood loss) did not cause extreme hemodilution or fatal outcome. This study confirms that real-time (in vivo) microvascular studies, which were conducted only in small rodent models in the past, can be performed simultaneously with systemic function, hemodynamic, and oxygenation studies in a large animal model for relevant data correlation. IMPLICATIONS: This is the first time that changes in the blood circulation have been studied, quantified, and correlated with systemic function, hemodynamic, and oxygenation changes in shock and during shock treatment in a large animal model. This study was performed by a new technology developed in-house to noninvasively and quantitatively study blood vessels in real time.

Inadequacy of low-volume resuscitation with hemoglobin-based oxygen carrier hemoglobin glutamer-200 (bovine) in canine hypovolemia.

Stroma-free hemoglobin-based oxygen carriers (HBOC) have been developed to overcome problems associated with transfusion of allogeneic blood. We have studied the efficacy of the first licensed veterinary blood substitute, hemoglobin glutamer-200 bovine (Oxyglobin; Biopure, Cambridge, MA, USA, Hb-200), in a canine model of acute hypovolemia and examined whether clinically commonly used criteria are adequate to guide fluid resuscitation with this product. Twelve anesthetized dogs were instrumented for measurements of physiological variables including hemodynamic, oxygenation, and blood gas and acid-base parameters. Dogs were bled to a mean arterial pressure (MAP) of 50 mmHg for 1 h followed by resuscitation with either shed blood (controls) or Hb-200 until heart rate (HR), MAP and central venous pressure (CVP) returned to baseline. Recordings were repeated immediately and 3 h after termination of fluid resuscitation. Hemorrhage (average 32 mL/kg) caused significant decreases in total hemoglobin (Hb), mean pulmonary arterial pressure (PAP), cardiac output (CO) and oxygen delivery (DO2I), increases in HR and systemic vascular resistance (SVRI), and lactic acidosis. In controls, only re-transfusion of all shed blood returned HR, MAP and CVP to prehemorrhage values, whereas in other dogs this endpoint was reached with infusion of 10 mL/kg Hb-200. Unlike blood transfusion, Hb-200 infusion failed to return CI and DO2I to baseline and to increase arterial oxygen content (CaO2) and total Hb; SVRI further increased. Thus, commonly used criteria (HR, MAP, CVP) to guide transfusion therapy in patients posthemorrhage prove insufficient when HBOCs with pronounced vasoconstrictive action are used and lead to inadequate volume repletion.

Does surgical correction of the superficial femoral vein valve change the course of varicose disease?

PURPOSE: We tested the hypothesis that the course of primary chronic venous insufficiency can be changed by correction of the incompetent valve in the superficial femoral vein. METHODS: This was a prospective, randomized, controlled study. A total of 125 extremities with reflux in greater saphenous and superficial femoral veins and belonging to clinical classes C2-C4 were analyzed. During the first 5 years, the type of clinical dynamics and changes in valvular function were determined in each patient. Patients were stratified according to the type of clinical dynamics and randomly assigned to treatment groups. Phlebectomy was performed in all extremities. In each of 64 extremities (the study group), the proximal incompetent superficial femoral vein valve was corrected as a part of the primary intervention. Patients were followed up for 7 to 8 years after surgery. RESULTS: The clinical dynamics of the extremity significantly depended on reflux changes. Increase in superficial femoral vein reflux was found in 74% of the extremities with progressive clinical dynamics but in only 47% of extremities with stable clinical dynamics (chi(2) = 9.71; P <.01). After surgical treatment, 65% of the extremities in the control group showed stable improvement; in 11%, recurrent varicosity was found; in 24%, the disease was aggravated. Of the extremities in the study group, 86% had stable improvement, 5% had recurrent varicosity, and 10% were aggravated (P <.05). Extremities with the progressive type of clinical dynamics were main contributors to this difference (chi(2) = 7.86; P <.05). In 92% of the extremities with corrected valves and in 50% of the extremities with increase in reflux after valvuloplasty, clinical improvement was observed (chi(2) = 11.5; P <.01). Extremities with corrected valvular function demonstrated superior results in comparison with extremities with stable valvular function in the control group (clinical improvement in 92% and 66% of extremities, respectively; P <.005). CONCLUSIONS: In patients with chronic venous insufficiency, two types of clinical dynamics, stable and progressive, can be identified. The progressive type is associated with the presence of superficial femoral vein reflux and increasing greater saphenous vein reflux. Superficial vein surgery neither corrects superficial femoral vein reflux nor prevents it from progressing further. Correction of a single superficial femoral vein valve during primary intervention significantly improves the long-term results of superficial venous surgery. This improvement is associated with the prevention of reflux progression. Surgical correction of the incompetent superficial femoral vein valve changes the course of primary chronic venous insufficiency.

A novel approach to measuring circulating blood volume: the use of a hemoglobin-based oxygen carrier in a rabbit model.

UNLABELLED: Hemoglobin-based oxygen carriers (HBOC) may be ideal for monitoring circulating plasma volume (CV-P) and circulating blood volume (CV-B). We used an HBOC (Hemoglobin glutamer-200 [bovine], Oxyglobin; Biopure, Cambridge, MA) as an indicator for relative CV-B in the rabbit model. Accuracy of the technique was determined by comparison with the Evans blue dye (EBD) dilution technique in 19 anesthetized female New Zealand rabbits weighing 2.0 to 10.6 kg. The measurements were performed at baseline, after hemorrhage (1/3 of CV-B), normovolemic hemodilution (replacement of 1/3 CV-B by Hextend; Abbot Laboratories, North Chicago, IL), and hypervolemic hemodilution (additional infusion of Hextend(R) in a volume equal to 1/3 of CV-B). Hemoglobin concentration was measured by using a HemoCue photometer (HemoCue AB, Angelholm, Sweden). EBD concentration was analyzed by using linear regression to estimate Time 0 concentration; Time 0 was defined as EBD injection time. The difference between CV-P values determined by EBD and HBOC dilution was independent from the magnitude of the CV-P value. The relative bias was 1.29 mL, and the precision (one SD) was 2.82 mL. The difference did not reach statistical significance. IMPLICATIONS: Circulating plasma and blood volumes can be accurately estimated by plasma hemoglobin concentration measurements by using hemoglobin-based oxygen carrier infusion.