1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase inhibitor, lowers L-NAME-induced hypertension through suppression of angiotensin-converting enzyme in rats.

OBJECTIVE: This study evaluated the efficacy of the soluble epoxide hydrolase (sEH) inhibitor, TPPU on chronic NG-Nitro L-arginine methyl ester (L-NAME)-induced hypertension in rats and its effects on plasma Angiotensin II (Ang II), cardiac Angiotensin-converting enzyme (ACE) and Angiotensin II receptor type 1 (AT1R) expressions. MATERIALS AND METHODS: Forty Sprague Dawley rats were divided into 5 groups. Two groups served as control and received orally either vehicle or TPPU (3 mg/kg) for five weeks. The other three groups were given L-NAME (50 mg/kg/day) in drinking water for five weeks. Two weeks after the L-NAME treatment, animals received orally either saline or TPPU (3 mg/kg/day) or lisinopril (10 mg/kg/day) daily for 3 weeks. Blood pressure (BP) was measured weekly. At the end of the experiment, plasma Ang II, cardiac ACE and AT1R protein and gene expressions were determined. RESULTS: L-NAME caused a significant increase in BP of the animals. TPPU and lisinopril resulted in normalization of L-NAME-induced hypertension. They also caused a significant reduction in Ang II and ACE protein and gene expressions compared to L-NAME and vehicle-treated animals. CONCLUSIONS: This study demonstrates that TPPU effectively lowers L-NAME-induced hypertension in rats. The mechanism of its antihypertensive effect is likely mediated by the suppression of ACE gene and protein expression, leading to a lower Ang II level.

Vascular hepoxilin and trioxilins mediate vasorelaxation through TP receptor inhibition in mouse arteries.

AIM: 12/15-lipoxygenase (12/15-LO) metabolizes arachidonic acid (AA) into several vasoactive eicosanoids. In mouse arteries, we previously characterized the enzyme's 15-LO metabolites 12(S)-hydroxyeicosatetraenoic acid (HETE), 15-HETE, hydroxyepoxyeicosatrienoic acids (HEETAs) and 11,12,15-trihydroxyeicosatrienoic acids (11,12,15-THETAs) as endothelium-derived relaxing factors. However, the observed 12-LO metabolites remained uncharacterized. The purpose of this study was to determine the structure and biological functions of eicosanoids generated by the enzyme's 12-LO activity. METHODS: Metabolites extracted from aortas of C57BL/6 male mice were separated using a series of reverse and normal phase chromatographic steps and identified as hepoxilin A3 , trioxilin A3 and trioxilin C3 by mass spectrometry. Activities of these natural compounds were tested on isometric tension and intracellular calcium release. The role of thromboxane (TP) receptor was determined in HEK293 cells overexpressing TPα receptor (TPα -HEK). RESULTS: All identified vascular 12-LO metabolites were biologically active. In mouse mesenteric arteries, trioxilin A3 , C3 and hepoxilin A3 (3 µm) relaxed arteries constricted with the thromboxane mimetic, U46619-constricted arteries (maximum relaxations of 78.9 ± 3.2, 29.7 ± 4.6, 82.2 ± 5.0 and 88.0 ± 2.4% respectively), but not phenylephrine-constricted arteries. In TPα-HEK cells, trioxilin A3 , C3 and hepoxilin A3 (10 µm) inhibited U46619 (10 nM)-induced increases in intracellular calcium by 53.0 ± 7.2%, 32.8 ± 5.0% and 37.9 ± 13.5% respectively. In contrast, trioxilin B3 and hepoxilin B3 were not synthesized in arteries and exhibited little biological activity. CONCLUSION: Trioxilin A3 and C3 and hepoxilin A3 are endogenous vascular relaxing factors. They are not endothelium-derived hyperpolarizing factors but mediate vascular relaxation by inhibiting TP agonist-induced increases in intracellular calcium. Thus, they regulate vascular homeostasis by acting as endogenous TP antagonists.

Practical guide to the Idea, Development and Exploration stages of the IDEAL Framework and Recommendations.

BACKGROUND: Evaluation of new surgical procedures is a complex process challenged by evolution of technique, operator learning curves, the possibility of variable procedural quality, and strong treatment preferences among patients and clinicians. Preliminary studies that address these issues are needed to prepare for a successful randomized trial. The IDEAL (Idea, Development, Exploration, Assessment and Long-term follow-up) Framework and Recommendations provide an integrated step-by-step evaluation pathway that can help investigators achieve this. METHODS: A practical guide was developed for investigators evaluating new surgical interventions in the earlier phases before a randomized trial (corresponding to stages 1, 2a and 2b of the IDEAL Framework). The examples and practical tips included were chosen and agreed upon by consensus among authors with experience either in designing and conducting IDEAL format studies, or in helping others to design such studies. They address the most common challenges encountered by authors attempting to follow the IDEAL Recommendations. RESULTS: A decision aid has been created to help identify the IDEAL stage of an innovation from literature reports, with advice on how to design and report the IDEAL study formats discussed, along with the ethical and scientific rationale for specific recommendations. CONCLUSION: The guide helps readers and researchers to understand and implement the IDEAL Framework and Recommendations to improve the quality of evidence supporting surgical innovation.

Survey of management of common iliac artery aneurysms by members of the Vascular Society of Great Britain and Ireland.

INTRODUCTION: The aim of this study was to determine whether the current management of common iliac artery aneurysms (CIAAs) by vascular surgeons is in tune with existing guidelines for referral. METHODS: This was a postal survey of members of the Vascular Society of Great Britain and Ireland. The main outcome measures were relative frequency of ruptured CIAA, respondents' size threshold for surveillance versus intervention, and their management strategies for isolated unilateral CIAAs, bilateral CIAAs and aortoiliac aneurysms. RESULTS: Two hundred and eighty-four (anonymous) replies were received (48% response rate). Respondents estimated that a ruptured abdominal aortic aneurysm (AAA) was 25 times more common than a ruptured CIAA. Most surgeons (64%) would wait until a CIAA reached 4 cm in diameter before considering intervention. This threshold was not affected by other scenarios such as the presence of a bilateral CIAA or a small (4 cm) AAA. Eighty per cent of surgeons would treat a non-ruptured CIAA by stenting, where possible. The majority of surgeons felt that ultrasonography surveillance should be commenced when a CIAA exceeds 1.5 cm, with a surveillance interval of 1 year but with more frequent surveillance for CIAAs wider than 3 cm. CONCLUSIONS: Existing guidelines that recommend referral for possible intervention for non-ruptured CIAAs at a diameter of 3 cm are out of tune with current practice. Most surgeons in this survey would wait until the diameter was 4 cm.

Prophylaxis of venous thromboembolism in general surgery: guidelines differ and we still need local policies.

INTRODUCTION: Venous thromboembolism (VTE) prophylaxis has become a major issue for surgeons both in the UK and worldwide. Several different sources of guidance on VTE prophylaxis are available but these differ in design and detail. METHODS: Two similar audits were performed, one year apart, on the VTE prophylaxis prescribed for all general surgical inpatients during a single week (90 patients and 101 patients). Classification of patients into different risk groups and compliance in prescribing prophylaxis were examined using different international, national and local guidelines. RESULTS: There were significant differences between the numbers of patients in high, moderate and low-risk groups according to the different guidelines. When groups were combined to indicate simply 'at risk' or 'not at risk' (in the manner of one of the guidelines), then differences were not significant. Our compliance improved from the first audit to the second. Patients at high risk received VTE prophylaxis according to guidance more consistently than those at low risk. CONCLUSIONS: Differences in guidance on VTE prophylaxis can affect compliance significantly when auditing practice, depending on the choice of 'gold standard'. National guidance does not remove the need for clear and detailed local policies. Making decisions about policies for lower-risk patients can be more difficult than for those at high risk.

A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: the VULCAN trial.

OBJECTIVE: To examine the effectiveness and cost-effectiveness of antimicrobial silver-donating dressings for venous leg ulcers compared with simple non-adherent (also known as low-adherent) dressings. DESIGN: A pragmatic, prospective randomised controlled trial (RCT) and cost-effectiveness analysis of silver-donating versus low-adherent dressings in the treatment of venous leg ulcers. A non-randomised observational group was also recruited. SETTING: Primary and secondary care services in the north and south of England (Sheffield and Exeter). PARTICIPANTS: Consenting patients with active ulceration of the lower leg that had been present for a period of greater than 6 weeks. INTERVENTIONS: Patients were randomised to receive either a silver-donating or non-silver low-adherent dressing applied beneath compression bandages or hosiery. The choice of dressing within these groups was left to clinician preference. Evaluation was by clinical assessment, supplemented by evaluation of quality of life and cost-effectiveness. MAIN OUTCOME MEASURES: The primary outcome measure was complete ulcer healing at 12 weeks in the index limb. Secondary measures were costs and quality-adjusted life-years (QALYs), cost-effectiveness, time to healing, and recurrence rate at 6 months and 1 year. RESULTS: In total, 304 participants were recruited to the clinical trial: 213 to the RCT and 91 to the observational arm. Within the RCT 107 were randomised to antimicrobial dressings and 106 to the control dressings. There were no significant differences (p > 0.05) between the two groups for the primary outcome measure of proportion of ulcers healed at 12 weeks (59.6% for silver and 56.7% for control dressings). The overall median time to healing was also not significantly different between the two groups (p = 0.408). A total of 24 patients had recurrent ulcers within 1 year; the recurrence rates of 11.6% (n = 11) for the antimicrobial and 14.4% (n = 13) for the control dressings were not significant. Mean utility valuations for both the EuroQol 5 dimensions (EQ-5D) quality of life questionnaire and Short Form 6 dimensions (SF-6D) utility index showed no differences for either group at 1, 3, 6 or 12 months. Compared with the control group, the antimicrobial group had an incremental cost of 97.85 pounds and an incremental QALY gain of 0.0002, giving an incremental cost-effectiveness ratio for the antimicrobial dressings of 489,250 pounds. Cost-effectiveness modelling of the results of the RCT showed that antimicrobial dressings were not cost-effective. CONCLUSIONS: No significant differences in either primary or secondary end points were found between the use of antimicrobial silver-donating dressings and the control group of low-adherent dressings. Modelling showed that antimicrobial silver dressings were not cost-effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN72485131.

Return to work, driving and other activities after varicose vein surgery is very variable and is influenced little by advice from specialists.

OBJECTIVES: To determine the effect of altering written advice on return to activities following varicose vein surgery. METHODS: During two consecutive four-month periods, 134 patients (84 female, median age 57 years) were given two different information booklets. The first booklet (76 patients) suggested 7-10 days before driving and 2-3 weeks before returning to work. The second booklet (58 patients) explicitly advised return to all activities as soon as possible. Patients were contacted 6 weeks following surgery. Advice was sought from motor insurance companies about their views on return to driving. RESULTS: There was huge variation in time to driving (0-35 days, median 7), work (1-45 days, median 14) and "all normal activities" (1-62 days, median 21), but no significant differences between the two groups. There were paradoxes in the delays to driving and different types of work. Delays to driving or work were longer after bilateral surgery (p=0.01). CONCLUSION: Changing written advice did not influence the time to return to activities following varicose vein surgery, which was highly variable. Other factors may influence recovery and may be challenging for specialists to change. Consistent advice is important when comparing recovery from different treatments.

The symptoms of varicose veins: difficult to determine and difficult to study.

OBJECTIVES: To investigate the activities which may exacerbate symptoms in patients with varicose veins. METHODS: Questionnaires sent to patients before clinics and at least six months later. RESULTS: Both questionnaires were returned by 149 of 203 patients (74%) but only 124 contained adequate data for comparison--55 from patients who had surgical treatment and 69 who had no surgery. At initial presentation, worsening of discomfort attributed to varicose veins was common during (58%) or after (48%) standing and in hot weather (44%), but less when sitting with the feet down (31%), and after (31%) or when walking (19%). Surgery significantly reduced the total number of symptoms reported by patients at follow-up (p<0.02). However, none of the symptoms reported during specific activities was significantly lessened by surgery compared with no treatment--possibly because the attrition of patients during the study resulted in small numbers for analysis. CONCLUSIONS: Symptoms are a common indication for treating varicose veins and it is therefore important to be sure that they are due to the veins, rather than other causes. This report highlights traditional and logical questions which may help to identify symptoms caused by varicose veins but illustrates the difficulty of validating them.

Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

OBJECTIVES: To establish the cost-effectiveness of surgery and sclerotherapy for the treatment of varicose veins. DESIGN: Randomised controlled trials (RCTs) were carried out for conservative treatment, sclerotherapy and surgery for varicose veins. An economic analysis was carried out alongside the randomised trial. Economic modelling was undertaken based on the primary data collection and a literature review (database searches undertaken in April 2000 and updated in March 2001). SETTING: Primary data collection was from a large district general hospital and a teaching hospital both in England over a 2-year period from January 1999. Cost-effectiveness analysis and economic modelling were carried out using an NHS perspective. PARTICIPANTS: A total of 1009 patients were recruited. INTERVENTIONS: Thirty-four patents were randomised in Group 1 (minor varicose veins with no reflux, randomised between conservative treatment and sclerotherapy), 77 in Group 2 (moderate varicose veins with reflux, randomised between surgery and sclerotherapy) and 246 in Group 3 (severe varicose veins with reflux, randomised between conservative treatment and surgery). The remaining 652 patients formed the observational part of the study. MAIN OUTCOME MEASURES: The cost-effectiveness analysis was based on NHS treatment costs for the 2002--3 financial year, and utilities based on the Short Form 6D (SF-6D) preference-based health measure. For the clinical trial, the outcome measures were health-related quality of life (HRQoL) [Short Form with 36 Items (SF-36), EuroQol quality of life questionnaire (EQ-5D), visual analogue scale (VAS) and standard gamble], symptomatic relief, anatomical extent (for which a new classification was developed and validated), patient satisfaction and the incidence of complications. RESULTS: Of the RCTs, only the Group 3 trial was large enough to provide clear results. This showed that surgical treatment produced better results than conservative treatment in terms of HRQoL, symptomatic relief, anatomical extent and patient satisfaction. Clinical outcomes of surgery and sclerotherapy showed significant improvement in the extent of varicose veins, symptomatic and HRQoL parameters. Cost-effectiveness analysis based on the Group 3 trial showed that the surgery produced an estimated discounted benefit of 0.054 quality-adjusted life-year (QALY) over a 2-year period, with an additional discounted cost of pound 387.45, giving an incremental cost-effectiveness ratio (ICER) of pound 7175 per QALY. Economic modelling suggested that surgery produced a still greater benefit when considered with a 10-year time horizon, with an ICER of pound 1936 per QALY. Injection sclerotherapy produced an incremental benefit of approximately 0.044 QALY at a cost of pound 155 when compared with conservative treatment, giving an ICER of pound 3500 per QALY. When surgery was compared with sclerotherapy, surgery produced greater benefit with a lower ICER (showing extended dominance). CONCLUSIONS: Standard surgical treatment of varicose veins by saphenofemoral ligation, stripping and multiple phlebectomies is a clinically effective and cost-effective treatment for varicose veins, with an ICER well below the threshold normally considered appropriate for the funding of treatments within the NHS. Injection sclerotherapy also appears to be cost-effective, but produces less overall benefit, with a higher ICER than surgery for patients with superficial venous reflux. In minor varicose veins without reflux, sclerotherapy is likely to provide a small average benefit with acceptable cost-effectiveness. Research is needed into methods for accurate and acceptable utility evaluations for conditions with relatively minor effect on HRQoL and also for a validated and standardised method of classification for varicose veins.

Use of a pneumatic tourniquet improves outcome following trans-tibial amputation.

BACKGROUND: It is traditionally taught that a pneumatic tourniquet is contraindicated for trans-tibial amputations in patients with peripheral arterial disease. However, tourniquets are used successfully during total knee arthroplasty in elderly patients. Vascular patients undergoing a trans-tibial amputation have a high perioperative mortality and morbidity-notably the need for wound revision or a higher amputation level. We hypothesised that a tourniquet, used during amputation, would reduce blood loss and subsequent complications without compromising healing. METHODS: This was a prospective non-randomized study of 89 adult patients who underwent a trans-tibial amputation between January 2001 and December 2003. The endpoints were: haemoglobin levels, the need for blood transfusion, perioperative morbidity, revision rate and mortality. Patients were divided into two groups: a group with a pneumatic tourniquet (n=42) and a group without (n=47). RESULTS: The haemoglobin fall was 14.8% in the non-tourniquet group and 5.6% in the tourniquet group, with a higher need for transfusion in the non-tourniquet group. The revision rate was 14.3% in the tourniquet group and significantly higher in the non-tourniquet group (38.3%). Mortality was similar in both groups: 7.1% for the tourniquet and 6.4% for the non-tourniquet group. CONCLUSION: The use of a pneumatic tourniquet is safe and significantly reduces both blood loss and transfusion requirements during trans-tibial amputation. A pneumatic tourniquet reduces revision rates by over 50%, with subsequent cost savings.

Cost-effectiveness analysis of surgery versus conservative treatment for uncomplicated varicose veins in a randomized clinical trial.

BACKGROUND: Despite being a common procedure, the cost effectiveness of surgery for varicose veins has not been established. METHODS: Cost-effectiveness analysis was carried out alongside a randomized clinical trial at two vascular units within National Health Service (NHS) hospitals. Some 246 patients with uncomplicated varicose veins and evidence of saphenofemoral or saphenopopliteal reflux were allocated randomly to receive either conservative management or surgical treatment. Incremental cost per quality-adjusted life year (QALY) gained at 24 months following randomization was calculated. RESULTS: Total NHS costs during the 2-year study period were higher for the surgically treated group (733 UK pounds) than for those who had conservative treatment (345 UK pounds). The difference in costs was statistically significant. The mean incremental health gain from surgical treatment at 24 months was 0.083 QALYs, leading to a base-case estimate of 4682 UK pounds per QALY gained. Assuming an implicit threshold maximum willingness-to-pay value of 20 000 UK pounds for a QALY, the probability of surgical treatment for varicose veins falling below this threshold value was 70 per cent. This result was found to be robust to sensitivity analysis. CONCLUSION: For patients with uncomplicated varicose veins and evidence of saphenofemoral or saphenopopliteal reflux, surgical treatment for varicose veins offers a modest health benefit for relatively little additional NHS cost relative to conservative treatment.

Randomized clinical trial comparing surgery with conservative treatment for uncomplicated varicose veins.

BACKGROUND: Surgical treatment of medically uncomplicated varicose veins is common, but its clinical effectiveness remains uncertain. METHODS: A randomized clinical trial was carried out at two large acute National Health Service hospitals in different parts of the UK (Sheffield and Exeter). Some 246 patients were recruited from 536 consecutive referrals to vascular outpatient clinics with uncomplicated varicose veins suitable for surgical treatment. Conservative management, consisting of lifestyle advice, was compared with surgical treatment (flush ligation of sites of reflux, stripping of the long saphenous vein and multiple phlebectomies, as appropriate). Changes in health status were measured using the Short Form (SF) 6D and EuroQol (EQ) 5D, quality of life instruments based on SF-36 and EuroQol, complications of treatment, symptomatic measures, anatomical extent of varicose veins and patient satisfaction. RESULTS: In the first 2 years after treatment there was a significant quality of life benefit for surgery of 0.083 (95 per cent confidence interval (c.i.) 0.005 to 0.16) quality-adjusted life years (QALYs) based on the SF-6D score and 0.13 (95 per cent c.i. 0.016 to 0.25) based on the EQ-5D score. Significant benefits were also seen in symptomatic and anatomical measures. CONCLUSION: Surgical treatment provides symptomatic relief and significant improvements in quality of life in patients referred to secondary care with uncomplicated varicose veins.

Most patients with varicose veins have fears or concerns about the future, in addition to their presenting symptoms.

INTRODUCTION: This study aimed to document fears and concerns of patients about their varicose veins. REPORT: Completed questionnaires about symptoms and concerns were brought to clinic by 62% (203/329) patients referred with uncomplicated primary varicose veins. 'Concerns, worries or fears' about their veins were reported by 79%. These were seldom mentioned in referral letters, and included fears about thrombosis (31%), trauma (16%), ulcers (15%) and general concerns about the future (57%). DISCUSSION: Many patients have unrecognised fears and concerns about their varicose veins. Specific enquiry and reassurance about these is part of good management and may avoid unnecessary treatment.

The clinical effectiveness of hand held Doppler examination for diagnosis of reflux in patients with varicose veins.

OBJECTIVE: To assess the accuracy of hand held Doppler (HHD) as a rapid screening test for selecting varicose vein patients for duplex imaging. DESIGN: Prospective single blind study of consecutive patients in a randomised trial. MATERIALS: Use of hand held Doppler and duplex ultrasound scanners. METHODS: One thousand two hundred and eighteen legs (943 patients) were examined by HHD and then duplex. HHD examiners recorded whether they would normally have requested duplex. RESULTS: HHD results of one Clinical Assistant (166 limbs) were significantly poorer than all others and his results were excluded from analysis. Duplex would not have been requested in 645 of 1052 (62%) limbs. Among these HHD missed significant reflux in the long saphenous vein in 18 (3%) and the short saphenous in 25 (4%). Reasons for requesting duplex were popliteal fossa reflux (202); recurrent (94) or atypical (86) varicose veins; and possible previous thrombosis (67). Differences were observed between staff and units in requests for duplex; and in thoroughness and style of duplex reporting. CONCLUSIONS: Selective use of HHD can avoid duplex imaging for many patients, with a low failure rate for detecting correctable venous reflux. Observed variations between individuals and units in results of HHD and duplex imaging have implications for the increasing use of duplex by clinicians.

Venous ulcer services in the United Kingdom.

OBJECTIVES: To obtain comprehensive information about venous ulcer services throughout the United Kingdom (UK). DESIGN: Questionnaire based survey. MATERIALS: Questionnaire. METHODS: Letters about venous ulcer services were sent to consultant vascular surgeons in all areas of the UK (total 181). Questionnaires were then directed to the appropriate clinician in each area. RESULTS: Responses were received from 177 (98%) areas. Fifteen (8%) had no dedicated service. Completed questionnaires were returned for 112 (63%) areas. Fifty-six (54%) services were managed by acute hospitals, 29 (28%) by primary care (community) and 19 (18%) jointly. Doctors supervised services in 65 (64%) (vascular surgeons 49, dermatologists 12, both 4) and nurses in 31 (33%). New referrals per week were 1-50 based on audit (33%) or estimates (67%). Sixty-three (58%) services had no database. Written guidelines existed for 76% services (90% nurse-supervised and 64% doctor-supervised services--p<0.02). CONCLUSIONS: Dedicated venous ulcer services have been shown to improve healing rates and quality of life. Although now present in most areas of the UK, their organisation varies considerably and many are not based in the community, near patients homes. This survey provides a benchmark for comparison with venous ulcer services in other countries.

Sites of implantation for central venous access devices (ports): a study of the experiences and preferences of patients.

OBJECTIVE: To obtain information which might guide vascular specialists and their patients in the choice of site for implantation of central venous access devices (CVADs). DESIGN: Questionnaire study. METHODS: Questionnaires were sent to 69 patients with cystic fibrosis and 54 (78%) responded (39 females: age 5-63, median 24 years). They had received a total of 79 CVADs placed in the upper chest (60), lower chest (13), thigh (3) and arm (3). Only 46% patients had been offered a choice of site. RESULTS: Questions about 14 specific areas of disability or concern found problems most frequently with discomfort (54%), wearing a seatbelt (51%), cosmetic appearance (44%), scarring (44%), choice of clothing (42%) and lying in bed or sleeping (42%). There were no significant differences between upper and lower chest CVADs. Patients with upper chest CVADs seldom had any problems with use of their arm (12%). 81% CVADs could not be accessed by the patients, and in 39% of these cases patients would have liked to do so. CONCLUSIONS: Many patients complain of few problems with their CVADs, regardless of site, but half have some persistent discomfort. Cosmetic considerations frequently cause concern and patients should be given choice in the site of their CVADs.