Gerard Stansby

COMPARISON OF LASER-DOPPLER PERFUSION IMAGING, LASER-DOPPLER FLOWMETRY, AND THERMOGRAPHIC IMAGING FOR ASSESSMENT OF BLOOD-FLOW IN HUMAN SKIN

In this study we compared three non-invasive methods of measuring skin perfusion, thermographic imaging (TI), laser Doppler flowmetry (LDF) and the new technique of laser Doppler imaging (LDI). Seven normal volunteers were studied in a temperature-controlled room with an ambient temperature of 22 +/- 1 degree C. Images of the left hand were recorded using LDI followed by TI. LDF was then used on two standard locations on the fingers and back of the hand. The measurements were then repeated for a hot (37 degrees C) and then a cold (10 degrees C) challenge. A significant linear correlation (r = 0.960, p < 0.01, with 95% confidence limit of 0.35-0.77, n = 38) was found between LDF and LDI. However, LDF and LDI did not correlate well with TI (r = 0.577, p < 0.01, with 95% confidence limit of 0.32-0.76, n = 38). The LDI method was found to be highly reproducible (mean +/- 1 SD; 625 +/- 30, with coefficient of variation 5%). The blood flow and temperature distribution of skin of the hand was then recorded using TI and LDI in 10 patients (mean age +/- SD, 41.7 +/- 9.9) with scleroderma and eight normal volunteers (mean age +/- SD, 30.6 +/- 6.5). The overall mean blood flow and temperature in the hands of patients with scleroderma (mean +/- SD 444 +/- 265 flux, 29.3 +/- 3.3 degrees C) was significantly (p < 0.0001) lower compared with the normal volunteers (mean +/- SD, 912 +/- 390 flux, 34.0 +/- 3.2 degrees).(ABSTRACT TRUNCATED AT 250 WORDS)

Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication

A systematic review and network meta‐analysis was undertaken to consider the evidence for the efficacy and tolerability of placebo, cilostazol, naftidrofuryl oxalate and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease (PAD).

Influence of platelet count and activity on thromboelastography parameters

It has been suggested that thromboelastography (TEG) can help in limiting or directing the appropriate use of blood products during surgery. However, the contribution of platelets to the TEG profile has not been studied in detail. Blood was taken from eight healthy subjects and eight patients with peripheral arterial disease (PAD). Immunomagnetic separation was achieved by the addition of Dynabeads® labeled with a CD41 murine antibody (to the GPIIb/IIIa receptor) to achieve 90-100% depletion of platelets from blood. This was then titrated with whole blood to achieve platelet counts of approximately 0, 25 and 50% of the original count to compare with whole blood using TEG. Platelet function was also assessed by spontaneous platelet aggregometry (SPA) at baseline and at the 50% dilution. SPA, maximum amplitude (MA) and K time were significantly different in PAD patients compared to controls (P < 0.05). In both controls and PAD patients there was a strong linear correlation between Log10 [platelet count] and MA (r=0.97 for controls, r=0.89 for PAD) and K time (r=−0.86 for controls, r=−0.68 for PAD). Correlation between Log10 [platelet count] and R time was poor in both groups. The MA and K TEG parameters may be most useful for assessing platelet transfusion requirements.

The use of citrated whole blood in thromboelastography.

H artet developed thromboelastography in 1948 (1). This technique is used to evaluate the viscoelastic properties of blood during coagulation. The Thrombelastograph Coagulation Analyzer 3000 (TEG; Haemoscope, Skokie, IL) can be used to assess the interaction of platelets with the protein coagulation cascade from the time of the initial platelet-fibrin interaction, through platelet aggregation, fibrin cross linkage to eventual clot lysis. Four main variables of clot formation can be measured: reaction time (r), coagulation time (k), angle (a) and maximum amplitude (MA) (2). “Fresh” native whole blood is usually used but must be placed in the TEG no longer than 6 min after venepuncture, ideally at the 4-min stage. Therefore, if delay between venepuncture and starting the profile cannot be avoided, an alternative to “fresh” native whole blood must be sought. Citrated whole blood can be stored at room temperature or at 4°C but must be recalcified before insertion of the pin in the cup. However, to use citrated whole blood, results need to be comparable with those obtained with “fresh” native whole blood. The aim of this study was to establish if “fresh” native whole blood and recalcified citrated whole blood produce comparable results. We also evaluated how long citrated whole blood can be stored and still provide meaningful TEG data.

A Systematic Review and Economic Evaluation of Cilostazol, Naftidrofuryl Oxalate, Pentoxifylline and Inositol Nicotinate for the Treatment of Intermittent Claudication in People with Peripheral Arterial Disease

BACKGROUND Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest. OBJECTIVE To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management. DATA SOURCE Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews). REVIEW METHODS Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle-brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%. RESULTS Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100-500 per year for the other drugs). CONCLUSIONS Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty.

A prospective comparison of bilateral photoplethysmography versus the ankle-brachial pressure index for detecting and quantifying lower limb peripheral arterial disease.

OBJECTIVE This study prospectively assessed the diagnostic accuracy of a novel bilateral photoplethysmography toe pulse measurement technique for the detection of significant lower limb peripheral arterial disease. METHOD Bilateral photoplethysmography toe pulse measurements were compared with the ankle-brachial pressure index (ABPI) gold standard reference. Pulse wave analysis techniques extracted timing, amplitude, and shape characteristics for the great toes and their right-to-left side differences. These characteristics were compared with previously obtained normative ranges, and the accuracy was assessed for all significant disease (ABPI <0.9) and higher-grade disease (ABPI <0.5). Measurements were collected in a controlled environment within a tertiary vascular surgical unit for 111 subjects (age range, 42-91 years), of whom 48 had significant lower limb peripheral arterial disease and 63 were healthy. Subjects were matched in age, sex, height, body mass index, and heart rate. Diagnostic performance was assessed using diagnostic sensitivity, specificity, accuracy, negative-predictive and positive-predictive value, and the kappa statistic representing agreement between techniques beyond chance. RESULTS The degree that pulse shape fell beyond the normal range of normalized pulse shapes was at the threshold of substantial to almost perfect agreement compared with ABPI for significant disease detection (diagnostic accuracy, 91% [kappa = 0.80]; sensitivity, 93%; specificity, 89%), and with 90% accuracy (kappa = 0.65) for higher-grade disease detection. Pulse transit time differences between right and left toes also had substantial agreement with ABPI, with diagnostic accuracy of 86% for significant disease detection (pulse transit time to pulse foot [kappa = 0.71] and to pulse peak [kappa = 0.70]) and reached at least 90% for these for the higher-grade disease. The performance ranking for the different pulse features mirrored an earlier pilot study. With the shape and pulse transit time measurements, the negative-predictive values of the 5% disease population screening-prevalence level were at least 99% and had positive-predictive values of at least 98% for the 90% disease-prevalence level for vascular laboratory referrals. CONCLUSION This simple-to-use technique could offer significant benefits for the diagnosis of peripheral arterial disease in settings such as primary care where noninvasive, accurate, and diagnostic techniques not requiring specialist training are desirable. Improved diagnosis and screening for peripheral arterial disease has the potential to allow identification and risk factor management for this high-risk group.

Current practice in the use of antiplatelet agents in the peri-operative period by UK vascular surgeons.

BACKGROUND There currently appears to be no firm consensus with regards to the use of antiplatelet agents during the peri-operative period in vascular surgical practice. METHODS A nine-part questionnaire relating to peri-operative antiplatelet use was sent to 137 ordinary members of the Vascular Surgical Society of Great Britain and Ireland (VSS-GBI). RESULTS Of the 137 questionnaires sent, 90 were returned (66%). For patients undergoing infra-inguinal bypass, carotid endarterectomy and varicose vein surgery, over 90% of vascular surgeons continue antiplatelet agents peri-operatively; however, in the case of aortic aneurysm repair, this figure is lower (77%). Three of the respondents stated that they would stop clopidogrel, but not aspirin, prior to surgery because of concerns over increased operative bleeding. In patients starting routine heparin prophylaxis against thrombosis, most surgeons opted to continue antiplatelet therapy (82%), although in patients requiring therapeutic heparin treatment, opinions were almost equally split. Most vascular surgeons (93%) would to start an alternative antiplatelet agent if a patient was intolerant of aspirin for gastrointestinal reasons. CONCLUSIONS Although the benefits of antiplatelet drugs in the long-term reduction of vascular events is established, evidence supporting their use in the peri-operative period is scarce. The general consensus of opinion from this survey suggests that most vascular surgeons do not stop antiplatelet drugs pre-operatively.

Management of venous thromboembolic diseases and the role of thrombophilia testing: summary of NICE guidance

Venous thromboembolic diseases range from asymptomatic deep venous thrombosis (DVT) to fatal pulmonary embolism. Non-fatal venous thromboembolic diseases may also cause serious long term conditions such as post-thrombotic syndrome or chronic thromboembolic pulmonary hypertension. In the United Kingdom, pathways to diagnosis and to decisions on long term treatment or further investigation for thrombophilia and cancer vary, so guidance is needed in these areas. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the management of confirmed or suspected venous thromboembolic diseases in adults (excluding pregnant women).1 NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Diagnostic investigations for deep venous thrombosis

Patients with atherosclerotic renovascular disease presenting to a renal unit: an audit of outcome.

During a 6 year period 60 patients with atherosclerotic renovascular disease were followed by a single renal unit. Angiotensin converting enzyme inhibitors were being taken by 22% of patients at the time of diagnosis of the atherosclerotic renovascular disease. Intervention to revascularize renal tissue by surgery or angioplasty was performed in 32 patients. Revascularization was not undertaken because of unilateral disease, patient preference, poor operative risk or renal size. The mean age for the nonintervention group was 66.9 years and 63.4 years for the intervention group. Peripheral vascular, disease was common in both groups (96% nonintervention group versus 86% intervention group). There was a statistically significant difference in improvement in renal function in the intervention group (34.4% versus 10.7%) in spite of more patients being dialysis dependent in the intervention group (28.1% versus 14.3%). There was no statistically significant difference in survival between the two groups although the trend was for better survival in the group with intervention. Patients presenting with impaired renal function and atherosclerotic renovascular disease can have useful improvement in renal function with revascularization without any detriment to survival.

Value of Thromboelastography in the Assessment of Platelet Function

Thromboelastography (TEG) is a useful measure of coagulation. Modified TEG (that is with the addition of a GP Ilb/Illa receptor antagonist) has been used to assess the contribution of the fibrinogen-platelet interaction to TEG parameters (in particular the maximum amplitude, MA). Modified TEG was compared with other investigations of platelet function to assess its sensitivity in both normal subjects and in patients with peripheral arterial disease (PAD), a condition associated with activated platelets. Blood was collected from eight healthy subjects and 12 PAD patients. Platelet function was measured by TEG, flow cytometry (using PAC-1, P-selectin, GP Illa and GP lb murine antibodies) and platelet aggregometry (spontaneous and ADP-induced) in the presence and absence of tirofiban (a GP JIb/lla receptor antagonist). TEG showed a statistically significant reduction in MA with tirofiban at 0.4 mg/L and an increase in k (kinetic time; which indicates how fast clot strength is increasing once clotting starts) at 0.2 and 0.4 mg/L of tirofiban in both healthy subjects and PAD patients. Flow cytometry showed a significant decrease in the PAC-1 binding index (at 0.2 mg/b). This finding was compatible with the significant reductions found in spontaneous and ADP-induced platelet aggregation. However, aggregometry and flow cytometry were more sensitive indicators of platelet inhibition than the TEG parameters. TEG does not provide a comprehensive or sensitive reflection of impaired platelet function. If TEG is used as an index of severely impaired platelet function, we recommend that the k parameter should be used as well as MA. TEG should be supplemented by other methods of platelet function assessment wherever possible.