In vitro experiments of cerebral blood flow during aspiration thrombectomy: potential effects on cerebral perfusion pressure and collateral flow.

BACKGROUND: Mechanical thrombectomy with stent retriever devices is associated with significantly better outcomes than thrombolysis alone in the treatment of acute ischemic stroke. Thrombus aspiration achieves high patency rates, but clinical outcomes are variable. The aim of this study was to examine the effect of different suction conditions on perfusate flow during aspiration thrombectomy. METHODS: A computational fluid dynamics model of an aspiration device within a patent and occluded blood vessel was used to simulate flow characteristics using fluid flow solver software. A physical particulate flow model of a patent vessel and a vessel occluded by thrombus was then used to visualize flow direction and measure flow rates with the aspiration catheter placed 1-10 mm proximal of the thrombus, and recorded on video. RESULTS: The mathematical model predicted that, in a patent vessel, perfusate is drawn from upstream of the catheter tip while, in an occluded system, perfusate is drawn from the vessel proximal to the device tip with no traction on the occlusion distal of the tip. The in vitro experiments confirmed the predictions of this model. In the occluded vessel aspiration had no effect on the thrombus unless the tip of the catheter was in direct contact with the thrombus. CONCLUSIONS: These experiments suggest that aspiration is only effective if the catheter tip is in direct contact with the thrombus. If the catheter tip is not in contact with the thrombus, aspirate is drawn from the vessels proximal of the occlusion. This could affect collateral flow in vivo.

Safety and effect of metoclopramide to prevent pneumonia in patients with stroke fed via nasogastric tubes trial.

BACKGROUND AND PURPOSE: Pneumonia is a major cause of mortality and morbidity in patients with stroke fed via nasogastric tubes and may be because of vomiting and gastro-oesophageal regurgitation. The aim of the study was to assess whether regular treatment with metoclopramide, a D2-receptor antagonist with antiemetic and gastric prokinetic actions, could reduce the rate of aspiration and pneumonia. METHODS: Patients with no signs of pneumonia within 7 days of stroke onset and 48 hours of insertion of a nasogastric tube were recruited into a double-blind randomized placebo-controlled trial. Participants received metoclopramide 10 mg or placebo 3× daily via the nasogastric tube for 21 days or until nasogastric feeds were discontinued. Clinical signs of pneumonia were recorded daily. Pneumonia was diagnosed if the patient had relevant clinical signs, high inflammatory markers, and new infiltrates on the chest radiograph. RESULTS: Sixty patients (mean age, 78 years; 38 women; mean National Institutes for Health Stroke Scale score, 19.25) were randomized in a 1:1 ratio. There were significantly more episodes of pneumonia in the placebo group than in the metoclopramide group (rate ratio, 5.24; P<0.001). There were also significant differences in favor of metoclopramide in the rate of aspiration, oxygen saturation, highest inflammatory markers, and National Institutes for Health Stroke Scale. There was no significant difference in mortality between the groups. CONCLUSIONS: This study suggests that metoclopramide may reduce the rate of pneumonia and may improve other clinical outcomes in patients with subacute stroke fed via nasogastric tube. These findings need to be confirmed in larger randomized and blinded trials. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrialsregister.eu. EudraCT no: 2006-002570-22, URL: http://www.controlled-trials.com/ISRCTN18034911/18034911.

Extending the role of peritoneal dialysis: can we win hearts and minds?

BACKGROUND: The ability of peritoneal dialysis (PD) to achieve low-molecular weight solute clearance and ultrafiltration at low haemodynamic cost makes it an attractive therapy in situations where more aggressive therapy may be undesirable due to sudden reductions in cerebral, coronary or renal blood flow. METHODS: We undertook a review of the literature to examine the recent evidence for this in two specific examples: the removal of glutamate following acute stroke and ultrafiltration for the treatment of diuretic resistant heart failure. RESULTS: In acute stroke, glutamate, when released into the extracellular tissues, causes neuronal cell death due to its excitotoxic properties. Experimental evidence from animal models indicates that its removal, including via PD, can reduce infarct size and restore functional brain tissue. PD is effective in removing glutamate in patients treated for renal failure. In heart failure, PD has a number of both theoretical and practical advantages for extending treatment, especially as an established home therapy. Several recent cohort studies describing its use in approaching 300 patients with diuretic resistance show consistent benefits in hospitalization and severity. CONCLUSION: Both these applications require substantial further clinical evaluation before they can justify wider adoption but their potential to alleviate morbidity on a large and potentially highly cost-effective scale demands further study.

The stroke oxygen pilot study: a randomized controlled trial of the effects of routine oxygen supplementation early after acute stroke--effect on key outcomes at six months.

INTRODUCTION: Post-stroke hypoxia is common, and may adversely affect outcome. We have recently shown that oxygen supplementation may improve early neurological recovery. Here, we report the six-month outcomes of this pilot study. METHODS: Patients with a clinical diagnosis of acute stroke were randomized within 24 h of admission to oxygen supplementation at 2 or 3 L/min for 72 h or to control treatment (room air). Outcomes (see below) were assessed by postal questionnaire at 6 months. Analysis was by intention-to-treat, and statistical significance was set at p ≤ 0.05. RESULTS: Out of 301 patients randomized two refused/withdrew consent and 289 (148 in the oxygen and 141 in the control group) were included in the analysis: males 44%, 51%; mean (SD) age 73 (12), 71 (12); median (IQR) National Institutes of Health Stroke Scale score 6 (3, 10), 5 (3, 10) for the two groups respectively. At six months 22 (15%) patients in the oxygen group and 20 (14%) in the control group had died; mean survival in both groups was 162 days (p = 0.99). Median (IQR) scores for the primary outcome, the modified Rankin Scale, were 3 (1, 5) and 3 (1, 4) for the oxygen and control groups respectively. The covariate-adjusted odds ratio was 1.04 (95% CI 0.67, 1.60), indicating that the odds of a lower (i.e. better) score were non-significantly higher in the oxygen group (p = 0.86). The mean differences in the ability to perform basic (Barthel Index) and extended activities of daily living (NEADL), and quality of life (EuroQol) were also non-significant. CONCLUSIONS: None of the key outcomes differed at 6 months between the groups. Although not statistically significant and generally of small magnitude, the effects were predominantly in favour of the oxygen group; a larger trial, powered to show differences in longer-term functional outcomes, is now on-going. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN12362720; Eudract.ema.europa.eu 2004-001866-41.

Mechanical thrombectomy in acute ischaemic stroke: a review of the literature, clinical effectiveness and future use.

The only effective treatment licensed for acute ischaemic stroke is intravenous thrombolysis within 4.5 hours from stroke onset. An alternative method of restoring blood flow is mechanical thrombectomy (MT). Although this is highly effective at recanalization, it remains unclear whether it is more effective than thrombolysis in improving clinical outcomes. This review examines key clinical outcomes from published studies and reviews ongoing studies to identify devices, patient population, and stated outcomes of MT. We discuss the issues when comparing clinical outcomes from different trials and suggest measures to help standardize reporting. We used routine review methodology to search relevant databases for stroke and MT published between 1999 - 2012 and active trials between August 2011 - May 2012. The studies in this review had an overall patient population of 8354. The most widely used primary outcome (94% of studies) was successful recanalization. The mean mortality across the studies was 17% (range 7 - 44), 64% of studies reported neurological improvement and 97% reported functional outcome with 42% (range 15 - 54)] achieving independence in activities of daily living. Mean symptomatic intracerebral haemorrhage was 11% (range 0 - 45%). There were significant differences in outcome reporting between studies. Evidence from published studies shows a strong relationship between recanalization and good outcomes although non-standardization makes comparisons difficult. There is a trend towards higher recanalization, lower mortality, and better functional outcome in more recent studies. To examine effectiveness of MT vs thrombolysis, randomized controlled trials are needed. Several are currently in progress but it remains to be seen if procedures and outcomes are reported in a standardized manner.

Exclusion of older people from clinical trials: professional views from nine European countries participating in the PREDICT study.

BACKGROUND: There has been concern about under-representation of older people in clinical trials. The PREDICT study reported that older people and those with co-morbidity continue to be excluded unjustifiably from clinical trials. However, there is no information about differences of opinion on these issues between EU countries. The results of a survey of health-related professionals from nine EU countries that participated in the PREDICT study are presented in this study. OBJECTIVE: The aim of the study was to identify and examine any differences of opinion between EU countries on the inclusion of older patients in clinical trials. METHODS: A questionnaire using a Likert scale and free text was completed by 521 general practitioners, geriatricians, clinical researchers, ethicists, nurses and industry pharmacologists/pharmacists. The questions explored the impact of the present situation, possible reasons for under-representation and potential methods of improving participation. Countries participating were the Czech Republic, Israel, Italy, Lithuania, the Netherlands, Poland, Romania, Spain and the UK. RESULTS: There was agreement that exclusion from clinical trials on age grounds alone was unjustified (87%) and that under-representation of older people in trials caused difficulties for prescribers (79%) and patients (73%). There were national differences between professionals. All but the Lithuanians believed that older people were disadvantaged because of under-representation. The Czech, Lithuanian and Romanian professionals felt that it was justified to have age limits based on co-morbidity (61-83%) and polypharmacy (63-85%). Romanians also thought that having age limits on trial participation was justified because of reduced life expectancy (62%) and physical disability (58%) in older people. All but the Romanian professionals felt that the present arrangements for clinical trials were satisfactory (62%). All but the Israelis (56%) and Lithuanians (70%) agreed that regulation of clinical trials needed alteration. CONCLUSIONS: Although respondent selection bias cannot be excluded, the differences that emerged between countries may be the result of the political and healthcare-system differences between older and newer members of the EU. These differences may influence decision making about clinical trial regulations and practice in older people.

The SOS pilot study: a RCT of routine oxygen supplementation early after acute stroke--effect on recovery of neurological function at one week.

UNLABELLED: Mild hypoxia is common after stroke and associated with poor long-term outcome. Oxygen supplementation could prevent hypoxia and improve recovery. A previous study of routine oxygen supplementation showed no significant benefit at 7 and 12 months. This pilot study reports the effects of routine oxygen supplementation for 72 hours on oxygen saturation and neurological outcomes at 1 week after a stroke. METHODS: Patients with a clinical diagnosis of acute stroke were recruited within 24 h of hospital admission between October 2004 and April 2008. Participants were randomized to oxygen via nasal cannulae (72 h) or control (room air, oxygen given only if clinically indicated). Clinical outcomes were assessed by research team members at 1 week. Baseline data for oxygen (n = 148) and control (n = 141) did not differ between groups. RESULTS: The median (interquartile range) National Institutes of Health Stroke Scale (NIHSS) score for the groups at baseline was 6 (7) and 5 (7) respectively. The median Nocturnal Oxygen Saturation during treatment was 1.4% (0.3) higher in the oxygen than in the control group (p<0.001) during the intervention. At 1 week, the median NIHSS score had reduced by 2 (3) in the oxygen and by 1 (2) in the control group. 31% of participants in the oxygen group and 14% in the control group had an improvement of ≥4 NIHSS points at 1 week doubling the odds of improvement in the oxygen group (OR: 2.9). CONCLUSION: Our data show that routine oxygen supplementation started within 24 hours of hospital admission with acute stroke led to a small, but statistically significant, improvement in neurological recovery at 1 week. However, the difference in NIHSS improvement may be due to baseline imbalance in stroke severity between the two groups and needs to be confirmed in a larger study and linked to longer-term clinical outcome. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN12362720; European Clinical Trials Database 2004-001866-41.

Comparison of the Effectiveness of Three Methods of Recanalization in a Model of the Middle Cerebral Artery: Thrombus Aspiration via a 4F Catheter, Thrombus Aspiration via the GP Thromboaspiration Device, and Mechanical Thrombectomy Using the Solitaire Thrombectomy Device.

Introduction. This paper compares different approaches to recanalization in a model of the middle cerebral artery (MCA). Methods. An occlusive thrombus (lamb's blood) was introduced into the MCA of a model of the cerebral circulation perfused with Hartmann's solution (80 pulsations/min, mean pressure 90 mm Hg). Three methods of clot retrieval were tested: thrombus aspiration via a 4F catheter (n = 26), thrombus aspiration via the GP thrombus aspiration device (GPTAD) (n = 30), and mechanical thrombectomy via the Solitaire Device (n = 30). Results. Recanalization rate was similar for all 3 approaches (62%, 77%, and 85%). Time to recanalization was faster with aspiration devices (41 SD 42 s for 4F and 61 SD 21 s for GPTAD) than with the Solitaire (197 SD 64 s P < .05 Kruksal-Wallis). Clot fragmentation was the same in the Solitaire (23%) and the GPTAD (23%), but higher with the 4F (53%, P < .05). Conclusion. In this model, thrombus aspiration was faster than mechanical thrombectomy, and similarly effective at recanalization. These results should be confirmed in vivo.

Understanding frailty.

The term "frailty" is used loosely to describe a range of conditions in older people, including general debility and cognitive impairment. There is no clear consensus on the definition of frailty; however, it is proposed that frailty comprises a collection of biomedical factors which influences an individual's physiological state in a way that reduces his or her capacity to withstand environmental stresses. Only a subset of older people are at risk of becoming frail; these are vulnerable, prone to dependency and have reduced life expectancy. These health outcomes contribute to an increased demand for medical and social care, and are associated with increased economic costs. As demographic trends indicate a rise in the older population, this healthcare burden will increase. This review aims to encapsulate the current debate surrounding the concept of frailty, with emphasis on proposed definitions of frailty which may be relevant to its identification in the clinical setting.

Phototoxicity and fluorotoxicity combine to alter the behavior of neutrophils in fluorescence microscopy based flow adhesion assays.

The use of fluorescent probes that allow visualization of leukocyte-endothelial cell (EC) interactions has greatly informed our understanding of leukocyte recruitment. However, effects of these agents on the biological functions of leukocytes are poorly described, leading to concerns about the interpretation of such data. Here we used two flow-based neutrophil adhesion assays to compare the effects of phase contrast illumination (PCI) with high intensity illumination (HII) used for fluorescent microscopy, in the presence or absence of five commonly used fluorochromes. Isolated neutrophils were either (1) perfused across P-selectin to establish a population of rolling cells, which were subsequently activated with fMLP; or (2) perfused across EC activated with TNF-alpha. In the absence of fluorescent dyes, HII did not affect levels of leukocyte adhesion; however, subsequent neutrophil behavior was dramatically altered when compared with cells under PCI, for example, dramatically reducing their migration velocities. In the presence of fluorescent dyes, the effects of HII were exacerbated, although the precise nature of the biological effects of these probes was agent specific. Thus, for the first time, our experiments describe the effects of fluorescent microscopy on the separate stages of the neutrophil recruitment process and reveal a previously unsuspected effect of HII on neutrophil migration.

A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium.

OBJECTIVE: Rheumatoid arthritis (RA) is classically thought of as a Th1, T lymphocyte-driven disease of the adaptive immune system. However, cells of the innate immune system, including neutrophils, are prevalent within the diseased joint, and accumulate in large numbers. This study was undertaken to determine whether cells of the rheumatoid stromal microenvironment could establish an inflammatory environment in which endothelial cells are conditioned in a disease-specific manner to support neutrophil recruitment. METHODS: Human umbilical vein endothelial cells (ECs) and fibroblasts isolated from the synovium or skin of RA patients were established in coculture on opposite sides of porous transwell filters. After 24 hours of EC conditioning, the membranes were incorporated into a parallel-plate, flow-based adhesion assay and levels of neutrophil adhesion to ECs were measured. RESULTS: ECs cocultured with synovial, but not skin, fibroblasts could recruit neutrophils in a manner that was dependent on the number of fibroblasts. Antibody blockade of P-selectin or E-selectin reduced neutrophil adhesion, and an antibody against CD18 (the beta2 integrin) abolished adhesion. Blockade of CXCR2, but not CXCR1, also greatly inhibited neutrophil recruitment. Interleukin-6 (IL-6) was detectable in coculture supernatants, and both IL-6 and neutrophil adhesion were reduced in a dose-dependent manner by hydrocortisone added to cocultures. Antibody blockade of IL-6 also effectively abolished neutrophil adhesion. CONCLUSION: Synovial fibroblasts from the rheumatoid joint play an important role in regulating the recruitment of inflammatory leukocytes during active disease. This process may depend on a previously unsuspected route of IL-6-mediated crosstalk between fibroblasts and endothelial cells.

Transmigrated neutrophils down-regulate the expression of VCAM-1 on endothelial cells and inhibit the adhesion of flowing lymphocytes.

As the first leukocytes recruited during inflammation, neutrophils are ideally situated to regulate the subsequent recruitment of mononuclear leukocytes. Here, we found that human neutrophils recruited by endothelial cells (EC), which had been stimulated with tumor necrosis factor alpha for 4 h, inhibited the adhesion of flowing, mixed mononuclear cells or purified lymphocytes over the subsequent 20 h but did not affect the adhesion of a secondary bolus of neutrophils. The degree of inhibition of lymphocyte adhesion increased with the duration of neutrophil-EC contact and with the number of recruited neutrophils. Antibody-blocking studies showed that lymphocyte adhesion was mediated predominantly by vascular cell adhesion molecule-1 (VCAM-1). Recruited neutrophils reduced the EC expression of VCAM-1 but not intercellular adhesion molecule-1 (ICAM-1) or E-selectin in a manner that mirrored the time- and number-dependent reduction in lymphocyte adhesion. VCAM-1 was not shed into the culture supernatant, and a panel of protease inhibitors was unable to reverse its down-regulation, indicating that it was not proteolytically degraded by neutrophils. In EC that had been in contact with neutrophils, the mRNA message for VCAM-1 but not ICAM-1 was down-regulated, indicating that alterations in transcriptional activity were responsible for the reduction in VCAM-1. Thus, under some inflammatory milieu, neutrophils may delay the recruitment of mononuclear leukocytes by regulating the expression of EC adhesion receptors.