The cerebral collateral circulation: Relevance to pathophysiology and treatment of stroke.

The brain's collateral circulation consists of arterial anastomotic channels capable of providing nutrient perfusion to brain regions whose normal sources of flow have become compromised, as occurs in acute ischemic stroke. Modern CT-based neuroimaging is capable of providing detailed information as to collateral extent and sufficiency and is complemented by magnetic resonance-based methods. In the present era of standard-of-care IV thrombolysis for acute ischemic stroke, and following the recent therapeutic successes of randomized clinical trials of acute endovascular intervention, the sufficiency of the collateral circulation has been convincingly established as a key factor influencing the likelihood of successful reperfusion and favorable clinical outcome.

Expanding the concept of neuroprotection for acute ischemic stroke: The pivotal roles of reperfusion and the collateral circulation.

This review surveys the efforts taken to achieve clinically efficacious protection of the ischemic brain and underscores the necessity of expanding our purview to include the essential role of cerebral perfusion and the collateral circulation. We consider the development of quantitative strategies to measure cerebral perfusion at the regional and local levels and the application of these methods to elucidate flow-related thresholds of ischemic viability and to characterize the ischemic penumbra. We stress that the modern concept of neuroprotection must consider perfusion, the necessary substrate upon which ischemic brain survival depends.

ALIAS (Albumin in Acute Ischemic Stroke) Trials: Analysis of the Combined Data From Parts 1 and 2.

Background And Purpose: The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject-level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size.

Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial.

Background: Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial.

Methods: Ischemic stroke patients, aged 18-83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset.

Symptomatic intracranial hemorrhage in the ALIAS Multicenter Trial: relationship to endovascular thrombolytic therapy.

Background: In the ALIAS (Albumin in Acute Stroke) Part 2 Multicenter Trial, 85% of subjects received standard-of-care intravenous tissue plasminogen activator, and 21% received some form of endovascular thrombolysis. The overall rate of symptomatic intracranial hemorrhage was within the expected range but was higher in albumin-treated subjects than in saline-treated subjects.

Aims And Methods: Using the trial's Public Use Dataset, we analyzed factors contributing to symptomatic and asymptomatic intracranial hemorrhage in the 'safety sample' of 830 subjects.

High-dose albumin treatment for acute ischaemic stroke (ALIAS) Part 2: a randomised, double-blind, phase 3, placebo-controlled trial.

Background: In animal models of ischaemic stroke, 25% albumin reduced brain infarction and improved neurobehavioural outcome. In a pilot clinical trial, albumin doses as high as 2 g/kg were safely tolerated. We aimed to assess whether albumin given within 5 h of the onset of acute ischaemic stroke increased the proportion of patients with a favourable outcome.

Albumin therapy enhances collateral perfusion after laser-induced middle cerebral artery branch occlusion: a laser speckle contrast flow study.

Laser speckle contrast (LSC) was used to compare the extent of cortical ischemia in two inbred mouse strains that differed in their degree of collateral circulation, after laser occlusion of the distal middle cerebral artery, and after treatment with 25% albumin (ALB) or saline (control). Sequential LSC images acquired over ∼90 minutes were coaligned, converted to relative flow, and normalized to baseline. After 3-day survival, infarction was quantified by triphenyl tetrazolium chloride or magnetic resonance imaging.

The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis.

Background And Purpose: The Albumin in Acute Stroke (ALIAS) Part 2 Trial is directly testing whether 2 g/kg of 25% human albumin (ALB) administered intravenously within 5 hours of ischemic stroke onset results in improved clinical outcome. Recruitment into Part 1 of the ALIAS Trial was halted for safety reasons. ALIAS Part 2 is a new, reformulated trial with more-stringent exclusion criteria.

The albumin in acute stroke (ALIAS) multicenter clinical trial: safety analysis of part 1 and rationale and design of part 2.

Background And Purpose: enrollment in the Albumin in Acute Stroke (ALIAS) Trial was suspended in late 2007 due to a safety concern. We present the safety data of that Trial ("Part 1") and the rationale for the design of Part 2.

Methods: ALIAS Part 1 was designed to assess whether 25% albumin (ALB) started within 5 hours of stroke onset would confer neuroprotection in subjects with acute ischemic stroke and baseline National Institutes of Health Stroke Scale of ≥ 6.

A web-based medical safety reporting system for a large multicenter clinical trial: the ALIAS experience.

An electronic safety reporting (ESR) module was developed and integrated into a home-grown web-based clinical trial management system (CTMS) to enhance the efficiency, completeness and consistency of reporting and reviewing serious adverse events, monitoring safety, and submitting safety reports to regulatory authorities for a large multicenter clinical trial. The architecture of this integrated module provided many advantages. First, the ESR module was developed based on a comprehensive procedure which incorporated both computer logic processing steps and human intervention steps in order to deal with the complex and unexpected situations where pre-programmed computer logic may fail.

Current status of neuroprotection for cerebral ischemia: synoptic overview.

Abundant preclinical studies have identified multiple mechanisms of ischemic brain injury and have provided proof of principle that strategies designed to counter these mechanisms can protect the ischemic brain. This review article emphasizes the translation of these strategies from the laboratory to clinical trials. It is a disappointing fact that many agents have been brought to clinical trial despite only modest or inconsistent preclinical evidence of neuroprotective efficacy.

The albumin in acute stroke trial (ALIAS); design and methodology.

Unlabelled: Stroke is a serious global illness. Human albumin has emerged as a putative therapy for ischaemic stroke based on strong evidence from animal models. Following confirmation of the safety and feasibility of high-dose albumin treatment for acute ischaemic stroke in a pilot study, the Albumin in Acute Stroke trial, a phase 3 randomised, double-blinded, placebo-controlled clinical trial was initiated to evaluate the efficacy of high-dose albumin compared to saline control within 5 h of ischaemic stroke onset.

Albumin therapy augments the effect of thrombolysis on local vascular dynamics in a rat model of arteriolar thrombosis: a two-photon laser-scanning microscopy study.

Background And Purpose: Results of our recent pilot clinical trial suggest that the efficacy of thrombolytic therapy in acute ischemic stroke may be enhanced by the coadministration of high-dose albumin. Here, we explored the microvascular hemodynamic effects of this combined therapy in a laboratory model of cortical arteriolar thrombosis.

Methods: We studied the cortical microcirculation of physiologically monitored rats in vivo by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran.

Neuroprotection for ischemic stroke: past, present and future.

Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection.

Albumin therapy improves local vascular dynamics in a rat model of primary microvascular thrombosis: a two-photon laser-scanning microscopy study.

Background And Purpose: High-dose human albumin is robustly neuroprotective in preclinical ischemia models and is currently in phase III clinical trial for acute ischemic stroke. To explore the hypothesis that albumin's protective effect is mediated in part by salutary intravascular mechanisms, we assessed microvascular hemodynamics in a model of laser-induced cortical arteriolar thrombosis.

Methods: The cortical microcirculation of anesthetized, physiologically monitored Sprague-Dawley rats was studied in vivo via a frontoparietal cranial window (intact dura) by two-photon laser-scanning microscopy after plasma-labeling with fluorescein-dextran.

Neuroprotective effect of STAZN, a novel azulenyl nitrone antioxidant, in focal cerebral ischemia in rats: dose-response and therapeutic window.

Stilbazulenyl nitrone (STAZN) is a potent antioxidant that, in a rat model of transient focal cerebral ischemia, confers significant enduring functional and morphological neuroprotection. This study investigated the influence of dose and time of administration on the neuroprotective effects of STAZN in the intraluminal suture model of middle cerebral artery occlusion (MCAo). Dose response: At 2 and 4 h after the onset of MCAo, animals received intravenously either STAZN (low dose=0.

Neuroprotective antioxidant STAZN protects against myocardial ischemia/reperfusion injury.

Background: Protecting the myocardium from ischemia-reperfusion injury has significant potential to reduce the complications of myocardial infarction and interventional revascularization procedures. Reperfusion damage is thought to result, in part, from oxidative stress. Here we use a novel method of percutaneous coronary occlusion to show that the potent antioxidant and neuroprotective free-radical scavenger, stilbazulenyl nitrone (STAZN), confers marked cardioprotection when given immediately prior to reperfusion.

Experimental intracerebral hematoma in the rat: characterization by sequential magnetic resonance imaging, behavior, and histopathology. Effect of albumin therapy.

We characterized acute intracerebral hemorrhage (ICH) in the rat by sequential magnetic resonance imaging (MRI) and correlated MRI findings with neurobehavior and histopathology. In addition, we investigated whether albumin treatment would reduce ICH-induced brain injury. ICH was produced in rats by a double-injection method in which 45 microl of fresh arterial blood was injected into the right striatum.

Life after cerovive: a personal perspective on ischemic neuroprotection in the post-NXY-059 era.

The SAINT II Trial, a large randomized multicenter clinical trial of the putative neuroprotectant, NXY-059, failed to demonstrate a treatment benefit in acute ischemic stroke. The further development of this agent was suspended. The implications of this outcome are considered from several perspectives, including: (1) the marginally positive antecedent trial, SAINT I, and the critical commentary stimulated by it, which called attention to its interpretively challenging primary outcome measure--a shift in the full-scale modified Rankin scale score--and to other statistical shortcomings; (2) the cogency of the STAIR recommendations, to which the development of NXY-059 closely adhered; and (3) the inherent physiochemical shortcomings of NXY-059 as a neuroprotective agent--its polar, nonlipophilic nature, poor blood-brain barrier penetrability, nonphysiological oxidation potential, and low potency.

Moderate loss of cerebellar Purkinje cells after chronic bilateral common carotid artery occlusion in rats.

Pathological effects of moderate ischemia (oligemia, hypoperfusion) are relevant in relation to vascular factors in dementia. Chronic bilateral common carotid artery occlusion (BCCAO) in adult Wistar rats induces oligemia and leads to acute changes in gene expression, subacute changes in cortical astrocytes and prolonged changes in white matter tracts, while largely sparing neurons in the forebrain areas. Dilation and remodeling of the basilar artery ensures blood flow to the forebrain.