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. This article reviews the features of the brain's collateral circulation; methods for its evaluation in the acute clinical setting; the relevance of collateral circulation to prognosis in acute ischemic stroke; the specific insights into the collateral circulation learned from recent trials of endovascular intervention; and the major influence of genetic factors. Finally, we emphasize the need to develop therapeutic approaches to augment collateral perfusion as an adjunctive strategy to be employed along with, or prior to, thrombolysis and endovascular interventions, and we highlight the possible potential of inhaled nitric oxide, albumin, and other approaches. This article is part of the Special Issue entitled 'Cerebral Ischemia'.

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. We survey the major mechanistic approaches to neuroprotection and review clinical neuroprotection trials, focusing on those phase 3 multicenter clinical trials for acute ischemic stroke that have been completed or terminated. We review the evolution of thrombolytic therapies; consider the lessons learned from the initial, negative multicenter trials of endovascular therapy; and emphasize the highly successful positive trials that have finally established a clinical role for endovascular clot removal. As these studies point to the brain's collateral circulation as key to successful reperfusion, we next review the anatomy and pathophysiology of collateral perfusion as it relates to ischemic infarction, as well as the molecular and genetic influences on collateral development. We discuss the current MR and CT-based diagnostic methods for assessing the collateral circulation and the prognostic significance of collaterals in ischemic stroke, and we consider past and possible future therapeutic directions.

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. METHODS: The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). RESULTS: The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87-15.57). CONCLUSIONS: Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00235495.

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. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism. RESULTS: Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI95 1.01-5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI95 4.3-26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%). CONCLUSIONS: ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke. TRIAL REGISTRATION: ClincalTrials.gov NCT00235495.

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. RESULTS: Four hundred sixteen subjects received albumin therapy, and 414 received saline. Intravenous tissue plasminogen activator was given to 68.2%; intravenous tissue plasminogen activator plus endovascular intervention in 16.4%; and endovascular therapy alone in 43%. Symptomatic intracranial hemorrhage occurred in 41 subjects - within the first 12 h in one-third of cases, and within the first day in ∼60%. Intravenous tissue plasminogen activator had been used in 78% of symptomatic intracranial hemorrhage subjects - no higher than in the overall cohort. In contrast, 48.8% of subjects with symptomatic intracranial hemorrhage had received endovascular therapy - a rate markedly higher than the 20.7% rate for the entire cohort (P = 0.0001). Sixty-eight point three percent of subjects with symptomatic intracranial hemorrhage had received albumin, and 31.7% saline (risk ratio 2.14, P = 0.025). Other factors associated with symptomatic intracranial hemorrhage were baseline NIHSS and ASPECTS scores and the SEDAN score. Forty-one point four percent of subjects with symptomatic intracranial hemorrhage died. The odds ratio for symptomatic intracranial hemorrhage was 3.89 (95% confidence interval 2.04-7.41) with endovascular therapy and 2.15 (confidence interval 1.08-4.25) with albumin. CONCLUSIONS: Endovascular thrombolysis was the major factor predisposing to symptomatic intracranial hemorrhage, and albumin contributed to this predisposition. The latter may be mediated by albumin's influence on platelet aggregation or collateral perfusion.

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. METHODS: We did a randomised, double-blind, parallel-group, phase 3, placebo-controlled trial between Feb 27, 2009, and Sept 10, 2012, at 69 sites in the USA, 13 sites in Canada, two sites in Finland, and five sites in Israel. Patients aged 18-83 years with ischaemic (ie, non-haemorrhagic) stroke with a baseline National Institutes of Health stroke scale (NIHSS) score of 6 or more who could be treated within 5 h of onset were randomly assigned (1:1), via a central web-based randomisation process with a biased coin minimisation approach, to receive 25% albumin (2 g [8 mL] per kg; maximum dose 750 mL) or the equivalent volume of isotonic saline. All study personnel and participants were masked to the identity of the study drug. The primary endpoint was favourable outcome, defined as either a modified Rankin scale score of 0 or 1, or an NIHSS score of 0 or 1, or both, at 90 days. Analysis was by intention to treat. Thrombolytic therapies were permitted. This trial is registered with ClinicalTrials.gov, number NCT00235495. FINDINGS: 422 participants were randomly assigned to receive albumin and 419 to receive saline. On Sept 12, 2012, the trial was stopped early for futility (n=841). The primary outcome did not differ between patients in the albumin group and those in the saline group (186 [44%] vs 185 [44%]; risk ratio 0·96, 95% CI 0·84-1·10, adjusted for baseline NIHSS score and thrombolysis stratum). Mild-to-moderate pulmonary oedema was more common in patients given albumin than in those given saline (54 [13%] of 412 vs 5 [1%] of 412 patients); symptomatic intracranial haemorrhage within 24 h was also more common in patients in the albumin group than in the placebo group (17 [4%] of 415 vs 7 [2%] of 414 patients). Although the rate of favourable outcome in patients given albumin remained consistent at 44-45% over the course of the trial, the cumulative rate of favourable outcome in patients given saline rose steadily from 31% to 44%. INTERPRETATION: Our findings show no clinical benefit of 25% albumin in patients with ischaemic stroke; however, they should not discourage further efforts to identify effective strategies to protect the ischaemic brain, especially because of preclinical literature showing convincing proof-of-principle for the possibility of this outcome. FUNDING: National Institute of Neurological Disorders and Stroke, US National Institutes of Health; and Baxter Healthcare Corporation.

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. In the sparsely collateralized BALB/c strain, mean flow fell to 13% to 14% and 33% to 34% of baseline in central (core) and peripheral (penumbral) regions of interest, and ALB treatment at 30 minutes enhanced perfusion in both regions by ∼2-fold relative to saline, restoring flow to the benign-oligemic range centrally, and to the hyperemic range peripherally. The ALB-induced increment in parenchymal perfusion was disproportionate to the subtle flow increase in the occluded artery itself, suggesting that ALB improved collateral circulation. Cortical infarction in BALB/c mice was reduced 45% by ALB treatment. In contrast to BALB/c mice, the better-collateralized CD-1 strain developed milder ischemia, had smaller infarcts, and showed no differential benefit of ALB. We conclude that where native collateralization is insufficient (BALB/c strain), ALB treatment exerts a significant therapeutic effect after ischemia by augmenting collateral perfusion.

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. Our aim was to explore the efficacy of ALB in the ALIAS Part 1 data and to assess the statistical assumptions underlying the ALIAS Part 2 Trial. METHODS: ALIAS is a multicenter, blinded, randomized controlled trial. Data on 434 subjects, comprising the ALIAS Part 1 subjects, were analyzed. We examined both the thrombolysis and nonthrombolysis cohorts combined and separately in a "target population" by excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter comprised patients >83 years of age, those with elevated baseline troponin values, and those with in-hospital stroke. We examined the differences in the primary composite outcome, defined as a modified Rankin Scale score of 0 to 1 and/or a National Institutes of Health Stroke Scale score of 0 to 1 at 90 days after randomization. RESULTS: In the combined thrombolysis plus nonthrombolysis cohorts of the target population, 44.7% of subjects in the ALB group had a favorable outcome compared with 36.0% in the saline group (absolute effect size=8.7%; 95% CI, -2.2% to 19.5%). Among thrombolyzed subjects of the target population, 46.7% had a favorable outcome in the ALB group compared with 36.6% in the saline group (absolute effect size=10.1%; 95% CI, -2.0% to 20.0%). CONCLUSIONS: Preliminary results from the ALIAS Part 1 suggest a trend toward a favorable primary outcome in subjects treated with ALB and support the validity of the statistical assumptions that underlie the ALIAS Part 2 Trial. The ALIAS Part 2 Trial will confirm or refute these results. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov/ALIAS. Unique identifier: NCT00235495.

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. Exclusion criteria included recent or current congestive heart failure, myocardial infarction, or cardiac surgery. The study comprised 2 cohorts: subjects who received thrombolysis and those who did not, each with 1:1 randomization to ALB or placebo. The primary outcome was the National Institutes of Health Stroke Scale and modified Rankin Scales at 90 days. The intended sample size was 1800. RESULTS: four hundred thirty-four subjects were enrolled, and 424 were used in the safety analysis (ALB 207, saline 217). There were 36 deaths within the first 30 days in the ALB group and 21 in the saline group. In contrast, death rates after 30 days were similar by treatment. Large strokes were the predominant cause of early death in both groups. In subjects >83 years of age, 90-day death rates were 2.3-fold higher with ALB than with saline (95% CI, 1.04 to 5.12). Similarly, 90-day deaths in subjects receiving excessive fluids were 2.10-fold greater with ALB than with saline (CI, 1.10 to 3.98). CONCLUSIONS: The ALIAS Part 2 Trial, which started in early 2009, was modified as follows to enhance safety: upper age limit of 83 years; requirement for normal baseline serum troponin level; restriction of total intravenous fluids in the first 48 hours to ≤ 4200 mL; mandatory diuretic at 12 to 24 hours; and detailed site retraining. Because of insufficient nonthrombolysed subjects (22%) in Part 1, the 2-cohort design was eliminated. The Data Safety Monitoring Board has reviewed the safety data of Part 2 3 times and has approved continuation of the trial.

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. Second, safety and efficacy data were managed within the same relational database. Relevant data captured on efficacy case report forms, such as demographics, medical history, lab data and concomitant medications, were directly retrievable for MedWatch report composition without requiring redundant data entry. Finally, the ESR module shared the same generic user interfaces and data processing functions with other modules in the CTMS. These generic components include data editing, data retrieving, data reporting, dictionary-based automatic and interactive coding, event-driven and calendar-driven automatic email notifications, and user privilege management. This integrated ESR module was implemented in the Albumin in Acute Stroke (ALIAS) Trial-Part 1. A total of 397 serious adverse event reports were processed and 33 FDA MedWatch reports, 28 initial reports, and 5 follow-up reports were submitted to FDA and Health Canada using this system. Experiences and lessons learned from the development and implementation of this system are presented in this paper.

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. Preclinical investigations require rigorous attention to a variety of variables that may influence outcome. The widely touted STAIR criteria represent constructive guidelines for preclinical testing but, as experience has shown, do not increase the likelihood of translational success. Of the approximately 160 clinical trials of neuroprotection for ischemic stroke conducted as of late 2007, only approximately 40 represent larger-phase completed trials, and fully one half of the latter utilized a window to treatment of >6 hours, despite strong preclinical evidence that this delay exceeds the likely therapeutic window of efficacy in acute stroke. Other shortcomings of these trials include the use of agents lacking robust, consistent preclinical efficacy; inability to achieve adequate dosing in humans; and suboptimal clinical and statistical design features. Taken together, these factors identify areas of needed improvement for future trials.

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. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safety-feasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6h therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials. This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized.

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. We induced focal thrombosis in 30- to 50-microm cortical arterioles by laser irradiation and measured arteriolar flow velocity by repeated line-scanning. At 30 minutes post-thrombosis, we treated animals with the thrombolytic agent, reteplase, which was coadministered with either human albumin, 2 g/kg, or with saline control. RESULTS: Baseline arteriolar flow velocity averaged 3.8+/-0.7 mm/s, was immediately reduced by thrombosis to 22% to 25% of control values, and remained unchanged before treatment. Subthrombolytic doses of reteplase combined with saline led to a median increase in flow velocity to 37% of control distal to the thrombus (P=nonsignificant versus pretreatment). By contrast, reteplase combined with albumin therapy resulted in a prompt, highly significant increase of median flow velocity to 58% of control levels (P=0.013 versus reteplase+saline), which remained significantly higher than the reteplase+saline group at multiple time-points over the subsequent hour. CONCLUSIONS: The beneficial effect of subthrombolytic doses of reteplase on microvascular hemodynamics distal to a cortical arteriolar thrombosis is markedly enhanced by the coadministration of high-dose albumin therapy; these results have important clinical implications for the management of patients with acute ischemic stroke.

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. METHODS AND RESULTS: Physiologically controlled male Sprague-Dawley rats were anesthetized with isoflurane, paralyzed with pancuronium and mechanically ventilated. A guide wire was introduced via the femoral artery and advanced retrogradely via the aorta into the left coronary artery under fluoroscopic guidance. Rats with established coronary ischemia (85 min after occlusion) were given STAZN 3.5 mg/kg or its vehicle 5 min before and 2 h after reperfusion, and were subjected to functional and histopathologic studies at 3 days. Ischemia-associated Q wave amplitude was reduced by 73% in STAZN-treated rats (P=0.01), while infarct-related ejection fraction, fractional shortening and severe regional wall-motion impairments were improved by 48%, 54% and 37%, respectively, relative to vehicle-treated controls (P=0.05). Total myocardial infarct volume in STAZN-treated rats was correspondingly reduced by 43% (P<0.05), representing a sparing of 14% of the total left ventricular myocardium. CONCLUSIONS: STAZN, a second-generation azulenyl nitrone with potent neuroprotective efficacy in brain ischemia, is also a rapidly acting and highly effective cardioprotective agent in acute coronary ischemia. Our results suggest the potential for clinical benefit in the setting of acute coronary syndromes.

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. Focal thrombosis was produced in 30- to 50-mum cortical arterioles by laser irradiation. Arteriolar flow velocity was measured repeatedly by line-scanning. At 30 minutes post-thrombosis, animals were treated with either human albumin, 2 g/kg, or with saline control. RESULTS: Baseline arteriolar flow velocity averaged 3.5+/-1.8 mm/s and was reduced to 10% to 13% of control values by laser-induced thrombosis, which also led to focal vasodilatation (mean, 49% above baseline diameter). Saline treatment at 30 minutes post-thrombosis failed to influence arteriolar flow velocity, which remained depressed at 10% to 22% of control throughout the subsequent 60- to 90-minute observation period. By contrast, albumin treatment induced a prompt rise in median flow velocity to 38% of control by 10 minutes post-treatment, and to 61% to 67% of control by 50 to 60 minutes. CONCLUSIONS: High-dose albumin therapy induces a prompt, sustained improvement in microvascular hemodynamics distal to a cortical arteriolar thrombosis; these data support an important intravascular component to albumin's protective effect in acute cerebral ischemia.