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Biomedical subjects

Patrick D Lyden

Publications and source records attributed to Patrick D Lyden.

18 recordsLinked to original sources
PubMed2006

Penetrating arterioles are a bottleneck in the perfusion of neocortex.

Penetrating arterioles bridge the mesh of communicating arterioles on the surface of cortex with the subsurface microvascular bed that feeds the underlying neural tissue. We tested the conjecture that penetrating arterioles, which are positioned to regulate the delivery of blood, are loci of severe ischemia in the event of occlusion. Focal photothrombosis was used to occlude single penetrating arterioles in rat parietal cortex, and the resultant changes in flow of red blood cells were measured with two-photon laser-scanning microscopy in individual subsurface microvessels that surround the occlusion. We observed that the average flow of red blood cells nearly stalls adjacent to the occlusion and remains within 30% of its baseline value in vessels as far as 10 branch points downstream from the occlusion. Preservation of average flow emerges 350 mum away; this length scale is consistent with the spatial distribution of penetrating arterioles. We conclude that penetrating arterioles are a bottleneck in the supply of blood to neocortex, at least to superficial layers.

Animals↗
PubMed2006

An expedited code stroke protocol is feasible and safe.

BACKGROUND AND PURPOSE: Stroke recovery critically depends on timely reperfusion. In July 2003, we set a benchmark onset-to-treatment time of < or =2 hours and instituted an expedited code stroke protocol to accomplish this. We aim to show that the protocol is feasible and safe. METHODS: The expedited protocol includes: Benchmark onset-to-treatment within 2 hours; in-person triage of all code stroke patients; unmixed tissue plasminogen activator at the bedside during evaluation; no delays pending coagulation tests, chest x-ray, or stool guiac unless specifically indicated; and no delays pending formal CT interpretation or written consent. RESULTS: Between July 2003 and June 2005, we evaluated 781 patients and treated 103 of 781 (13.2%) with intravenous recombinant tissue plasminogen activator within 3 hours. Of these, we treated 49 of 103 (47.6%) within 2 hours of symptom onset, and 54 of 103 (52.4%) between 2 and 3 hours. The overall risk of symptomatic intracerebral hemorrhage was 4 of 103 (3.9%; 95% CI, 1.1%, 9.6%), and not significantly different from 6.4% (P=0.42). The hemorrhage risks in those treated within 2 hours of symptom onset and those treated between 2 and 3 hours were not significantly different from each other or from 6.4%. CONCLUSIONS: The expedited code stroke protocol is feasible and appears safe. Further study is warranted to confirm its safety and determine whether it results in better clinical outcomes.

Adult↗
PubMed2006

Stroke-evoked angiogenesis results in a transient population of microvessels.

The role of angiogenesis after stroke is unclear; if angiogenesis supports long-term recovery of blood flow, then microvessel hyperdensity consequent to angiogenesis should persist in infarcted cortex. Here, we assess the long-term stability of ischemia-induced microvessels after 2-h transient rat middle cerebral artery occlusion (tMCAo) followed by 30, 90, or 165 days of reperfusion. Stereological measures of microvessel density were taken adjacent to and within cortical cysts. Vascular permeability was documented by extravasation of immunoglobulin (IgG) and of fluorescein-dextran. After 30 days reperfusion, a significantly increased microvessel volume density (V(V)) was restricted to the inner margin of cystic infarcts as compared with the region external to the infarct or contralateral control cortex (F=42.675, P<0.001). The hyperdense ischemic vasculature was abnormally leaky to IgG and fluorescein-dextran. Between 30 and 90 days of reperfusion, this vessel hyperdensity regressed significantly and then regressed further but less drastically between 90 and 165 days. Phagocytic macrophages were restricted to the infarct and dynamic changes in their number correlated with microvessel regression. Additional ED-1 labeled inflammatory cells were widely distributed inside and external to the infarct, even after 165 days of reperfusion. These data show that ischemia evoked angiogenesis results, at least in part, in transient populations of leaky microvessels and phagocytic macrophages. This suggests that a major role of this angiogenesis is for the removal of necrotic brain tissue.

Animals↗
PubMed2006

A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology.

BACKGROUND: Therapeutic hypothermia has been shown to be of benefit in improving neurological outcome in cardiac arrest. It now is being investigated in acute stroke and myocardial infarction. The majority of the literature describes its use in intubated, pharmacologically paralyzed patients, using surface cooling techniques that are susceptible to patient shivering, imprecise temperature control, time lag to target-temperature acquisition, and rebound hyperthermia. OBJECTIVES: To develop a method of inducing therapeutic hypothermia in a rapid, precise, and tolerable fashion in awake, nonintubated patients. METHODS: This method was developed for an ongoing clinical trial investigating a combination of therapeutic hypothermia and intravenous thrombolysis for acute ischemic stroke. In the protocol, an endovascular cooling device is placed in the inferior vena cava of a patient, and a combination of buspirone, meperidine, and cutaneous warming with a heating blanket is used to suppress shivering as the patient is cooled to a target temperature of 33 degrees C, kept there for a total of 24 hours from hypothermia initiation, and then rewarmed in a controlled fashion during the next 12 hours. RESULTS: Ten patients underwent the therapeutic hypothermia protocol. The median pretreatment core temperature was 36.1 degrees C (interquartile range [IQR]: 35.8 degrees C-36.4 degrees C). On initiation of cooling, the core temperatures dropped rapidly and then leveled off, approaching a median plateau value of 33.4 degrees C (IQR: 33.2 degrees C-33.9 degrees C) in a mean time of 1.7 (+/- 0.7) hours from cooling initiation, with a median average postplateau temperature during the cooling phase of 33.8 degrees C (IQR: 33.3 degrees C-34.6 degrees C), and a median lowest temperature of 33.1 degrees C (IQR: 33.0 degrees C-33.3 degrees C). The procedure was well tolerated, with minimal shivering and no rebound hyperthermia. CONCLUSIONS: This is a method by which a rapid and precise therapeutic decrease in core temperature can be achieved without the necessity for intubation or neuromuscular blockade and with minimal patient discomfort or shivering.

Adolescent↗
PubMed2006

Contraindications of VEGF-based therapeutic angiogenesis: effects on macrophage density and histology of normal and ischemic brains.

Therapeutic angiogenesis by vascular endothelial growth factor (VEGF) is advocated as a promising treatment strategy for brain ischemic stroke. However, data in the literature demonstrating the benefit of therapeutic angiogenesis are contradictory. In this paper, we describe the effects of non-angiogenic and angiogenic doses of VEGF165 on macrophage density and histology of normal and ischemic brains of adult rats. VEGF165 was administered intra-arterially for 7 days following temporary occlusion of the middle cerebral artery. In contrast to ischemic brains treated with non-angiogenic doses of VEGF165 which showed preserved neuropil and reduced numbers of macrophages, ischemic brains treated by an angiogenic dose showed phagocytized neuropil and high macrophage density. Though neither non-angiogenic nor angiogenic doses caused macrophage infiltration in normal brains, damage of the brain matrix occurred with the angiogenic dose. These results suggest an angiogenic dose of VEGF165 injures the nervous tissue rather than promote recovery. Angiogenesis by VEGF monotherapy for ischemic stroke should be viewed with caution, or avoided. Since our data show intravascular administration of VEGF165 does not cause macrophage inflammation, in contrast to reports in the literature whereby VEGF165 was applied directly to the brain, our findings also indicate the relationships between VEGF, angiogenesis, and macrophage inflammation are governed by the route VEGF is administered to the brain.

Animals↗
PubMed2006

Two-photon imaging of cortical surface microvessels reveals a robust redistribution in blood flow after vascular occlusion.

A highly interconnected network of arterioles overlies mammalian cortex to route blood to the cortical mantle. Here we test if this angioarchitecture can ensure that the supply of blood is redistributed after vascular occlusion. We use rodent parietal cortex as a model system and image the flow of red blood cells in individual microvessels. Changes in flow are quantified in response to photothrombotic occlusions to individual pial arterioles as well as to physical occlusions of the middle cerebral artery (MCA), the primary source of blood to this network. We observe that perfusion is rapidly reestablished at the first branch downstream from a photothrombotic occlusion through a reversal in flow in one vessel. More distal downstream arterioles also show reversals in flow. Further, occlusion of the MCA leads to reversals in flow through approximately half of the downstream but distant arterioles. Thus the cortical arteriolar network supports collateral flow that may mitigate the effects of vessel obstruction, as may occur secondary to neurovascular pathology.

Animals↗
PubMed2006

Targeted insult to subsurface cortical blood vessels using ultrashort laser pulses: three models of stroke.

We present a method to produce vascular disruptions within rat brain parenchyma that targets single microvessels. We used two-photon microscopy to image vascular architecture, to select a vessel for injury and to measure blood-flow dynamics. We irradiated the vessel with high-fluence, ultrashort laser pulses and achieved three forms of vascular insult. (i) Vessel rupture was induced at the highest optical energies; this provides a model for hemorrhage. (ii) Extravasation of blood components was induced near the lowest energies and was accompanied by maintained flow in the target vessel. (iii) An intravascular clot evolved when an extravasated vessel was further irradiated. Such clots dramatically impaired blood flow in downstream vessels, in which speeds dropped to as low as approximately 10% of baseline values. This demonstrates that a single blockage to a microvessel can lead to local cortical ischemia. Lastly, we show that hemodilution leads to a restoration of flow in secondary downstream vessels.

Animals↗
PubMed2005

A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke.

BACKGROUND AND PURPOSE: Recombinant tissue-type plasminogen activator (rtPA) is the only approved treatment in acute ischemic stroke. However, intracerebral hemorrhage (ICH) occurs in 6.4% of patients treated with rtPA and limits its use. Tenecteplase (TNK) is a modified form of rtPA, with longer half-life and greater fibrin specificity. Patients after myocardial infarction had fewer systemic hemorrhages when treated with TNK compared with rtPA. This open-label, dose-escalation safety study was conducted to develop initial experience with TNK in the treatment of ischemic stroke. METHODS: Eligible patients were treated with an intravenous bolus infusion of TNK within 3 hours of stroke onset. The dose escalation was conducted in tiers of 25 patients, starting at 0.1 mg/kg, to a planned maximum of 0.6 mg/kg. The primary endpoint was symptomatic intracranial hemorrhage within 36 hours of treatment. All patients were followed-up for 3 months. RESULTS: Eighty-eight (88) patients were treated in 4 dosing tiers. In the first 3 tiers (0.1, 0.2, 0.4 mg/kg) of 25 patients each, no symptomatic and 2 (8%), 8 (32%), and 7 (28%) asymptomatic ICHs occurred. Enrollment into the fourth tier at 0.5 mg/kg was closed after 2 of 13 patients (15%) had symptomatic and 3 (23%) had asymptomatic ICHs. Overall, modified Rankin scores at 3 months were similar to those of historical controls treated with rtPA and not significantly different between treatment groups. CONCLUSIONS: TNK doses of 0.1 to 0.4 mg/kg are safe in ischemic stroke. Future trials are needed to compare the effect of TNK on neurological outcome and safety as compared with rtPA.

Aged↗
PubMed2005

Transcranial ultrasound angiography (T USA): a new approach for contrast specific imaging of intracranial arteries.

The goal was to develop an ultrasound contrast agent-specific imaging mode that offers an angiography-like view of the intracranial arteries and enables lower mechanical index MI settings compared to conventional transcranial duplex sonography. We studied 12 patients with transcranial ultrasound angiography (t USA) via the temporal bone window after an IV bolus injection of a perfluorocarbon-based microbubble contrast agent (Imagent). The aim was to display the intracranial vessel segments of the middle cerebral artery (M1, M2 and M3), the anterior cerebral artery (A1 and A2), the posterior cerebral artery (P1, P2 and P3) and the internal carotid artery (C1/2 and C3/4). t USA is a B-mode phase inversion imaging technique that uses wideband harmonic signals for image generation. We demonstrate, in this report, that t USA provides detailed anatomical display at native B-mode spatial resolution with fewer artifacts, yielding improved delineation of intracranial vessels that are in the 1- to 2-mm range.

Adolescent↗
PubMed2004

Beyond subgroup analysis: improving the clinical interpretation of treatment effects in stroke research.

In large clinical trials designed to determine efficacy of an experimental treatment, patients are enrolled with presence or absence of various risk factors, such as diabetes or history of atrial fibrillation. A treatment-by-risk factor interaction indicates that the treatment effect may depend on the risk factor presence or absence. It is important to identify such interaction, since a treatment may fail or cause adverse events in the presence of the risk. Although statistical methods exist to identify such interaction, they are underutilized in clinical stroke research. This paper reviews the notion of treatment-by-risk factor interaction and identifies two types of interaction, quantitative and qualitative, using a graphical technique and statistical testing. We illustrate how to avoid drawing the erroneous conclusions regarding the treatment effect on subgroups when failing to detect an interaction, and provide rigorous tools to estimate the treatment effect on subgroups when an interaction is observed. Applications are presented using the data collected from the NINDS t-PA stroke studies. In stroke clinical trials, a treatment-by-risk factor interaction must be considered if the data permit. The graphical approach provides a heuristic illustration of interactions. Qualitative interactions are more important than quantitative interactions on therapeutic conclusion. Results of NINDS t-PA stroke studies confirmed our previous conclusions on the treatment t-PA benefit within 3-h therapeutic window. No subgroup of patients would lead a physician to withhold the t-PA treatment.

Algorithms↗
PubMed2004

Early impairment in consciousness predicts mortality after hemispheric ischemic stroke.

OBJECTIVE: Early predictors of poor outcome after acute ischemic stroke may be useful in selecting patients for potentially beneficial but high-risk interventions. DESIGN: Cohort study of patients given placebo in a randomized clinical trial. SETTING: Multicenter trial at 139 U.S. and 14 Canadian hospitals. PATIENTS: A cohort of 564 placebo-treated patients with major anterior circulation ischemic stroke enrolled in the Clomethiazole in Acute Stroke Study-Ischemic Stroke (CLASS-I) trial. Patients did not have significant impairment in consciousness at baseline and were enrolled within 12 hrs of symptom onset. INTERVENTIONS: Prospective data collection of a number of clinical variables including use of a 6-point level of consciousness scale (1 = awake, 6 = no reaction to pain) to measure patients' level of consciousness at enrollment and 12 additional times during the first 24 hrs after enrollment. The ability of level of consciousness score and additional clinical data to predict 30-day mortality was assessed. MEASUREMENTS AND MAIN RESULTS: At 1 month, 114 of 564 patients (20%) had died. In univariate analysis, factors significantly associated with mortality included older age, white race, higher National Institutes of Health Stroke Scale score, higher serum glucose, atrial fibrillation, and any impairment in level of consciousness (p <.05). After controlling for these factors, increasing level of consciousness score at 3 hrs after enrollment and at all but one subsequent time point was significantly associated with increased mortality (odds ratio, 1.8 per point; 95% confidence interval, 1.2-2.6; p =.003 at 3-hr time point). Maximum level of consciousness score during the initial 24 hrs of monitoring also predicted mortality (odds ratio, 1.9 per point; 95% confidence interval, 1.4-2.5; p <.001). CONCLUSION: The development of a decreased level of consciousness within the initial hours after stroke onset, as evaluated by a simple six-point scale, is a powerful independent predictor of mortality after major anterior circulation ischemic stroke.

Age Distribution↗
PubMed2004

Neuroprotection of ischemic brain by vascular endothelial growth factor is critically dependent on proper dosage and may be compromised by angiogenesis.

Vascular endothelial growth factor (VEGF) is currently considered a potential pharmacologic agent for stroke therapy because of its strong neuroprotective and angiogenic capacities. Nonetheless, it is unclear how neuroprotection and angiogenesis by exogenous VEGF are related and whether they are concurrent events. In this study, the authors evaluated by stereology the effect of VEGF on neuronal and vascular volume densities of normal and ischemic brain cortices of adult male Sprague-Dawley rats. Ischemia was induced by a 4-hour occlusion of the middle cerebral artery. Low, intermediate, and high doses of VEGF165 were infused through the internal carotid artery for 7 days by an indwelling osmotic pump. The low and intermediate doses, which did not induce angiogenesis, significantly promoted neuroprotection of ischemic brains and did not damage neurons of normal brains. In contrast, the high dose that induced angiogenesis showed no neuroprotection of ischemic brains and damaged neurons of normal brains. These findings suggest that in vivo neuroprotection of ischemic brains by exogenous VEGF does not necessarily occur simultaneously with angiogenesis. Instead, neuroprotection may be greatly compromised by doses of VEGF capable of inducing angiogenesis. Stroke intervention efforts attempting to induce neuroprotection and angiogenesis concurrently through VEGF monotherapy should be approached with caution.

Animals↗
PubMed2002

Inter-relationships between spinal cord blood flow, neuronal death and neurological function in rabbit spinal cord ischemia.

Following rabbit spinal cord ischemia we measured histology, neurological outcome and spinal cord blood flow to investigate relationships between these quantities over a range of ischemia durations. Rabbits underwent reversible spinal cord ischemia induced by temporary aortic artery occlusion for zero to 65 min. In one cohort, surviving spinal cord cells were counted after 4 days of reperfusion using computer image analysis (n=23). Neurological outcome (paraplegic or non-paraplegic) was assessed in another group (n=381) after 18 h of reperfusion. A third group (n=8) had spinal cord blood flow measured by radioactive tracer immediately after ischemia. Histological analysis showed fewer motor neurons and astrocytes surviving as ischemia duration increased. Following 13 min (95% confidence interval (CI), 6 to 27) of ischemia 50% of low lumbar cord motor neurons remained alive; 50% of rabbits were paraplegic following 28.4 (26.7 to 30.0) min of ischemia; 28% (17% to 48%) of low lumbar motor neurons survived at this duration; 5% of rabbits were permanently paraplegic following 13.6 (10.6 to 16.1) min of ischemia, although only 52% (30% to 87%) of lower spinal cord motor neurons survived. Low lumbar cord blood flow was reduced to 2% of flow in non-ischemic thoracic cord after 25 and 60 min of ischemia (0.52 and 0.59 ml/100 g/min, respectively). These data support a fundamental hypothesis on which experimental ischemia is based: that substantial neuronal death follows directly from reversible ischemia and leads to permanent neurological deficit.

Animals↗
PubMed2002

Modified National Institutes of Health Stroke Scale for use in stroke clinical trials: prospective reliability and validity.

BACKGROUND AND PURPOSE: To prospectively evaluate the reliability and validity of this previously developed stroke scale in an independently collected cohort. The National Institutes of Health Stroke Scale (NIHSS) has been criticized for its complexity and variability. Prior formal clinimetric analyses were used to obtain a modified version of NIHSS (mNIHSS), which retrospectively demonstrated improved reliability and validity. We sought to prospectively measure the reliability and validity of the mNIHSS. METHODS: Forty-five patients with a history of stroke or intracerebral hemorrhage were evaluated at the University of California, San Diego, Stroke Center from September 2000 through March 2001. Each patient was tested by 2 NIHSS-certified neurologists using the NIHSS, mNIHSS, Barthel Index, and Modified Rankin scales. RESULTS: There were a large percentage of high kappa values using the mNIHSS. Only 10 (66.67%) of 15 NIHSS kappa scores showed excellent agreement, whereas 10 (90.91%) of 11 mNIHSS kappa scores showed excellent agreement. As predicted, the mNIHSS was more reliable than the NIHSS because of the exclusion of items with low kappa values. With the use of correlation coefficient analysis, the mNIHSS was as valid as the NIHSS. CONCLUSIONS: This prospective study found high reliability and continued validity by using a previously developed mNIHSS. Items found to have low kappa values were consistent with the previously derived retrospective mNIHSS. The resulting mNIHSS scale has much higher kappa values. The mNIHSS showed improved agreement between examiners and was also easier to administer, having fewer and simpler items. Further prospective evaluation should assess whether the mNIHSS could be used in lieu of the NIHSS.

Academic Medical Centers↗