Article

Serum Glucose Level and Diabetes Predict Tissue Plasminogen Activator Related Intracerebral Hemorrhage in Acute Ischemic Stroke

January 1999
Stroke 30(1):34-9

January 1999
30(1):34-9

DOI:10.1161/01.STR.30.1.34

Source
PubMed

Authors:

Andrew Demchuk

The University of Calgary

Derk W Krieger

University of Copenhagen

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Five pretreatment variables (P<0.1 univariate analysis), including serum glucose (>300 mg/dL), predicted symptomatic intracerebral hemorrhage (ICH) in the National Institute of Neurological Disorders and Stroke rtPA trial. We retrospectively studied stroke patients treated <3 hours from onset with intravenous rtPA at 2 institutions to evaluate the role of these variables in predicting ICH. Baseline characteristics, including 5 prespecified variables (age, baseline glucose, smoking status, National Institutes of Health Stroke Scale [NIHSS] score, and CT changes [>33% middle cerebral artery territory hypodensity]), were reviewed in 138 consecutive patients. Variables were evaluated by logistic regression as predictors of all hemorrhage (including hemorrhagic transformation) and symptomatic hemorrhage on follow-up CT scan. Variables significant at P<0.25 level were included in a multivariate analysis. Diabetes was substituted for glucose in a repeat analysis. Symptomatic hemorrhage rate was 9% (13 of 138). Any hemorrhage rate was 30% (42 of 138). Baseline serum glucose (5.5-mmol/L increments) was the only independent predictor of both symptomatic hemorrhage [OR, 2.26 (CI, 1.05 to 4.83), P=0.03] and all hemorrhage [OR, 2.26 (CI, 1.07 to 4.69), P=0.04]. Serum glucose >11.1 mmol/L was associated with a 25% symptomatic hemorrhage rate. Baseline NIHSS (5-point increments) was an independent predictor of all hemorrhage only [OR, 12.42 (CI, 1.64 to 94.3), P=0.01]. Univariate analysis demonstrated a trend for nonsmoking as a predictor of all hemorrhage [OR, 0.45 (CI, 0.19 to 1. 08), P=0.07]. Diabetes was also an independent predictor of ICH when substituted for glucose in repeat analysis. Serum glucose and diabetes were predictors of ICH in rtPA-treated patients. This novel association requires confirmation in a larger cohort.

Intravenous Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Patients With History of Stroke Plus Diabetes Mellitus

Article

Apr 2019

Background and Purpose— Acute ischemic stroke patients with history of prior ischemic stroke plus concomitant diabetes mellitus (DM) were excluded from the ECASS III trial (European Cooperative Acute Stroke Study) because of safety concerns. However, there are few data on use of intravenous tissue-type plasminogen activator and symptomatic intracerebral hemorrhage or outcomes in this population. Methods— Using data from the Get With The Guidelines–Stroke Registry between February 2009 and September 2017 (n=1619 hospitals), we examined characteristics and outcomes among patients with acute ischemic stroke treated with tissue-type plasminogen activator within the 3- to 4.5-hour window who had a history of stroke plus diabetes mellitus (HxS+DM) (n=2129) versus those without either history (n=16 690). Results— Compared with patients without either history, those with both prior stroke and DM treated with tissue-type plasminogen activator after an acute ischemic stroke had a higher prevalence of cardiovascular risk factors in addition to history of stroke, DM, and more severe stroke (National Institutes of Health Stroke Scale: median, 8 [interquartile range, 5–15] versus 7 [4–13]). The unadjusted rates of symptomatic intracerebral hemorrhage and in-hospital mortality were 4.3% (HxS+DM) versus 3.8% (without either history; P =0.31) and 6.2% versus 5.5% ( P =0.20), respectively. These differences were not statistically significant after risk adjustment (symptomatic intracerebral hemorrhage: adjusted odds ratio, 0.79 [95% CI, 0.51–1.21]; P =0.28; in-hospital mortality: odds ratio, 0.77 [95% CI, 0.52–1.14]; P =0.19). Unadjusted rate of functional independence (modified Rankin Scale score, 0–2) at discharge was lower in those with HxS+DM (30.9% HxS+DM versus 44.8% without either history; P ≤0.0001), and this difference persisted after adjusting for baseline clinical factors (adjusted odds ratio, 0.76 [95% CI, 0.59–0.99]; P =0.04). Conclusions— Among patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator within the 3- to 4.5-hour window, HxS+DM was not associated with statistically significant increased symptomatic intracerebral hemorrhage or mortality risk.

SYSTEMATIC REVIEW OF INTRAVENOUS THROMBOLYSIS IN ACUTE ISCHAEMIC STROKE

Research

Full-text available

Jun 2024

Penatalaksanaan Anestesi pada Perdarahan Intraserebral dengan Hidrosefalus dan Diabetes Melitus

Article

Full-text available

Feb 2022

Perdarahan Intraserebral (PIS) adalah ekstravasasi darah yang masuk kedalam parenkim otak, yang dapat berkembang ke ruang ventrikel dan subarahnoid, terjadi spontan dan bukan disebabkan oleh trauma (non traumatis) dan merupakan salah satu penyebab tersering pada pasien yang dirawat di unit perawatan kritis saraf. Kejadian PIS 10-15% dari semua stroke dengan tingkat angka kematian tertinggi dari subtipe stroke dan diperkirakan 60% tidak bertahan lebih dari satu tahun. Kasus: Laki-laki 57 tahun, datang dengan keluhan penurunan kesadaran yang terjadi pada saat mau makan. Pada pemeriksaan didapatkan kesadaran GCS E1M4V1 dengan hemodinamik stabil, dan terdapat hemiplegi sinistra. Pasien diintubasi dan memakai ventilator di ruangan Instalasi Gawat Darurat Disaster sambil menunggu hasil skrining Covid 19 dengan swab polymerase chain reaction (PCR). Pada CT-scan ditemukan adanya PIS 48,93 cc di basal ganglia, capsula eksterna sampai periventrikel lateralis kanan, terjadi distorsi midline sejauh 1 cm ke kiri. Ventrikulomegali disertai perdarahan intraventrikel yang mengisi ventrikel lateralis kanan dan kiri, ventrikel III dan IV. Laboratorium menunjukkan gula darah di atas 200 mg/dl setelah dilakukan koreksi gula darah diputuskan untuk dilakukan tindakan kraniotomi evakuasi segera dengan pemeriksaan penunjang yang cukup. Tindakan kraniotomi evakuasi pada pasien PIS menjadi tantangan bagi seorang anestesi, sehingga diperlukan pengetahuan akan patofisiologi, mortalitas PIS dan tindakan anestesi yang harus dipersiapkan dan dikerjakan dengan tepat.

Effect of Sociodemographic Factors, Concomitant Disease States, and Measures Performed in the Emergency Department on Patient Disability in Ischemic Stroke: Retrospective Study from Lebanon

Article

Full-text available

May 2021

Background. Stroke is a leading cause of death and disability in developed countries. The major factor affecting long-term survival other than age is the disability severity caused by stroke. The modified Rankin Scale (mRS) is a global functional endpoint measurement used in acute stroke to evaluate the degree of disability or dependence in daily life activities. The objective of this study was to assess the effects of sociodemographic factors, concomitant disease states, and some measures performed in the emergency department (ED) on patients’ disability. Methods. We conducted a retrospective study on ischemic stroke patients admitted to Intensive Care Unit of three Lebanese university hospitals between June and December 2016. Patients were excluded if they had been discharged from ED without hospital admission or if mRS was not performed. The mRS was further subdivided into two categories considered as “good prognosis” (0-2 or 0-3) and “poor prognosis” (>2 or > 3). Results. 204 patients were included in the study with mean age of years, hypertension was the most previous concomitant past medical disease (77.1%), and 27.1% of these patients had previous history of stroke. No significant differences were found in both mRS categories for all sociodemographic factors, and past medical history except that arrhythmia was significantly more common in the higher mRS and > 3. Based on multivariable analysis, there was a trend for previous intake of calcium channel blocker to be associated with lower mRS at admission (beta -0.586). However, intracranial arterial stenosis, ED mg/dL, and performing brain imaging above 20 minutes after patient presentation to ED were significantly associated with higher mRS scores at discharge with an ORa and (confidence interval) of 2.986 (0.814, 10.962), 3.301 (1.072, 1.261), and 1.138 (1.071, 9.080), respectively. Conclusion. mRS is affected by previous disease states, prescribed medications, and acute measures performed in ED. It is also influenced by intracranial arterial stenosis etiology, which is associated with worse outcome. 1. Introduction Stroke is the third leading cause of mortality after heart diseases and cancer and a principal cause of severe long-term disability in adults [1]. The majority of strokes (80–85%) are of ischemic origin [2, 3]. In the last decade, several outcome measures were developed to assess the degree of poststroke disability, such as modified Rankin Scale (mRS), Barthel Index (BI), health-related quality of life (EQ5D-3L) [4]. However, mRS is a global functional endpoint measurement and the most frequently used index in acute stroke to evaluate the degree of disability or dependence in daily life activities following stroke and thereby easily communicate effects of treatments to physicians and patients [4, 5]. This scale is also a standard element in clinical practice and an outcome measure that must be used in all stroke survivors according to the Get with the Guidelines [6]. The mRS is an ordinal disability score which categorizes patients among 7 levels ranging from 0 “no disability” to 6 “death” [7]. In clinical practice, interpretation of mRS is challenging since it is a nonlinear scale; thus, dichotomization of outcomes has been performed in research studies to ensure consistent scoring, minimization of both subjective judgment, and variability in score assignment [8–11]. Indeed, in clinical trials, mRS is often further subdivided into two categories according to a cut-off value of either 2 or 3 defining good prognosis as or < 4 and poor prognosis otherwise [12]. However, in current practice, even if patients with mRS of 3 are grouped with patients with mRS of 4-6 with the basic assumption that score of 3 is more similar to 4 than to 2 in terms of clinical outcomes, it raises concerns regarding the validity of this dichotomization given that mRS of 3 is typically considered of good clinical outcome and that patients with mRS 2 or 3 share a similar 7-year survival [13, 14]. The optimal and most objective cut-off value for mRS dichotomization is debatable as it depends on stroke severity, lacks the incorporation of the entire possible range of outcomes across the mRS, and raises difficulty as regards the interpretation of borderline score values of 2 and 3. Several investigators performed poststroke outcome measurement following the entire ordinal distribution values of mRS, as this strategy is more powerful than the dichotomization approach, especially because it takes into consideration treatment effect that might occur over the entire range of mRS [15]. Result performance using the entire distribution of mRS values has greater statistical power as well than the dichotomized approach, mainly when treatment benefit is a continuous process [16]. Although mRS is widely applied for evaluating stroke patient outcomes, it has several pitfalls when used to measure poststroke disability. An extensive literature documents the negative effect of patient comorbidities including cardiovascular disease, diabetes, arthritis, surgery, and socioeconomic factors on physical functioning, cognitive abilities, and overall health status so that these factors may have detrimental effect on the mRS [17–22]. This is extremely important as comorbidities are common in stroke patients, and stroke incidence in low socioeconomic populations is especially high [23]. It is essential for clinicians to take into account these various attributes and avoid misapplication and misinterpretation of mRS. Hence, the objective of this study was to compare the effects of sociodemographic factors, concomitant disease states, and some measures performed in the ED on mRS. 2. Methods 2.1. Study Design This was a retrospective observational study in which hospital records of all patients admitted to the Intensive Care Unit (ICU) of three Lebanese university hospitals between June and December 2016 were reviewed for inclusion. The list of hospitals, provided by the Lebanese Ministry of Public Health, was used to randomly select the centers. All adult patients presented to the emergency department with the diagnosis of ischemic stroke during the study period and who were subsequently admitted to the ICU were included in the study. No attempt was made to verify accuracy of the physician’s diagnosis, because the aim of this study was to assess the impact of sociodemographic factors and medical history on mRS prognosis. Patients were excluded if the patient had been diagnosed with transient ischemic attack, had been discharged from the ED without hospital admission, or if the mRS was not available. Eligible participants were randomly selected from each center using the list generated from the hospital administrator for all patients diagnosed with ischemic stroke from the medical record department for possible enrollment in the study. 2.2. Data Collection A medical record review was performed on site by the principal investigator, through a standardized data collection sheet. We collected baseline information including patient demographics, vascular risk factors, stroke severity (mRS at admission and upon discharge), and acute stroke management. mRS was documented by the attending physician on all patients’ medical charts both upon presentation to the emergency department and upon discharge. Vascular risk factors included hypertension, dyslipidemia, atrial fibrillation, previous stroke, smoking history, alcohol consumption, marital status, and body mass index (BMI) at admission which was categorized into underweight, normal, overweight, and obese [24]. Hypertension was defined as systolic mmHg or diastolic mmHg, any use of antihypertensive drug, or self-reported history of hypertension. We also included detailed assessment of antihypertensive medications including dose, frequency of administration, and therapeutic class [25]. Diabetes mellitus was defined as fasting glucose mmol/L, nonfasting glucose mmol/L, use of any glucose-lowering drugs, or self-reported history of diabetes [26]. Dyslipidemia was defined as serum mmol/L, low-density lipoprotein mmol/L, high-density lipoprotein mmol/L, use of any lipid-lowering drugs, or self-reported history of dyslipidemia [27]. Atrial fibrillation was defined as history of atrial fibrillation confirmed by at least one electrocardiogram or presence of arrhythmia during hospitalization. The treatment of atrial fibrillation defined by the use of anticoagulation agents or antiplatelet drugs during hospitalization and after discharge was also considered [28]. We followed the diagnosis of ischemic stroke set by the physician on the medical chart which is “an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction based on pathological, imaging, or other objective evidence of ischemic injury in a defined vascular distribution.” Etiologic subtypes of ischemic stroke were classified into cardioembolic, intracranial arterial stenosis, or other origins [29]. In addition, neurological assessment was documented through mRS. We then subdivided the mRS into two categories as “good prognosis” (either 0-2 or 0-3) and poor prognosis (either >2 or> 3) [12]. Data collection also gathered information about all measures done in the ED including brain imaging performance delay (within 20 minutes versus >20 minutes from hospital presentation) and administration of antiplatelet and antihypertensive medications. 2.3. Outcomes The primary outcome was to assess the impact of different factors including prestroke sociodemographic factors and medication prescriptions along with etiologic subtypes of stroke on mRS scores both at hospital admission and discharge. The secondary outcome was to assess the impact of different measures performed in the hospital like brain imaging delay, glucose level, and antithrombotic therapy in the ED on mRS at discharge. 2.4. Statistical Analysis The questionnaires were coded, and the collected data were introduced using the Statistical Package for Social Sciences (SPSS) software, version 23.0 by an independent person who was unaware of the objectives of the study. All continuous variables were presented as mean and standard deviation (SD), and categorical variables were presented as percentages. Correlations between sociodemographic factors, medical history, and mRS categories were determined by the Pearson chi-square test or Fisher’s exact test when Pearson chi-square test could not be applied. Paired sample -test was used to assess mean difference between mRS values at hospital admission and discharge. Multiple logistic regression models were used to assess association between sociodemographic factors, medical history that showed a in the bivariate analysis and mRS both at hospital admission and discharge (taken as the dependent variable). Potential confounders may be eliminated only if , in order to protect against residual confounding. We also performed a linear regression taking both mRS at hospital admission and discharge as the dependent variable and all other variables as independent. We ensured model adequacy by the use of the Hosmer Lemeshow test which is done for the logistic variables (mRS categories) to calculate if the observed event rates match the expected event rates. A was considered as statistically significant. 3. Results 3.1. Sociodemographic Characteristics of Participants From a total number of 400 patients screened for possible inclusion in the study, 204 subjects had documented mRS values at hospital admission and discharge and were enrolled in the study. Among the 204 participants, 132 (64.7%) were males. Mean age was years. Concerning BMI categories, 12 (29.3%) patients were normal, 17 (41.4%) overweight, and 12 (29.3%) obese. Almost half of the participants were smokers (48.5%), while the majority was nonalcoholic (64.7%), 75.1% were married, and 52.9% lived in Beirut district. Only 0.5% of the participants were physically active. As regards past medical history, hypertension was present in 77.1%; previous stroke or TIA prevalence was 27.1%. Atrial fibrillation, hyperlipidemia, and coronary artery bypass graft (CABG) were, respectively, found in 12.5%, 19.8%, and 4.2% of the participants. Regarding past medication history, 5.7% of the patients were on oral vitamin K antagonists, 0.5% on Low Molecular weight Heparin (LMWH), 38.8% on aspirin, 19.2% on clopidogrel, and 36.1% on lipid lowering therapy. Among patients with hypertension, 55.4% were on beta blockers, 34% were on calcium channel blockers (CCBs), and 25.3% were on dual antihypertensive drugs. The mean mRS scores at baseline and upon discharge were, respectively, and (see Table 1). Variable (%) Mean age 65.40 years Gender Male 132 (64.7) Female 72 (35.3) BMI Normal 12 (29.3) Overweight 17 (41.4) Obese 12 (29.3) Marital status Single 39 (21.1) Married 139 (75.1) Divorced 7 (3.8) Residence area Beirut 108 (60.3) Mount Lebanon 33 (18.4) Bekaa 5 (2.8) North Lebanon 2 (1.1) South Lebanon 31 (17.3) Cigarette smoker Yes 99 (48.5) Alcohol consumption Yes 21 (11.4) Past medical history Hypertension 74 (77.1) Stroke or TIA 26 (27.1) Atrial fibrillation 12 (12.5) Hyperlipidemia 19 (19.8) Baseline mRS upon admission mean 1 interquartile range (2, 6) Baseline mRS upon hospital discharge mean 2 interquartile range (0, 6)

Diabetes, stroke, and neuroresilience: looking beyond hyperglycemia

Article

Full-text available

Feb 2021
ANN NY ACAD SCI

Ischemic stroke is a leading cause of morbidity and mortality among type 2 diabetic patients. Preclinical and translational studies have identified critical pathophysiological mediators of stroke risk, recurrence, and poor outcome in diabetic patients, including endothelial dysfunction and inflammation. Most clinical trials of diabetes and stroke have focused on treating hyperglycemia alone. Pioglitazone has shown promise in secondary stroke prevention for insulin‐resistant patients; however, its use is not yet widespread. Additional research into clinical therapies directed at diabetic pathophysiological processes to prevent stroke and improve outcome for diabetic stroke survivors is necessary. Resilience is the process of active adaptation to a stressor. In patients with diabetes, stroke recovery is impaired by insulin resistance, endothelial dysfunction, and inflammation, which impair key neuroresilience pathways maintaining cerebrovascular integrity, resolving poststroke inflammation, stimulating neural plasticity, and preventing neurodegeneration. Our review summarizes the underpinnings of stroke risk in diabetes, the clinical consequences of stroke in diabetic patients, and proposes hypotheses and new avenues of research for therapeutics to stimulate neuroresilience pathways and improve stroke outcome in diabetic patients.

Effet protecteur des HDL en phase aiguë d’AVC ischémique en condition d’hyperglycémie

Thesis

Dec 2018

David Couret

Les accidents vasculaires cérébraux (AVC) ischémiques sont un problème majeur de santé publique. Les thérapies actuellement disponibles se fondent sur une approche vasculaire de la prise en charge. L’arrivée de la thrombectomie mécanique comme traitement de routine de l’AVC, expose le patient à des lésions de reperfusion comme les transformations hémorragiques (TH). L’hyperglycémie aiguë, augmente ce risque. Nous avons mis au point un modèle préclinique pertinent et reproductible chez la souris permettant d’étudier les mécanismes de ces TH. Les lipoprotéines de haute densité (HDL) sont des complexes moléculaires ayant des propriétés protectrices. Nous avons démontré que lors de la phase aiguë de l’AVC, ces HDL subissaient des modifications structurelles et devenaient dysfonctionnelles. Un des mécanismes de cette altération est représenté par l’oxydation des protéines de surface notamment l’apoA-1 par la myéloperoxydase (MPO) libérée par les neutrophiles recrutés dans la zone ischémiée. Le dosage du taux plasmatique de MPO en phase aiguë d’AVC pourrait permettre de mieux caractériser ce mécanisme. L’injection de HDL a déjà prouvé son efficacité dans la diminution de la taille des infarctus cérébraux ainsi que dans la survenue des complications hémorragiques sur des modèles murin d’ischémie cérébrale. L’hypothèse d’un défaut d’efficacité des HDL dans cette condition pathologique particulière nous conduit à envisager une amélioration de leurs fonctions grâce à leur propriété de vecteur de molécules protectrices. Ces HDL seraient alors utilisées comme transporteur de molécules augmentant leur potentiel neuro- et endothélio-protecteur dans le traitement de l’AVC ischémique.

Prediction of hemorrhagic transformation in patients with mild atrial fibrillation-associated stroke treated with early anticoagulation: Post hoc analysis of the Triple AXEL Trial

Article

Sep 2018
CLIN NEUROL NEUROSUR

Objectives: To investigate the predictors of hemorrhagic transformation (HT) in patients with mild atrial fibrillation-related stroke who were treated with early anticoagulation. We conducted a post-hoc subgroup analysis from Acute Cerebral Infarction Patients with Non-valvular Atrial Fibrillation (Triple AXEL) study. Patients and methods: The Triple AXEL study was a randomized, multicenter, open-label, blinded end-point evaluation, comparative phase 2 trial. To identify the relationship between the type of HT and risk factors. We analyzed various factors using data from the Triple AXEL study, such as sex, history of hypertension, diabetes, microbleeds, concomitant antiplatelet use, initial infarction volume, initial infarction location, and new intracranial hemorrhage on follow-up gradient recalled echo or susceptibility-weighted imaging. Results: We analyzed various factors by dividing patients into a new HT group and a no HT group. No correlation was found between HT and risk factors that were significantly associated with HT, including age, sex, history of hypertension, diabetes, microbleeds, concomitant antiplatelet use, and initial infarction volume. When the initial infarction was classified into anterior circulation infarction (ACI) and posterior circulation infarction (PCI), the occurrence of new HT was significantly more associated with PCI than with ACI (57.6% vs 24.0%, P = 0.001). Multivariate logistic regression analysis was performed using HT as a response variable. Only the location of initial infarction according to the vascular territory contributed to the increased risk of HT (OR2.3, 95%CI1.33-3.91, P = 0.003). Conclusion: PCI is a very important independent risk factor for HT in patients with mild AF-related stroke treated with early anticoagulation.

Treatment with exenatide in acute ischemic stroke trial protocol: A prospective, randomized, open label, blinded end-point study of exenatide vs. standard care in post stroke hyperglycemia

Article

Jul 2018

Rationale Post-stroke hyperglycemia occurs in up to 50% of patients presenting with acute ischemic stroke. It reduces the efficacy of thrombolysis, increases infarct size, and worsens clinical outcomes. Insulin-based therapies have generally not been beneficial in treating post-stroke hyperglycemia as they are difficult to implement, may cause hypoglycaemia, possibly increase mortality and worsen clinical outcomes. Exenatide may be a safer, simpler, and more effective alternative to insulin in acute ischemic stroke. Design TEXAIS is a three year, Phase 2, multi-center, prospective, randomized, open label, blinded end-point trial comparing exenatide to standard of care. It aims to recruit 528 patients with a primary end point of major neurological improvement at 7 days defined as a ≥8-point improvement in NIHSS score, or NIHSS 0-1. Secondary outcomes of hyper- and hypoglycaemia at 5 days and NIHSS and mRS at 90 days will be measured. The treatment arm will receive exenatide 5 µg subcutaneously twice daily. The control arm will receive standard stroke unit care. Continuous glucose monitors will track the dynamic variability of glucose. Conclusion TEXAIS aims to show that exenatide is safe and effective in the treatment of post-stroke hyperglycemia. It has been designed to be highly generalizable with an ability to enroll a large percentage of patients with acute ischemic stroke, regardless of admission blood glucose level, diabetes status, or stroke severity, with very low risk of hypoglycemia. Trial registration: ClinicalTrials.gov/ANZCTR NTA1127.

Stress hyperglycemia exacerbates inflammatory brain injury after stroke

Preprint

May 2024

Post-stroke hyperglycemia occurs in 30% - 60% of ischemic stroke patients as part of the systemic stress response, but neither clinical evidence nor pre-clinical studies indicate whether post-stroke hyperglycemia affects stroke outcome. Here we investigated this issue using a mouse model of permanent ischemia. Mice were maintained either normoglycemic or hyperglycemic during the interval of 17 - 48 hours after ischemia onset. Post-stroke hyperglycemia was found to increase infarct volume, blood-brain barrier disruption, and hemorrhage formation, and to impair motor recovery. Post-stroke hyperglycemia also increased superoxide formation by peri-infarct microglia/macrophages. In contrast, post-stroke hyperglycemia did not increase superoxide formation or exacerbate motor impairment in p47 phox-/- mice, which cannot form an active superoxide-producing NADPH oxidase-2 complex. These results suggest that hyperglycemia occurring hours-to-days after ischemia can increase oxidative stress in peri-infarct tissues by fueling NADPH oxidase activity in reactive microglia/macrophages, and by this mechanism contribute to worsened functional outcome.

Hemorrhagic Coagulation Disorders and Ischemic Stroke: How to Reconcile Both?

Article

Full-text available

Nov 2023

Pietro Crispino

Coagulation and fibrinolytic system disorders are conditions in which the blood’s ability to clot is impaired, resulting in an increased risk of thrombosis or bleeding. Although these disorders are the expression of two opposing tendencies, they can often be associated with or be a consequence of each other, contributing to making the prognosis of acute cerebrovascular events more difficult. It is important to recognize those conditions that are characterized by dual alterations in the coagulation and fibrinolytic systems to reduce the prognostic impact of clinical conditions with difficult treatment and often unfortunate outcomes. Management of these individuals can be challenging, as clinicians must balance the need to prevent bleeding episodes with the potential risk of clot formation. Treatment decisions should be made on an individual basis, considering the specific bleeding disorder, its severity, and the patient’s general medical condition. This review aims to deal with all those forms in which coagulation and fibrinolysis represent two sides of the same media in the correct management of patients with acute neurological syndrome. Precision medicine, personalized treatment, advanced anticoagulant strategies, and innovations in bleeding control represent future directions in the management of these complex pathologies in which stroke can be the evolution of two different acute events or be the first manifestation of an occult or unknown underlying pathology.

Early Hemorrhagic Transformation after Reperfusion Therapy in Patients with Acute Ischemic Stroke: Analysis of Risk Factors and Predictors

Article

Full-text available

May 2023
BSRCCS

Background: The standard reperfusion therapy for acute ischemic stroke (AIS) is considered to be thrombolysis, but its application is limited by the high risk of hemorrhagic transformation (HT). This study aimed to analyze risk factors and predictors of early HT after reperfusion therapy (intravenous thrombolysis or mechanical thrombectomy). Material and methods: Patients with acute ischemic stroke who developed HT in the first 24 h after receiving rtPA thrombolysis or performing mechanical thrombectomy were retrospectively reviewed. They were divided into two groups, respectively, the early-HT group and the without-early-HT group based on cranial computed tomography performed at 24 h, regardless of the type of hemorrhagic transformation. Results: A total of 211 consecutive patients were enrolled in this study. Among these patients, 20.37% (n = 43; age: median 70.00 years; 51.2% males) had early HT. Multivariate analysis of independent risk factors associated with early HT found that male gender increased the risk by 2.7-fold, the presence of baseline high blood pressure by 2.4-fold, and high glycemic values by 1.2-fold. Higher values of NIHSS at 24 h increased the risk of hemorrhagic transformation by 1.18-fold, while higher values of ASPECTS at 24 h decreased the risk of hemorrhagic transformation by 0.6-fold. Conclusions: In our study, male gender, baseline high blood pressure, and high glycemic values, along with higher values of NIHSS were associated with the increased risk of early HT. Furthermore, the identification of early-HT predictors is critical in patients with AIS for the clinical outcome after reperfusion therapy. Predictive models to be used in the future to select more careful patients with a low risk of early HT need to be developed in order to minimize the impact of HT associated with reperfusion techniques.

Predictors and long-term outcome of intracranial hemorrhage after thrombolytic therapy for acute ischemic stroke—A prospective single-center study

Article

Full-text available

Feb 2023

Introduction Acute ischemic stroke (AIS) is a potentially devastating disease with high disability and mortality. Recombinant tissue plasminogen activator (rt-PA) is an effective treatment with a 2–8% possible risk for symptomatic intracranial hemorrhage (sICH). Our aim was to investigate the risk factors and long-term clinical outcomes of ICH in patients after rt-PA treatment. Methods Consecutive patients with AIS, thrombolysed at the Department of Neurology, University of Debrecen, between 1 January 2004 and 31 August 2016 were enrolled prospectively. Risk factors, stroke severity based on the National Institute of Health Stroke Scale (NIHSS), functional outcome using the modified Rankin scale, and mortality at 1 year were compared in patients with and without ICH following rt-PA treatment. We evaluated clinical characteristics and prognosis by hemorrhage type based on the Heidelberg Bleeding Classification. Descriptive statistics, the chi-square test, the Mann–Whitney U-test, ANOVA, the Kruskal–Wallis test, a survival analysis, and logistic regression were performed as appropriate. Results Out of 1,252 patients with thrombolysis, ICH developed in 138 patients, with 37 (2.95%) being symptomatic. Mean ages in the ICH and non-ICH groups differed significantly (p = 0.041). On admission, the 24-h NIHSS after thrombolysis was higher in patients with ICH (p < 0.0001). Large vessel occlusion was more prevalent in patients with ICH (p = 0.0095). The ICH risk was lower after intravenous thrombolysis than intra-arterial or combined thrombolysis (p < 0.0001). Both at 3 months and 1 year, the outcome was worse in patients with ICH compared to patients without ICH group (p < 0.0001). Mortality and poor outcome were more prevalent in all hemorrhage types with a tendency for massive bleeding associated with unfavorable prognosis. At 3 months with the logistic regression model, the worse outcome was detected in patients with ICH after thrombolysis, at 1 year in patients with ICH after thrombolysis and smoking. Discussion Older age, higher NIHSS, large vessel occlusion, and intra-arterial thrombolysis may correlate with ICH. The unfavorable outcome is more common in patients with ICH. Precise scoring of post-thrombolysis bleeding might be a useful tool in the evaluation of the patient's prognosis. Our findings may help to identify predictors and estimate the prognosis of ICH in patients with AIS treated with rt-PA.

Safety outcomes of early initiation of antithrombotic agents within 24 h after intravenous alteplase at 0.6 mg/kg

Article

Jan 2023
J NEUROL SCI

Background: We examined outcome of acute ischemic stroke (AIS) with administration of antithrombotics within 24 hours after intravenous low-dose alteplase. Methods: Consecutive AIS patients who were treated with intravenous alteplase at 0.6 mg/kg from 2005 to 2021 were retrospectively included in our single-center registry. Patients were classified into two groups: those who received antithrombotics within 24 hours after intravenous alteplase (early initiation group) and those who did not (control group). Safety outcomes were any intracranial hemorrhage (ICH), symptomatic ICH (sICH) within 36 hours after onset, and death within 3 months. sICH was defined as any ICH with a ≥4-point increase in the National Institutes of Health Stroke Scale (NIHSS) score or death within 36 hours. Results: Of 1111 patients (women, 426; median age, 76 [interquartile range, 69–83] years; median NIHSS score, 11 [6–19]; cardioembolism, 580 [52.2%]), early initiation group comprised 58 patients (22; 72 [65–80] years; 7 [4–12]; 11 [19.0%]) and control group comprised 1053 patients (404; 77 [69–84] years; 11 [6–19]; 569 [54.1%]). No significant between-group differences were observed in the incidence of any ICH (17.2% vs. 21.6%; adjusted odds ratio [aOR], 1.18; 95% confidence interval [CI], 0.57–2.44), sICH (0% vs. 0.9%, P=1.00), or death within 3 months (5.2% vs. 6.7%; aOR, 1.23; 95% CI, 0.36–4.23). Conclusions: Early initiation of antithrombotics after intravenous alteplase at 0.6 mg/kg did not increase the rate of sICH or death within 3 months and may be used with caution in patients with advanced neurological deterioration.

Intravenous Thrombolysis With Alteplase at 0.6 mg/kg in Patients With Ischemic Stroke Taking Direct Oral Anticoagulants

Article

Full-text available

Sep 2022

BACKGROUND: We elucidated the safety of treatment with alteplase at 0.6 mg/kg within 24 hours for patients on direct oral anticoagulants (DOACs) before ischemic stroke onset. METHODS AND RESULTS: Consecutive patients with acute ischemic stroke who underwent intravenous thrombolysis using alteplase at 0.6 mg/kg from 2011 to 2021 were enrolled from our single-center prospective stroke registry. We compared outcomes between patients taking DOACs and those not taking oral anticoagulants within 48 hours of stroke onset. The primary safety outcome was the rate of symptomatic intracranial hemorrhage with a ≥4-point increase on the National Institutes of Health Stroke Scale score from baseline. The efficacy outcome was defined as 3-month modified Rankin Scale score of 0 to 2 after stroke onset. Of 915 patients with acute ischemic stroke who received intravenous thrombolysis (358 women; median age, 76 years; median National Institutes of Health Stroke Scale score, 10), 40 patients took DOACs (6 took dabigatran, 8 took rivaroxaban, 16 took apixaban, and 10 took edoxaban) within 24 hours of onset and 753 patients did not take any oral anticoagulants. The rate of symptomatic intracranial hemorrhage was comparable between patients on DOACs and those not on oral anticoagulants (2.5% versus 2.4%, P=0.95). The rate of favorable outcomes was comparable between the 2 groups (59.4% versus 58.2%, P=0.46), although the admission National Institutes of Health Stroke Scale score was higher in patients on DOACs. No significant differences showed in any intracranial hemorrhage within 36 hours or mortality at 3 months. CONCLUSIONS: Intravenous thrombolysis would be safely performed for patients on DOACs following the recommendations of the Japanese guidelines.

High glycemic albumin representing prestroke glycemic variability is associated with hemorrhagic transformation in patients receiving intravenous thrombolysis

Article

Full-text available

Jan 2022

We evaluated the impact of prestroke glycemic variability estimated by glycated albumin (GA) on symptomatic hemorrhagic transformation (SHT) in patients with intravenous thrombolysis (IVT). Using a multicenter database, we consecutively enrolled acute ischemic stroke patients receiving IVT. A total of 378 patients were included in this study. Higher GA was defined as GA ≥ 16.0%. The primary outcome measure was SHT. Multivariate regression analysis and a receiver operating characteristic curve were used to assess risks and predictive ability for SHT. Among the 378 patients who were enrolled in this study, 27 patients (7.1%) had SHT as defined by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SHT SITS ). The rate of SHT SITS was higher in the higher GA group than in the lower GA group (18.0% vs. 1.6%, p < 0.001). A higher GA level (GA ≥ 16.0%) significantly increased the risk of SHT SITS (adjusted odds ratio [OR], [95% confidence interval, CI], 12.57 [3.08–41.54]) in the logistic regression analysis. The predictive ability of the GA level for SHT SITS was good (AUC [95% CI]: 0.83 [0.77–0.90], p < 0.001), and the cutoff value of GA in SHT was 16.3%. GA was a reliable predictor of SHT after IVT in acute ischemic stroke in this study.

Initial Stress Hyperglycemia Is Associated With Malignant Cerebral Edema, Hemorrhage, and Poor Functional Outcome After Mechanical Thrombectomy

Article

Full-text available

Jan 2022

Background: Malignant cerebral edema (MCE) and intracranial hemorrhage (ICH) are associated with poor neurological outcomes despite revascularization after mechanical thrombectomy (MT). The factors associated with the development of MCE and ICH after MT are not well understood. Objective: To determine periprocedural factors associated with MCE, ICH, and poor functional outcome. Methods: We retrospectively analyzed anterior cerebral circulation large vessel occlusion cases that underwent MT from 2012 to 2019 at a single Comprehensive Stroke Center. Multivariate logistic regression analyses were performed to determine significant predictors of MCE, ICH, and poor functional outcome (modified Rankin Scale, 3-6) at 90 d. Results: Four hundred patients were included. Significant independent predictors of MCE after MT included initial stress glucose ratio (iSGR) (odds ratio [OR], 14.26; 95% CI, 3.82-53.26; P < .001), National Institutes of Health Stroke Scale (NIHSS) (OR, 1.10; 95% CI, 1.03-1.18; P = .008), internal carotid artery compared with M1 or M2 occlusion, and absence of successful revascularization (OR, 0.16; 95% CI, 0.06-0.44; P < .001). Significant independent predictors of poor functional outcome included MCE (OR, 7.47; 95% CI, 2.20-25.37; P = .001), iSGR (OR, 5.15; 95% CI, 1.82-14.53; P = .002), ICH (OR, 4.77; 95% CI, 1.20-18.69; P = .024), NIHSS (OR, 1.10; 95% CI, 1.05-1.16; P < .001), age (OR, 1.04; 95% CI, 1.03-1.07; P < .001), and thrombolysis in cerebral infarction 2C/3 recanalization (OR, 0.12; 95% CI, 0.05-0.29; P < .001). Conclusion: Elevated iSGR significantly increases the risk of MCE and ICH and is an independent predictor of poor functional outcome. Thrombolysis in cerebral infarction 2C/3 revascularization is associated with reduced risk of MCE, ICH, and poor functional outcome. Whether stress hyperglycemia represents a modifiable risk factor is uncertain, and further investigation is warranted.

Lack of Neuroprotective Effects of High-Density Lipoprotein Therapy in Stroke under Acute Hyperglycemic Conditions

Article

Full-text available

Oct 2021
MOLECULES

Introduction: The pleiotropic protective effects of high-density lipoproteins (HDLs) on cerebral ischemia have never been tested under acute hyperglycemic conditions. The aim of this study is to evaluate the potential neuroprotective effect of HDL intracarotid injection in a mouse model of middle cerebral artery occlusion (MCAO) under hyperglycemic conditions. Methods: Forty-two mice were randomized to receive either an intracarotid injection of HDLs or saline. Acute hyperglycemia was induced by an intraperitoneal injection of glucose (2.2 g/kg) 20 min before MCAO. Infarct size (2,3,5-triphenyltetrazolium chloride (TTC)-staining), blood-brain barrier leakage (IgG infiltration), and hemorrhagic changes (hemoglobin assay by ELISA and hemorrhagic transformation score) were analyzed 24 h post-stroke. Brain tissue inflammation (IL-6 by ELISA, neutrophil infiltration and myeloperoxidase by immunohisto-fluorescence) and apoptosis (caspase 3 activation) were also assessed. Results: Intraperitoneal D-glucose injection allowed HDL- and saline-treated groups to reach a blood glucose level of 300 mg/dl in the acute phase of cerebral ischemia. HDL injection did not significantly reduce mortality (19% versus 29% in the saline-injected group) or cerebral infarct size (p = 0.25). Hemorrhagic transformations and inflammation parameters were not different between the two groups. In addition, HDL did not inhibit apoptosis under acute hyperglycemic conditions. Conclusion: We observed a nonsignificant decrease in cerebral infarct size in the HDL group. The deleterious consequences of reperfusion such as hemorrhagic transformation or inflammation were not improved by HDL infusion. In acute hyperglycemia, HDLs are not potent enough to counteract the adverse effects of hyperglycemia. The addition of antioxidants to therapeutic HDLs could improve their neuroprotective capacity.

Factors Contributing to an Efficacious Endovascular Treatment for Acute Ischemic Stroke in Asian Population

Article

Full-text available

Mar 2021

Although randomized control trials about endovascular treatment (EVT) of emergent large vessel occlusion (LVO) have demonstrated the success of mechanical thrombectomy as the choice of treatment, a wide range of caveats remain unaddressed. Asian patients were rarely included in the trials, thereby raising the question of whether the treatment could be generalized. In addition, there remains a concern on the feasibility of the method with respect to its application against intracranial atherosclerosis (ICAS)-related LVO, frequently observed in the Asian population. It is important to include evidence on ICAS LVO from Asian countries in the future for a comprehensive understanding of LVO etiology. Besides the issues with EVT, prognostic concerns in diabetes patients, acute kidney injury following EVT, neuroprotective management against reperfusion injury, and other peri-EVT issues should be considered in clinical practice. In the current article, we present an in-depth review of the literature that revises information pertaining to such concerns.

Additional factors to corelate with a more than 30% NIHSS score improvement in patients 7 days after fibrinolytic and/or endovascular treatment for ischemic stroke

Article

Full-text available

Nov 2020
BMC NEUROL

Background Our objective was to find which additional factors can influence the favorable result in stroke patients after receiving fibrinolytic and/or endovascular treatment, quantified as a more than 30% improvement of the NIHSS score at 7 days. Methods This is a retrospective study to find factors that could influence a favorable evolution of patients with stroke that underwent fibrinolytic and or thrombectomy using the NIHSS score changes. At the admission in the hospital, blood glucose, blood count, coagulation time, INR, aPTT, PT, platelet count, NIHSS questionnaire and ASPECTS score were collected. NIHSS was assessed at the admission, after 1 h, after 2 h, after 24 h and after 7 days. Results As compared to the initial evaluation, at 7 days after admission 59% (72) of patients have improved with more than 30% the NIHSS. Higher levels of systolic blood pressure, glycemia and lower ASPECTS score at admission were observed in non-achievers. The value of INR contributed to model: for every unit increase of INR, the chance of better outcome decreases by 90,1%. High glycemia has also a negative impact: for every unit increase, the chance of better outcome decreases by 24%. Higher initial ASPECTS score is associated with better outcomes: each point increase of ASPECTS score at initial evaluation, increases the chance of better outcome by 154.2%. Conclusion Males, older age, diabetes, and hyperglycemia correlate with a worse outcome after cerebral stroke regardless of the benefit yielded fibrinolytic and/or thrombectomy therapy. In this study, patients with the above-mentioned factors did not improve more than 30% of baseline NIHSS score from admission to the 7th day.

Clinical Characteristics and Outcome of Patients With Hemorrhagic Transformation After Intravenous Thrombolysis in the WAKE-UP Trial

Article

Full-text available

Aug 2020

Background: Hemorrhagic transformation (HT) is an important complication of intravenous thrombolysis with alteplase. HT can show a wide range from petechiae to parenchymal hematoma with mass effect with varying clinical impact. We studied clinical and imaging characteristics of patients with HT and evaluated whether different types of HT are associated with functional outcome. Methods: We performed a post-hoc analysis of WAKE-UP, a multicenter, randomized, placebo-controlled trial of MRI-guided intravenous alteplase in unknown onset stroke. HT was assessed on follow-up MRI or CT and diagnosed as hemorrhagic infarction type 1 and type 2 (HI1 and HI2, combined as HI), and parenchymal hemorrhage type 1 and type 2 (PH1 and PH2, combined as PH). Severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS) at baseline. Stroke lesion volume was measured on baseline diffusion weighted imaging (DWI). Primary endpoint was a favorable outcome defined as a modified Rankin Scale score 0–1 at 90 days. Results: Of 483 patients included in the analysis, 95 (19.7%) showed HI and 21 (4.4%) had PH. Multiple logistic regression analysis identified treatment with alteplase (OR, 2.08 [95% CI, 1.28–3.40]), baseline NIHSS score (OR, 1.11 [95% CI, 1.05–1.17]), DWI lesion volume (OR, 1.03 [95% CI, 1.01–1.05]), baseline glucose levels (OR, 1.01 [95% CI, 1.00–1.01]) and atrial fibrillation (OR, 3.02 [95% CI, 1.57–5.80]) as predictors of any HT. The same parameters predicted HI. Predictors of PH were baseline NIHSS score (OR, 1.11 [95% CI, 1.01–1.22]) and as a trend treatment with alteplase (OR, 2.40 [95% CI, 0.93–6.96]). PH was associated with lower odds of favorable outcome (OR 0.25, 95% [CI 0.05–0.86]), while HI was not. Conclusion: Our results indicate that HI is associated with stroke severity, cardiovascular risk factors and thrombolysis. PH is a rare complication, more frequent in severe stroke and with thrombolysis. In contrast to HI, PH is associated with worse functional outcome. The impact of HT after MRI-guided intravenous alteplase for unknown onset stroke on clinical outcome is similar as in the trials of stroke thrombolysis within a known early time-window.

Stress hyperglycemia is predictive of worse outcome in patients with acute ischemic stroke undergoing intravenous thrombolysis

Article

Full-text available

Apr 2021
J THROMB THROMBOLYS

No study investigated the possible detrimental effect of stress hyperglycemia on patients affected acute ischemic stroke (AIS) undergoing intravenous thrombolysis (IVT). A new index, the glucose-to-glycated hemoglobin ratio (GAR), has been developed for assessing stress hyperglycemia. We retrospectively analyzed data from a prospectively collected database of consecutive patients admitted to the Udine University Hospital with AIS that were treated with IVT from January 2015 to December 2019. Four hundred and fourteen consecutive patients with AIS undergoing IVT entered the study. The patients were then stratified into four groups by quartiles of GAR (Q1–Q4). The higher GAR index was, the more severe stress hyperglycemia was considered. Prevalence of 3 months poor outcome (37.7% for Q1, 34% for Q2, 46.9% for Q3, and 66.7% for Q4, p for trend = 0.001), 3 months mortality (10.5% for Q1, 7.5% for Q2, 11.2% for Q3, and 27.1% for Q4, p for trend = 0.001), and symptomatic intracranial hemorrhage (0.9% for Q1, 0.9% for Q2, 5.1% for Q3, and 17.7% for Q4, p for trend = 0.001) was significant different among the four groups. AIS patients with severe stress hyperglycemia had a significantly increased risk of 3 months poor outcome (OR 2.43, 95% CI 1.14–5.22, p = 0.02), 3 months mortality (OR 2.38, 95% CI 1.01–5.60, p = 0.04), and symptomatic intracranial hemorrhage (OR 16.76, 95% CI 2.09–134.58, p = 0.008) after IVT. In conclusion, we demonstrated that stress hyperglycemia, as measured by the GAR index, is associated to worse outcome in AIS patients undergoing IVT.

High Neutrophil-to-Lymphocyte Ratio Predicts Hemorrhagic Transformation in Acute Ischemic Stroke Patients Treated with Intravenous Thrombolysis

Article

Full-text available

Feb 2020

Background. The relationship between the neutrophil-to-lymphocyte ratio (NLR) and hemorrhagic transformation (HT) in acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT) remains unclear. This study assessed whether high NLR is associated with HT in this population. Methods. Data were prospectively collected for continuous patients with AIS treated with IVT and retrospectively analyzed. Clinical variables included age, sex, vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score, onset-to-treatment time, and initial hematologic and neuroimaging findings. HT was confirmed by imaging performed within 3 days after IVT. Symptomatic HT (sHT) was defined as NIHSS score increased by 4 points compared with that on admission according to previously published criteria. The NLR value was based on the blood examination before IVT, and high NLR was defined as ≥75th percentile. Results. The study included 285 patients (201 (70.5%) males, the mean age was 62.3 years (range 29–89)). Seventy-two (25.3%) patients presented with HT, including three (1.1%) with sHT. The median NLR was 2.700 (1.820–4.255, interquartile range). Seventy-one (24.9%) patients had a high NLR (≥4.255) on admission. Univariate analysis indicated that patients with HT had higher NIHSS scores (P

Comorbidity and age in the modelling of stroke: are we still failing to consider the characteristics of stroke patients?

Article

Full-text available

Feb 2020

Stroke is a significant cause of mortality and morbidity for which there are limited treatment options. Virtually all drug interventions that have been successful preclinically in experimental stroke have failed to translate to an effective treatment in the clinical setting. In this review, we examine one of the factors likely contributing to this lack of translation, the failure of preclinical studies to consider fully the advanced age and comorbidities (eg, hypertension or diabetes) present in most patients with stroke. Age and comorbidities affect the likelihood of suffering a stroke, disease progression and the response to treatment. Analysing data from preclinical systematic reviews of interventions for ischaemic stroke we show that only 11.4% of studies included an aged or comorbid model, with hypertension being the most frequent. The degree of protection (% reduction in infarct volume) varied depending on the comorbidity and the type of intervention. We consider reasons for the lack of attention to comorbid and aged animals in stroke research and discuss the value of testing a potential therapy in models representing a range of comorbidities that affect patients with stroke. These models can help establish any limits to a treatment’s efficacy and inform the design of clinical trials in appropriate patient populations.

The Potentials of Spring Water in Brintik Indonesia as the Stroke Therapy Medium

Conference Paper

Full-text available

Jan 2018

Highly glycosylated CD147 promotes hemorrhagic transformation after rt-PA treatment in diabetes: a novel therapeutic target?

Article

Full-text available

Apr 2019
J NEUROINFLAMM

Background Diabetes is known to be a main risk factor of post-stroke hemorrhagic transformation following recombinant tissue plasminogen activator (rt-PA) therapy. However, the mechanism through which diabetes exacerbates hemorrhagic transformation is insufficiently understood. We aimed to verify that CD147, the extracellular matrix metalloproteinase (MMP) inducer, played a vital role in the progress. Methods We performed middle cerebral artery occlusion on diabetic and non-diabetic rats, with or without rt-PA treatment, and then compared the glycosylation level of CD147, caveolin-1, MMPs activities, and blood-brain barrier (BBB) permeability. In vitro, tunicamycin treatment and genetic tools were used to produce non-glycosylated and lowly glycosylated CD147. An endogenous glucagon-like peptide-1 receptor (GLP-1R) agonist was used to downregulate the glycosylation of CD147 in vivo. Results Compared with non-diabetic rats, diabetic rats expressed higher levels of highly glycosylated CD147 in endothelium and astrocytes following rt-PA treatment accompanied by higher activity of MMPs and BBB permeability, in the middle cerebral artery occlusion model. Caveolin-1 was also overexpressed and co-localized with CD147 in astrocytes and endothelium in diabetic rats. In vitro, advanced glycation end products increased the expression of highly glycosylated CD147 in astrocytes and endothelial cells. Downregulating the glycosylation of CD147 lowered the activity of MMPs and promoted the expression of tight junction proteins. The expression of caveolin-1 in endothelial cells and astrocytes was not inhibited by tunicamycin, which revealed that caveolin-1 was an upstream of CD147. In vivo, GLP-1R agonist downregulated the glycosylation of CD147 and further reduced the activity of MMPs and protected the BBB in diabetic rats. Conclusion CD147 is essential for diabetes-associated rt-PA-induced hemorrhagic transformation, and downregulation of CD147 glycosylation is a promising therapy for neurovascular-unit repair after rt-PA treatment of patients with diabetes. Electronic supplementary material The online version of this article (10.1186/s12974-019-1460-1) contains supplementary material, which is available to authorized users.

Improved outcome of patients with diabetes mellitus with good glycemic control in the cardiac intensive care unit: A retrospective study

Article

Full-text available

Jan 2019
CARDIOVASC DIABETOL

Background Diabetes mellitus (DM) is a prevalent metabolic disease characterized by chronic hyperglycemia. A primary burden of DM is related to its long-term complications, which have been shown to impact the course of hospitalization and to influence patients’ outcome. Aim To assess the role of in-hospital glucose control on length of stay, 30-days and 1-year mortality. Methods This is a retrospective study that included patients admitted to the cardiac intensive care unit (CICU) of the Edith Wolfson Medical Centre between 01 January, 2010 and 31 December 2013. Blood glucose was measured by glucometer and fed into an interactive database. Glucose status was referred to as controlled when more than 50% of a given patients glucose values were between 71 and 200 mg/dL. Chisquared tests were used to assess the distribution of categorical variables, while the ttest was applied for continuous variables. A multivariate logistic regression model was used to analyze the association between glucose control and mortality. Cox regression was conducted to assess survival and 1-year mortality. Results 2466 patients were admitted to the CICU over the study period, of which 370 had concomitant diabetes mellitus. Controlled glucose status was associated with shorter length of hospital stay (1.6 ± 1.7 versus 2.6 ± 3.0, p < 0.001), reduced 30-day mortality (0.7% versus 4.6%, p < 0.001), and improved 1-year mortality (2.2% versus 7.5%, p < 0.001). Moreover, attainment of glucose control was independently associated with a significant decrease in 1-year mortality (OR = 0.371, 95% CI 0.140–0.988, p = 0.047). Conclusion In-hospital control of glucose parameters is associated with shorter length of hospital stay, and lowered 30-day and 1-year mortality. An effort to maintain glucose levels within reference ranges is warranted in critically ill patients to reduce mortality.

Autonomic Disturbances in Acute Cerebrovascular Disease

Article

Full-text available

Oct 2018

Autonomic disturbances often occur in patients with acute cerebrovascular disease due to damage of the central autonomic network. We summarize the structures of the central autonomic network and the clinical tests used to evaluate the functions of the autonomic nervous system. We review the clinical and experimental findings as well as management strategies of post-stroke autonomic disturbances including electrocardiographic changes, cardiac arrhythmias, myocardial damage, thermoregulatory dysfunction, gastrointestinal dysfunction, urinary incontinence, sexual disorders, and hyperglycemia. The occurrence of autonomic disturbances has been associated with poor outcomes in stroke patients. Autonomic nervous system modulation appears to be an emerging therapeutic strategy for stroke management in addition to treatments for sensorimotor dysfunction.

Evaluation of Patients with Ischemic Stroke Receiving iv t-PA in the Emergency Department

Article

Full-text available

Jun 2018

Aim: The aim of the present study was to determine the demographic characteristics, localization of emboli, imaging findings, National Institutes of Health Stroke Scale (NIHSS) scores, and complications of patients who received intravenous (iv) tissue plasminogen activator (t-PA) due to early period of ischemic cerebrovascular disease (CVD) during the 6-year period in a tertiary level emergency department of a university hospital.Materials and Methods: The study was retrospectively performed in 65 patients aged ≥18 years and who underwent iv t-PA with a diagnosis of ischemic CVD. Demographic data, such as age, gender, and smoking, were obtained by examining the medical records of the patients. The baseline Glasgow Coma Scale, NIHSS, start time of the event, time of admission to the hospital, and prognosis of the patients were recorded.Results: Intracranial hemorrhage was detected in 16.9% of the patients after treatment. On examination of the patients’ outcome, a total of 32.3% (n=21) died after therapy. A significant correlation was observed between high NIHSS score and complications.Conclusion: In our study, a high NIHSS score at the time of admission has been found to increase both the risk of intracerebral hemorrhagic complication and mortality. We hypothesize that iv t-PA treatment gives successful results despite the complications, and emergency physicians should be more courageous in their application.

Glucose Control and Risk of Symptomatic Intracerebral Hemorrhage Following Thrombolysis for Acute Ischemic Stroke: A SHINE Trial Analysis

Article

Apr 2024
NEUROLOGY

Background and objectives: Baseline hyperglycemia is associated with worse outcomes in acute ischemic stroke (AIS), including higher risk of symptomatic intracerebral hemorrhage (sICH) following treatment with thrombolysis. Prospective data are lacking to inform management of post-thrombolysis hyperglycemia. In a prespecified analysis from the Stroke Hyperglycemia Insulin Network Effort (SHINE) trial of hyperglycemic stroke management, we hypothesized that post-thrombolysis hyperglycemia is associated with a higher risk of sICH. Methods: Hyperglycemic AIS patients <12 hours onset were randomized to intensive insulin (target range 80-130 mg/dL) vs standard sliding scale (80-179 mg/dL) over a 72-hour period, stratified by treatment with thrombolysis. Three board-certified vascular neurologists independently reviewed all sICH events occurring within 7 days, defined by neurologic deterioration of ≥4 points on the NIH Stroke Scale (NIHSS). Associations between blood glucose control and sICH were analyzed using logistic regression accounting for NIHSS, age, systolic blood pressure, onset to thrombolysis time, and endovascular therapy (odds ratios [OR], 95% CI). Additional analysis compared patients in a high-risk group (age older than 60 years and NIHSS ≥8) vs all others. Categorical variables and outcomes were compared using the χ2 test (p < 0.05). Results: Of 1151 SHINE participants, 725 (63%) received thrombolysis (median age 65 years, 46% women, 29% Black, 18% Hispanic). The median NIHSS was 7, baseline blood glucose was 187 (interquartile range 153-247) mg/dL, and 80% were diabetic. Onset to thrombolysis time was 2.2 hours (1.6-2.9). Post-thrombolysis sICH occurred in 3.6% (3.0% intensive vs 4.3% standard glucose control, OR 1.10, 0.60-2.01, p = 0.697). In the first 12 hours, every 10 mg/dL higher glucose increased the odds of sICH (OR 1.08, 1.03-1.14, p = 0.004), and a greater proportion of glucose measures in the normal range (80-130 mg/dL) decreased the odds of sICH (0.89, 0.80-0.99, p = 0.030). These associations were strongest in the high-risk group (age older than 60 years and NIHSS ≥8). Discussion: In this prespecified analysis from the SHINE trial, intensive insulin therapy was not associated with a reduced risk of post-thrombolysis sICH compared with standard sliding scale. However, early post-thrombolysis hyperglycemia was associated with a higher risk of sICH overall, particularly in older patients with more severe strokes. Further prospective research is warranted to address the risk of sICH in hyperglycemic stroke patients undergoing endovascular therapy. Trial registration information: NCT01369069.

Clinically asymptomatic hemorrhagic conversion is associated with need for inpatient rehabilitation following mechanical thrombectomy for anterior circulation ischemic stroke

Article

Mar 2024

Cerebrovascular Disease and Diabetes

Chapter

Jan 2024

Machine learning-based prediction of symptomatic intracerebral hemorrhage after intravenous thrombolysis for stroke: a large multicenter study

Article

Full-text available

Oct 2023

Background This study aimed to compare the performance of different machine learning models in predicting symptomatic intracranial hemorrhage (sICH) after thrombolysis treatment for ischemic stroke. Methods This multicenter study utilized the Shenyang Stroke Emergency Map database, comprising 8,924 acute ischemic stroke patients from 29 comprehensive hospitals who underwent thrombolysis between January 2019 and December 2021. An independent testing cohort was further established, including 1,921 patients from the First People’s Hospital of Shenyang. The structured dataset encompassed 15 variables, including clinical and therapeutic metrics. The primary outcome was the sICH occurrence post-thrombolysis. Models were developed using an 80/20 split for training and internal validation. Performance was assessed using machine learning classifiers, including logistic regression with lasso regularization, support vector machine (SVM), random forest, gradient-boosted decision tree (GBDT), and multilayer perceptron (MLP). The model boasting the highest area under the curve (AUC) was specifically employed to highlight feature importance. Results Baseline characteristics were compared between the training cohort (n = 6,369) and the external validation cohort (n = 1,921), with the sICH incidence being slightly higher in the training cohort (1.6%) compared to the validation cohort (1.1%). Among the evaluated models, the logistic regression with lasso regularization achieved the highest AUC of 0.87 (95% confidence interval [CI]: 0.79–0.95; p < 0.001), followed by the MLP model with an AUC of 0.766 (95% CI: 0.637–0.894; p = 0.04). The reference model and SVM showed AUCs of 0.575 and 0.582, respectively, while the random forest and GBDT models performed less optimally with AUCs of 0.536 and 0.436, respectively. Decision curve analysis revealed net benefits primarily for the SVM and MLP models. Feature importance from the logistic regression model emphasized anticoagulation therapy as the most significant negative predictor (coefficient: −2.0833) and recombinant tissue plasminogen activator as the principal positive predictor (coefficient: 0.5082). Conclusion After a comprehensive evaluation, the MLP model is recommended due to its superior ability to predict the risk of symptomatic hemorrhage post-thrombolysis in ischemic stroke patients. Based on decision curve analysis, the MLP-based model was chosen and demonstrated enhanced discriminative ability compared to the reference. This model serves as a valuable tool for clinicians, aiding in treatment planning and ensuring more precise forecasting of patient outcomes.

Diabetes and Cerebrovascular Disease

Chapter

Jun 2023

Diabetes mellitus (DM) is a major risk factor for cerebrovascular disease, particularly ischemic stroke. Hyperglycemia and insulin resistance promote functional and structural changes in the cerebral vasculature and induce a prothrombotic state resulting in micro- and macrovascular injury. The clinical correlates are overt stroke and vascular cognitive impairment and dementia. Diabetic patients have a high prevalence of comorbid vascular risk factors necessitating a careful and comprehensive approach to cardiovascular risk mitigation; the choice of hypoglycemic agents should be tailored to each patient’s circumstances. Hyperglycemia is detrimental in the acute phase of stroke but clinical trials of tight glycemic control regimens have not yielded the expected benefits. An individualized approach with emphasis on avoiding wide excursions and excessive glycemic corrections with hypoglycemic events is the mainstay of glycemic control in the acute phase of stroke.KeywordsStrokeCerebrovascular diseaseVascular cognitive impairmentDementiaBrain atrophyHyperglycemia

Patterns and Outcomes of Intensive Care on Acute Ischemic Stroke Patients in the US

Article

Feb 2023

Background: Up to 20% of acute ischemic stroke (AIS) patients may benefit from intensive care unit (ICU)-level care; however, there are few studies evaluating ICU availability for AIS. We aim to summarize the proportion of elderly AIS patients in the United States who are admitted to an ICU and assess the national availability of ICU-level care in AIS. Methods: We performed a retrospective cohort study using de-identified Medicare inpatient datasets from January 1, 2016 through December 31, 2019 for US individuals aged ≥65 years. We used validated International Classification of Diseases, Tenth Revision, Clinical Modification codes to identify AIS admission and interventions. ICU-level care was identified by revenue center code. AIS patient characteristics and interventions were stratified by receipt of ICU-level care, comparing differences through calculated standardized mean difference score due to large sample sizes. Results: From 2016 through 2019, a total of 952 400 admissions by 850 055 individuals met criteria for hospital admission for AIS with 19.9% involving ICU-level care. Individuals were predominantly >75 years of age (58.5%) and identified as white (80.0%). Hospitals on average admitted 11.4% (SD 14.6) of AIS patients to the ICU, with the median hospital admitting 7.7% of AIS patients to the ICU. The ICU admissions were younger and more likely to receive reperfusion therapy but had more comorbid conditions and neurologic complications. Of the 5084 hospitals included, 1971 (38.8%) reported no ICU-level AIS care. Teaching hospitals (36.9% versus 1.6%, P<0.0001) with larger AIS volume (P<0.0001) or in larger metropolitan areas (P<0.0001) were more likely to have an ICU available. Conclusions: We found evidence of national variation in the availability of ICU-level care for AIS admissions. Since ICUs may provide comprehensive care for the most severe AIS patients, continued effort is needed to examine ICU accessibility and utility among AIS.

Acute Ischemic Stroke by Middle Cerebral Artery Occlusion in Rat Models of Diabetes: Importance of Pre-op and Post-op Care, Severity of Hyperglycemia, and Sex

Chapter

Jan 2023

Diabetes mellitus (DM) is associated with poor stroke outcomes, including high mortality and disability rates. Ischemic injury modeling large artery stroke in diabetic animals also results in high mortality and poor acute and long-term outcomes. In this chapter, we describe middle cerebral artery occlusion (MCAO) in a high-fat diet/low-dose streptozotocin (STZ) model of diabetes including details on pre-op and post-op care that improve survival rate for successful completion of the studies.Key wordsDiabetes Hyperglycemia Stroke Hemorrhagic transformation Outcomes

Timing of Direct Oral Anticoagulants for Hemorrhagic Transformation After Endovascular Treatment in Acute Ischemic Stroke

Article

Apr 2022

Objectives: The purpose of this study is to investigate the relationship between the timing of starting direct oral anticoagulants (DOACs) and subsequent clinical outcomes in patients with hemorrhagic transformation (HT) after endovascular treatment (EVT). Materials and methods: The subjects were patients with acute cardioembolic stroke who underwent EVT and received DOACs in our department from February 2017 to August 2021. Based on CT at 24 h after EVT, the patients were classified using European Collaborative Acute Stroke Study criteria into three groups: no HT, hemorrhagic infarction (HI), and parenchymal hematoma (PH). Outcomes were assessed for incidence of recurrent ischemic stroke (RIS), new intracranial hemorrhage (ICH), and worsened HT associated with DOACs. Results: Of 111 patients, 29 (26.1%) had HT, including 16 (14.4%) with HI and 13 (11.7%) with PH. The start of DOACs was significantly delayed in the PH group (no HT: 1.0 (1.0-3.0) days vs. HI: 3.0 (2.0-5.0) days vs. PH: 7.0 (7.0-10.0) days, P < 0.01). The incidence of RIS did not differ significantly among the three groups, but tended to be higher in the PH group (no HT: 3.7% vs. HI: 6.3% vs. PH: 15.4%, p = 0.12). There were no cases of new symptomatic ICH. New asymptomatic ICH occurred in 2 cases in the no HT group. Worsened HT after initiation of DOACs did not occur in the HI or PH group. Conclusions: The timing of starting DOACs in patients with HT after EVT may be divided by subtypes of HI and PH. In patients with HI, early initiation of DOACs can prevent RIS and is unlikely to cause new ICH or worsened HI. In PH, initiation of DOACs within 14 days appears to be safe and does not exacerbate PH. The later the start of DOACs, the higher the frequency of RIS, so early initiation of DOACs is desirable.

Clinical and Imaging Indicators of Hemorrhagic Transformation in Acute Ischemic Stroke After Endovascular Thrombectomy

Article

Dec 2021

Background and Purpose Prior studies have investigated the clinical and imaging factors for hemorrhagic transformation (HT), especially symptomatic intracranial hemorrhage (sICH); however, whether alteplase increases the risk of HT after endovascular thrombectomy (EVT) is unknown. This study aimed to assess clinical and imaging features associated with HT, sICH, and parenchymal hematoma (PH) in patients with acute ischemic stroke after EVT, with and without intravenous alteplase in DIRECT-MT (Direct Intraarterial Thrombectomy to Revascularize Acute Ischemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicenter Randomized Clinical Trial). Methods The DIRECT-MT trial is a randomized trial of EVT alone versus intravenous thrombolysis combined with EVT. HT, sICH, and PH was evaluated on follow-up computed tomography. Multivariable ordinal logistic regression analysis was used to test the association of stepwise selected determinants with HT, sICH, and PH. Results In total, 633 patients were analyzed; 261 (41.2%) had HT; 34 (5.4%) had sICH; and 85 (13.4%) had PH. The median age was 69, and 56.7% were men. The median National Institutes of Health Stroke Scale score was 18, and 320 patients were in combination-therapy group. Symptomatic intracranial hemorrhage was associated with higher baseline National Institutes of Health Stroke Scale score (adjusted odds ratio [OR], 1.06 [95% CI, 1.10–1.12]) and higher glucose level at hospital arrival (adjusted OR, 1.14 [95% CI, 1.00–1.29]). No association was found between alteplase treatment and HT, sICH, or PH. The independent predictor of sICH was higher baseline National Institutes of Health Stroke Scale score (adjusted OR, 1.09 [95% CI, 1.01–1.18]) in EVT alone group, and history of anticoagulant drugs (adjusted OR, 3.75 [95% CI, 1.07–13.06]), higher glucose level at hospital arrival (adjusted OR, 1.19 [95% CI, 1.03–1.38]), >3 passes of device (adjusted OR, 4.42 [95% CI, 1.36–14.32]) in combination-therapy group. Conclusions In DIRECT-MT, independent predictors of sICH were baseline National Institutes of Health Stroke Scale score and glucose level at hospital arrival. Alteplase treatment did not increase the risk of HT, sICH, or PH after EVT. The independent predictor of sICH was different in EVT alone group and combination-therapy group. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03469206.

VASOESPASMO CEREBRAL RELACIONADO A HIPERGLICEMIA EN PACIENTE CON HEMORRAGIA SUBARACNOIDEA ANEURISMATICA: CASO CLÍNICO Y REVISIÓN DE LA LITERATURA

Article

Full-text available

Jan 2021

Aneurysmal subarachnoid hemorrhage is a very serious phenomenon associated with high rates of morbidity and mortality, this depends on the initial severity. The control of glucose is one of the care that must be taken into account since it is closely related to the development of secondary complications. We present the clinical case of a patient with a history of type 2 diabetes treated irregularly, who presented an aneurysmal subarachnoid hemorrhage, complicated by cerebral vasospasm, infarction, secondary hydrocephalus and pulmonary infections in relation to hyperglycemia during the post-operative period of difficult and refractory treatment. We expose the pathophysiological mechanisms that cause alterations in the cerebral vascular self-regulation phenomena and consequently cerebral perfusion disorders that decrease the neurological state of the patient, highlighting that the control of glycemia in the course of a subarachnoid hemorrhage can help a better outcome of the patients.

Medical Therapy of Intracerebral and Intraventricular Hemorrhage

Chapter

Jan 2022

Patients with intracerebral hemorrhage (ICH) should be cared for in specialized units with a focus on monitoring for deterioration and avoiding medical complications such as fever, hyper- or hypoglycemia, and deep vein thrombosis. Blood pressure lowering after ICH to a target systolic blood pressure (SBP) less than 140 mm Hg is probably safe but has not been shown to reduce the outcome of death or disability. Indications for craniotomy and hematoma removal remain uncertain for most cases of supratentorial ICH, though minimally invasive surgical treatments may be an emerging treatment option based on recent clinical trial outcomes. For cerebellar hemorrhage with mass effect or hydrocephalus, surgical hematoma evacuation can be lifesaving. Outcome prediction after ICH may be confounded by very frequent limitations in life-sustaining treatments. Clinicians should be cautious of early limitations in the supportive treatment provided, and work to ensure that the goals of treatment are in line with patient and family values and treatment preferences.

General Stroke Management and Stroke Units

Chapter

Jan 2022

While most acute treatments could still be given to a limited number of patients with stroke, stroke unit care has the advantage of being suitable to almost all stroke patients. This chapter characterizes stroke unit care, including all aspects of general stroke management that can optimally be delivered in stroke units. There is strong evidence that treatment of patients with stroke in dedicated stroke units results in significantly lower rates of death, dependency, and the need for institutional care compared to treatment in general medical wards. Stroke units are key elements in the organized stroke care pathway, preceded by prehospital and hyperacute care and followed by rehabilitation. This chapter covers stroke care after a patient has received acute treatment and has been transferred to a stroke unit.

Peroxynitrite activates NLRP3 inflammasome and contributes to hemorrhagic transformation and poor outcome in ischemic stroke with hyperglycemia

Article

Jan 2021
FREE RADICAL BIO MED

This study aims to test the hypothesis that peroxynitrite-mediated inflammasome activation could be a crucial player in the blood-brain barrier (BBB) disruption, hemorrhagic transformation (HT) and poor outcome in ischemic stroke with hyperglycemia. We used an experimental rat stroke model subjected to 90 min of middle cerebral artery occlusion plus 24 hours or 7 days of reperfusion with or without acute hyperglycemia. We detected the production of peroxynitrite, the expression of NADPH oxidase, iNOS, MMPs and NLRP3 inflammasome in the ischemic brains, and evaluated infarct volume, brain edema, HT, neurological deficit score and survival rates. Our results show that: (1) Hyperglycemia increased the expression of NADPH oxidase subunits p47phox and p67phox, and iNOS, and the production of peroxynitrite. (2) Hyperglycemia increased infarct volume, aggravated the BBB hyperpermeability, induced brain edema and HT, and worsened neurological outcomes. These brain damages and poor outcome were reversed by the treatments of FeTmPyP (a representative peroxynitrite decomposition catalyst, PDC), peroxynitrite scavenger uric acid, and iNOS inhibitor 1400W. Furthermore, the activations of MMPs and NLRP3 inflammasome including pro/active-caspase-1 and IL-1β were inhibited both PDC and 1400W, indicating the roles of peroxynitrite in the inductions of MMPs and NLRP3 inflammasome in the ischemic brains under hyperglycemia. (3) NLRP3 inflammasome inhibitor MCC950, caspase-1 inhibitor VX-765 and IL-1β inhibitor diacerein attenuated brain edema, minimized hemorrhagic transformation and improved neurological outcome, demonstrating the roles of NLRP3 inflammasome in the hyperglycemia-mediated HT and poor outcome in the ischemic stroke rats with acute hyperglycemia. In conclusion, peroxynitrite could mediate activations of MMPs and NLRP3 inflammasome, aggravate the BBB damage and HT, and induce poor outcome in ischemic stroke with hyperglycemia. Therefore, targeting peroxynitrite–mediated NLRP3 inflammasome could be a promising strategy for ischemic stroke with hyperglycemia.

Prognosis and risk factors of asymptomatic intracranial hemorrhage after endovascular treatment of large vessel occlusion stroke: a prospective multicenter cohort study

Article

Sep 2020
EUR J NEUROL

Background: Asymptomatic intracranial hemorrhage (aICH) is a common occurrence after endovascular therapy (EVT) for acute ischemic stroke (AIS). The aims of this study are to address its impact on 3-month functional outcome and to identify risk factors for aICH after EVT. Methods: Patients with AIS due to anterior circulation large vessel occlusion treated by EVT were enrolled in a multicenter prospective registry. Based on imaging performed 22h-36h post-EVT, we included patients with no ICH or aICH. Poor outcome defined as a 3-month mRS 4-6 and overall 3-month mRS distribution were compared according to presence/absence of aICH, and aICH subtype using logistic regression. We assessed the risk factors of aICH using a multivariate logistic-regression model. Results: Among 1,526 patients included, 653 (42.7%) had aICH. Patient with aICH had a higher rate of poor outcome OR 1.88 [95%CI, 1.44 to 2.44]. Shift analysis of mRS found a fully-adjusted OR of 1.79 [95%CI, 1.47 to 2.18]. Hemorrhagic infarction (OR 1.63 [95%CI, 1.22 to 2.18]) and parenchymal hematoma (OR 2.99 [95%CI, 1.77 to 5.02]) were associated with higher risk of poor outcome. Male sex, diabetes, coronary artery disease, baseline NIHSS and ASPECTS, number of passes and onset to groin puncture time were independently associated with aICH. Conclusions: Patients with aICH, irrespectively of the radiological pattern, have a worse functional outcome at 3-months compared with those without ICH after EVT for AIS. The number of EVT passes and the time from onset to groin puncture are factors that could be modified to reduce these deleterious ICH.

YiQiFuMai Lyophilized Injection ameliorates tPA-Induced hemorrhagic transformation by inhibiting cytoskeletal rearrangement associated with ROCK1 and NF-κB signaling pathways

Article

Jul 2020
J ETHNOPHARMACOL

Ethnopharmacological relevance Thrombolytic therapy with tissue plasminogen activator (tPA) after ischemic stroke exacerbates blood–brain barrier (BBB) breakdown and leads to hemorrhagic transformation (HT). YiQiFuMai Lyophilized Injection (YQFM) is a modern preparation derived from Sheng-mai San, (a traditional Chinese medicine). YQFM attenuates the BBB dysfunction induced by cerebral ischemia–reperfusion injury. However, whether YQFM can suppress tPA-induced HT remains unknown. Aim of the study We investigated the therapeutic effect of YQFM on tPA-induced HT and explored the underlying mechanisms in vivo and in vitro to improve the safety of tPA use against stroke. Methods Male C57BL/6J mice were subjected to 45 min of ischemia and 24 h of reperfusion. tPA (10 mg/kg) were infused 2 h after occlusion and YQFM (0.671 g/kg) was injected 2.5 h after occlusion. The in vitro effect of YQFM (100, 200, 400 μg/mL) was observed in tPA (60 μg/mL)-induced dysfunction of the microvascular endothelial barrier in the brain following oxygen-glucose deprivation/reoxygenation (OGD/R) in bEnd.3 cells. Results YQFM suppressed tPA-induced high hemoglobin level in the brain, mortality, neurologic severity score, BBB permeability, expression and activation of matrix metalloproteinase (MMP)-9 and MMP-2, and degradation of tight-junction proteins. Furthermore, YQFM significantly blocked tPA-induced brain microvascular endothelial permeability and phosphorylation of Rho-associated kinase (ROCK)1, myosin light chain (MLC), cofilin and p65 in vivo and in vitro. Conclusion YQFM suppressed tPA-induced HT by inhibiting cytoskeletal rearrangement linked with ROCK-cofilin/MLC pathways and inhibiting the nuclear factor-kappa B pathway to ameliorate BBB damage caused by tPA.

Abstracts 14th YES Meeting

Poster

Full-text available

Nov 2019

Ana Rita Brás

Introduction: Obesity prevalence has increased in the past few decades. Diet has been the main factor in this increase. The consequences of high fat and/or high sugar consumption go beyond obesity and have impact also in the brain and even on cognitive performance. Adolescence is the period in which the brain goes through great development, and so is more susceptible to impairments. It is also a period in which individuals start gaining independence on their choices and are prone to succumb to bad eating behaviors. Aim: As animal submitted to caloric diets show impaired spatial memory and increased anxiety, we aimed to find neurochemical changes causing these effects. Since hippocampus is a mediator of learning and memory, we focused our attention on this structure. Methods: Male wistar rats, 4 weeks old were randomly allocated to control (C), high-sugar diet (HS) or cafeteria diet (CAF) groups and fed accordingly for 8 weeks. After treatment, behavioural tests were performed to analyse anxiety and cognition. Animals were sacrificed and the brains collected for immunohistochemical studies targeting parvalbumin, calretinin, calbindin, neuropeptide Y, somatostatin, and vesicular acetylcholine transporter. Results: We have found that CAF diet is associated with impaired spatial learning and memory, and increased anxiety levels. Moreover, we have found that CAF diet induces alterations in neurogenesis. Relative to GABAergic circuit, CAF diet induced alterations in the expression of the calcium-binding proteins, namely a reduction in the expression of parvalbumin and an increase in the expression of calbindin in the dentate hilus, that was accompanied by an increase the density of cholinergic varicosities. Conclusion: These results suggest that cafeteria diets, rich in saturated fats and sugar, are more detrimental for juvenile rats than diets with high-sugar content alone. These ﬁndings may help explain the cognitive disturbances observed in obese human adolescents, who consume high-caloric diets.

Predictors for the extent of pial collateral recruitment in acute ischemic stroke

Article

Jan 2020

Background: Pial arterioles can provide a variable degree of collateral flow to ischemic vascular territories during acute ischemic stroke. This study sought to identify predictive factors of the degree of pial collateral recruitment in acute ischemic stroke. Methods: Clinical information and arteriograms from 62 consecutive patients with stroke due to either middle cerebral artery (MCA) M1 segment or internal carotid artery (ICA) terminus occlusion within 6 h following symptom onset were retrospectively reviewed. Pial collaterals were defined based on the extent of reconstitution of the MCA territory. Patients with slow antegrade flow distal to the occlusion site were excluded and no anesthetics were used prior or during angiography. Results were analyzed using multivariate nominal logistic regression. Results: Better pial collateral recruitment was associated with proximal MCA versus ICA terminus occlusion (p = 0.005; odds ratio (OR) = 9.3; 95% confidence interval (CI), 2.16-53.3), lower presenting National Institutes of Health Stroke Scale Score (NIHSSS) (p = 0.023; OR = 6.51; 95% CI, 1.49-41.7), and lower diastolic blood pressure (p = 0.0411; OR = 5.05; 95% CI, 1.20-29.2). Age, gender, symptom duration, diabetes, laterality, systolic blood pressure, glucose level, hematocrit, platelet level, and white blood cell count at presentation were not found to have a statistically significant association with pial collateral recruitment. Conclusions: Extent of pial collateral recruitment is strongly associated with the occlusion site (MCA M1 segment versus ICA terminus) and less strongly associated with presenting NIHSSS and diastolic blood pressure.

Mild hypothermia alleviates diabetes aggravated cerebral ischemic injury via activating autophagy and inhibiting pyroptosis

Article

May 2019
BRAIN RES BULL

Diabetic patients manifest with more severe neurological deficits than non-diabetes after ischemic stroke. It has been shown that hypothermia has neuroprotective effects on cerebral ischemia, but whether it is effective for cerebral ischemia in diabetic patients remains unknown. The aim of this study was to investigate whether hypothermia can alleviate cerebral ischemic injury in diabetic rats and the regulation of autophagy and pyroptosis of the treatment. We introduced permanent middle cerebral artery occlusion (pMCAO) in a model of type 2 diabetic rats prepared by high-fat diet combined with intraperitoneal injection of STZ in vivo and mimicked cerebral ischemia with diabetes by employing high glucose stimulation and oxygen–glucose deprivation/reoxygenation (OGD/R) in vitro. Moreover, 3-methyladenine and bafilomycin A1 were used to evaluate the association between autophagy and pyroptosis in vitro. Our results showed that diabetes aggravated neurological deficits, increased the volume of cerebral infarction and brain edema as well as the blood brain barrier permeability after cerebral ischemia, which were alleviated by mild hypothermia. Compared with the pMCAO model in non-diabetic rats and OGD/R model without high glucose stimulation in vitro, the expression of P62, NOD-like receptor protein 3 (NLRP3), cleaved caspase-1 and Gasdermin-N increased and the ratio of microtubule-associated protein 1 light chain 3B (LC3B) Ⅱ/Ⅰ decreased in the pMCAO model in diabetic rats and OGD/R model with high glucose stimulation, which could be reversed by mild hypothermia. In conclusion, mild hypothermia alleviated diabetes aggravated cerebral ischemic injury via activating autophagy and inhibiting pyroptosis.

Personified Approaches to Reperfusion Therapy of Ischemic Stroke

Article

Dec 2018

Introduction: Systemic thrombolytic therapy (STLT) with recombinant tissue plasminogen activator (rtPA) is the “gold standard” of reperfusion therapy in certain patients with ischemic stroke during the first 4.5 h after stroke onset. Objective: To assess the clinical (severity of neurological symptoms) and laboratory (complete blood cell count test) factors that affect the disease outcome after STLT. Materials and methods: Seventy patients (48 males and 22 females) aged 61 [54; 69] years with ischemic stroke who received rtPA therapy at a dose of 0.9 mg/kg were prospectively studied. Blood for the complete blood count test including neutrophil and lymphocyte counts was sampled before the thrombolytic therapy. The severity of neurological impairment was assessed using the NIH Stroke Scale (NIHSS). The functional outcome was assessed 3 months after stroke with the modified Rankin scale (mRS). ROC analysis was used to reveal factors of unfavorable outcome in acute phase of ischemic stroke (mRS score ≥ 3). Results: Severity of neurological deficit was assessed according to the NIHSS at admission was 15 [11; 17] points. Time between the manifestation of neurological symptoms and admission to the hospital was 138 [117; 170] min, and time between admission and initiation of STLT (the door-to-needle time), was 40 [30; 55] min. An unfavourable functional outcome of systemic thrombolytic therapy can be predicted according to the results of ROC analysis: the NIHSS score upon admission 12 or higher (sensitivity, 94%; specificity, 57%); neutrophil count, >7.8 × 10⁹/L (sensitivity, 45.5%; specificity, 90.6%); lymphocyte count < 1.8 × 10⁹/L (sensitivity, 81.8%; specificity, 59.4%). Conclusions: Personalized approach to systemic thrombolytic therapy may help to predict its effectiveness and contribute the development of more reliable strategies of patient management. Patients with potentially unfavorable outcome after intravenous thrombolysis can be the target group for mechanical reperfusion techniques such as thrombus extraction.

Impact of Hyperglycemia According to the Collateral Status on Outcomes in Mechanical Thrombectomy

Article

Full-text available

Sep 2018

Background and Purpose— Understanding the influence of hyperglycemia on outcomes in terms of the pretreatment collateral status might contribute to the achievement of case-specific glucose management in acute ischemic stroke. We sought to investigate whether the glucose level can influence the pretreatment collateral status and functional outcomes of endovascular thrombectomy in acute ischemic stroke and whether the impact of hyperglycemia on outcomes can be modified by the pretreatment collateral status. Methods— We analyzed the Triple-S database, which includes individual patient data pooled from 3 prospective Solitaire stent retriever studies (SWIFT [Solitaire With the Intention for Thrombectomy], SWIFT PRIME [SWIFT as Primary Endovascular Treatment], and STAR [Solitaire Flow Restoration Thrombectomy for Acute Revascularization]). Patients were eligible if they had acute ischemic stroke with moderate to severe neurological deficits, harbored angiographically confirmed large vessel occlusion, and were treatable by endovascular thrombectomy within 8 hours of onset. Pretreatment catheter angiograms were scored for collateral grades by a core imaging laboratory. The main outcome was 3-month good outcome (modified Rankin Scale score of 0–2). Results— Angiographic data on collaterals were available in 309 patients (age, 67±12 years; glucose, 131±55 mg/dL). Overall, the glucose level at presentation was not associated with pretreatment collateral status but was significantly lower in patients with a good outcome at 90 days (124 versus 140 mg/dL). Collateral grades modified the effect of glucose on good outcomes at 90 days ( P int =0.03). Among patients with poor collaterals (collateral grades, 0–2), higher glucose levels did not alter the outcome, whereas among patients with good collaterals (3–4), higher glucose levels reduced the likelihood of a good outcome at 90 days (per 10 mg/dL increase: odds ratio, 0.81; 95% CI, 0.69–0.95). Conclusions— Our study revealed that higher glucose levels reduce the likelihood of a good outcome among patients with good collaterals, but their effects on the outcome are less significant for patients with poor collaterals. The results suggest that good collaterals at presentation may be targets for more intensive glucose control and future studies relating to glucose management.

Hemoglobin A1c Predicts Hemorrhagic Transformation and Poor Outcomes after Acute Anterior Stroke

Article

Jun 2018

Background and purpose Hemorrhagic transformation (HT) is a major complication of acute ischemic stroke that is potentially related to clinical deterioration. The objective of this study was to assess whether chronic hyperglycemia is a predictive factor of HT in patients with acute anterior stroke. Methods Patients with acute anterior stroke were included in this study. Hemoglobin A1c (HbA1c) was measured the morning after hospitalization. HT was detected by CT scans or gradient echo MRI performed 4 days (±2) after onset. Uni‐ and multivariate logistic regression analyses were used to assess the risks for HT and short‐term outcomes. Results Among the 426 patients included, 93 (21.8%) had HT: 61 (14.3%) presented with hemorrhagic infarction (HI), and 32 (7.5%) presented with parenchymal hematoma (PH). Fifty‐four patients received thrombolytic treatment, and 18 (33.3%) were found to have HT. In the multivariate analysis, HbA1c (OR 1.294, 95% CI 1.097‐1.528), infarction size (OR 3.358, 95% CI 1.748‐6.449) and thrombolytic therapy (OR 3.469, 95% CI 1.757‐6.847) were predictors of HT. When patients were stratified according to the levels of fasting blood glucose, the predictive effect of HbA1c on HT was still observed in both groups. In the multilogistic regression analysis, HbA1c was found to be a predictor of poor outcomes (OR 1.482, 95% CI 1.228‐1.788). Conclusions Higher HbA1c was independently related to HT and poor neurological outcomes in patients with ischemic stroke. These findings have significant implications for the treatment of diabetes and glucose management in patients with diabetes mellitus (DM) and/or acute ischemic stroke. This article is protected by copyright. All rights reserved.

Cerebral Vascular Injury in Diabetic Ischemia and Reperfusion

Chapter

Jun 2018

About 30% of stroke patients are diabetic and more than 90% of them comprise type 2 diabetes (T2D). Diabetic stroke patients have higher mortality and worse neurological outcomes. Emerging clinical and experimental data suggest that blood-brain barrier (BBB) disruption, neuroinflammation, and stroke recovery impairment are exacerbated in diabetic patients. Hence, finding therapeutic approaches that can target these specific diabetic mechanisms in stroke is the thrust of the present translational study. Here, we summarize the ischemia-reperfusion injury in stroke, presenting the clinical evidence for involvement of hyperglycemia in severe damage of cerebral ischemia-reperfusion. We go on to consider the mechanisms that underlie such pathology, and highlight areas for future basic research and clinical studies into diabetic ischemia and reperfusion.

Increasing age, diabetes mellitus and recovery from stroke

Article

Full-text available

Nov 1989

In a prospective study of 200 patients with acute stroke, blood glucose and glycated haemoglobin (HbA1) were measured within 72 hours of onset. Unrecognized hyperglycaemia as defined by a raised stable HbA1 more than two s.d. above the mean reference value and no previous history of diabetes was present in 27%. No correlation existed between patient age and admission blood glucose or HbA1 levels (r = 0.1). Cumulative mortality and recovery of limb function was assessed in the first 136 patients with carotid distribution events. Admission blood glucose greater than or equal to 8 mmol/l was shown to be associated with a significantly greater mortality at 4 and 12 weeks (P less than 0.05). Multivariate analysis with age, glucose, HbA1 as independent variables demonstrated that age was the only significant predictor for death at 4 weeks (P less than 0.05) but at 12 weeks both age and blood glucose were significant (P less than 0.05). In patients less than 65 years blood glucose was a significant predictor for death (P less than 0.05) but in patients less than or equal to 65 years HbA1 and not glucose was significantly (P less than 0.05). Patients greater than or equal to 65 years with HbA1 greater than or equal to 7.5% were significantly more likely to have a raised admission blood glucose. Hyperglycaemia on admission was not shown to influence recovery of limb function. Increasing age is of greatest importance in predicting mortality although blood glucose is of prognostic value especially in the young stroke patient.

The effect of postischemic blood glucose levels on ischemic brain damage in the rat

Article

Full-text available

Nov 1988

The effect of insulin-induced hypoglycemia following 10.5 minutes of forebrain ischemia was studied in the rat. All groups received preischemic glucose loading (2 gm/kg) to promote brain infarction. Following completion of ischemia, rats received either 2 to 3 IU/kg (low-dose group) or 8 to 20 IU/kg (high-dose group) insulin. During the survival period, blood glucose concentrations were maintained in the ranges of 1.2 to 2.9 mM and 2.9 to 4.9 mM, respectively, for the low-dose and high-dose insulin groups. Control rats were given 2 gm/kg glucose immediately following ischemia. During the recovery period, until perfusion at 7 days, they were given glucose, 2 gm/kg, twice daily by intraperitoneal injection, and their drinking water was supplemented with 25% glucose. Mortality (p less than 0.05) and postischemic seizure incidence (p less than 0.01) were significantly reduced in the low-dose insulin group compared to the control group. Mortality was increased in the high-dose insulin group compared to the control group and was associated with an increased incidence of postischemic seizures. Neuropathological examination revealed no cortical infarction in the low-dose or high-dose insulin-treated rats compared to a 60% incidence of cortical infarction in the control group. In addition, the high-dose insulin-treated group showed a significant reduction in striatal and hippocampal CA1 selective neuronal necrosis compared to control rats with comparable survivals (p less than 0.05). The findings suggest that postischemic blood glucose concentrations play an important role in modulating both ischemic infarction and selective neuronal necrosis.

Hydrogen Ions Kill Brain at Concentrations Reached in Ischemia

Article

Full-text available

Sep 1987

Elevation of brain glucose before the onset of nearly complete ischemia leads to increased lactic acid within brain. When excessive, such acidosis may be a necessary factor for converting selective neuronal loss to brain infarction from nearly complete ischemia. To examine the potential neurotoxicity of excessive lactic acid concentrations, we microinjected (0.5 microliter/min) 150 mM sodium lactate solutions (adjusted to 6.50-4.00 pH) for 20 min into parietal cortex of anesthetized rats. Interstitial pH (pH0) was monitored with hydrogen ion-selective microelectrodes. Animals were allowed to recover for 24 h before injection zones were examined with the light microscope. Injectants produced brain necrosis in a histological pattern resembling ischemic infarction only when pH0 was less than or equal to 5.30. Nonlethal injections showed only needle tract injuries. Abrupt deterioration of brain acid-base homeostatic mechanisms correlated with necrosis since pH0 returned to baseline more slowly after lethal tissue injections than after nonlethal ones. The slowed return of pH0 to baseline after the severely acidic injections may reflect altered function of plasma membrane antiport systems for pH regulation and loss of brain hydrogen ion buffers.

Influence of Acidosis on Lipid Peroxidation in Brain Tissues In Vitro

Article

Full-text available

Jul 1985

To study the influence of acidosis on free radical formation and lipid peroxidation in brain tissues, homogenates fortified with ferrous ions and, in some experiments, with ascorbic acid were equilibrated with 5-15% O2 at pH values of 7.0, 6.5, 6.0, and 5.0, with subsequent measurements of thiobarbituric acid-reactive (TBAR) material, as well as of water- and lipid-soluble antioxidants (glutathione, ascorbate, and alpha-tocopherol) and phospholipid-bound fatty acids (FAs). Moderate to marked acidosis (pH 6.5-6.0) was found to grossly exaggerate the formation of TBAR material and the decrease in alpha-tocopherol content and to enhance degradation of phospholipid-bound, polyenoic FAs. These effects were reversed at pH 5.0, suggesting a pH optimum at pH 6.0-6.5. It is concluded that acidosis of a degree encountered in ischemic brain tissues has the potential of triggering increased free radical formation. This effect may involve increased formation of the protonated form of superoxide radicals, which is strongly prooxidant and lipid soluble, and/or the decompartmentalization of iron bound to cellular macromolecules like ferritin.

Brain Lactic Acidosis and Ischemic Cell Damage: 2. Histopathology

Article

Full-text available

Feb 1981

The influence of severe tissue lactic acidosis during incomplete brain ischemia (30 min) on cortex morphology was studied in fasted rats. Production of lactate in the ischemic tissue was varied by preischemic infusions (i.v.) of either a saline or a glucose solution. The brains were fixed by perfusion with glutaraldehyde at 0, 5, or 90 min of recirculation. In saline-infused animals (tissue lactate about 15 mumol g-1), changes observed at 0 and 5 min of recirculation were strikingly discrete: slight condensation of nuclear chromatin, mild to moderate mitochondrial swelling, and only slight astrocyte edema. These changes had virtually disappeared after 90 min recirculation and, at this time, only discrete ribosomal changes were observed. In contrast, glucose-infused rats (tissue lactate about 35 mumol g-1) showed severe changes: marked clumping of nuclear chromatin and cell sap in all cells was already evident at 0 and 5 min recirculation, while mitochondrial swelling was mild to moderate. Although tissue fixation was inadequate at 90 min, the ultrastructural appearance indicated extensive damage. It is concluded that excessive tissue lactic acidosis during brain ischemia exaggerates structural alterations and leads to irreversible cellular damage. A tentative explanation is offered for the paucity (less than 0.2%) of condensed neurons with grossly swollen mitochondria, previously considered a hallmark of ischemic cell injury.

Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator for Acute Hemispheric Stroke: The European Cooperative Acute Stroke Study (ECASS)

Article

Full-text available

Oct 1995

To evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke. Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial. A total of 75 hospitals in 14 European countries. A total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT). Patients were randomized to treatment with 1.1 mg per kilogram of body weight of rt-PA (alteplase) or placebo within 6 hours from the onset of symptoms. Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. Secondary end points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30-day mortality. Tertiary end points included early neurologic recovery (SSS) and duration of in-hospital stay. Safety parameters included mortality and incidence of intracranial or extracranial hemorrhage. The distribution of demographic variables was similar among patients in the rt-PA and placebo treatment arms in both the intention-to-treat (ITT) analysis and the explanatory analysis for the target population (TP). A total of 109 patients (17.4%) were included in the trial despite major protocol violations but excluded from the TP. There was no difference in the primary end points in the ITT analysis, while the TP analysis revealed a significant difference in the RS in favor of rt-PA-treated patients (P = .035). Of the secondary end points, the combined BI and RS showed a difference in favor of rt-PA-treated patients in both analyses (P < .001). Neurologic recovery at 90 days was significantly better for rt-PA-treated patients in the TP (P = .03). The speed of neurologic recovery assessed by the SSS was significantly better up to 7 days in the ITT analysis and up to 30 days for the TP in the rt-PA treatment arm. In-hospital stay was significantly shorter in the rt-PA treatment arm in both analyses. There were no statistically significant differences in the mortality rate at 30 days or in the overall incidence of intracerebral hemorrhages among the rt-PA and placebo treatment arms in either analysis. However, the occurrence of large parenchymal hemorrhages was significantly more frequent in the rt-PA-treated patients. Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction. Therefore, since treating ineligible patients is associated with an unacceptable increase of hemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients.

Insulin Reduction of Cerebral Infarction Due to Transient Focal Ischemia

Article

Full-text available

Mar 1995
J NEUROSURG

Insulin has recently been shown to ameliorate damage in models of global brain ischemia. To determine whether insulin is also neuroprotective in focal ischemia, 20 rats were given 2 to 3 IU/kg insulin and 10 did not receive treatment prior to normothermic transient middle cerebral artery occlusion for 2 hours at a blood pressure of 60 mm Hg. To further elucidate whether infarction volume is influenced by variations in blood glucose levels within the physiological range, blood glucose was raised in 10 of the insulin-treated animals to levels comparable with the untreated controls. At 1-week survival, damage was assessed using quantitative neuropathological examination of 25 coronal planes. It was found that preischemic insulin lowered the mean intraischemic blood glucose level from 8.4 +/- 0.2 mM (mu +/- standard error of the mean) in the control group to 3.4 +/- 0.2 mM and reduced total damage (atrophy plus cortical and striatal necrosis), expressed as the percentage of the normal hemisphere, from a control of 28.5% +/- 2.9% to 14.5% +/- 1.6% (p < 0.005). Coadministration of glucose and insulin resulted in a mean intraischemic blood glucose level of 10.1 +/- 0.5 mM, with 27.0% +/- 2.4% total damage (p = 0.96, compared with control). Total ischemic damage showed an independent correlation with blood glucose levels (r = 0.67, p = 0.0018). The findings indicate that insulin benefits transient focal ischemia and that reducing the blood glucose from 8 to 9 mM to the low-normal range of 3 to 4 mM with insulin dramatically reduces subsequent infarction. The data suggest that the neuroprotective mechanism of insulin action in focal middle cerebral artery occlusion is mediated predominantly via alterations in blood glucose levels. In comparison to global ischemia, focal ischemia appears to show only a minor direct central nervous system effect of insulin. In clinical situations in which transient focal ischemia to the hemisphere can be anticipated, insulin-induced hypoglycemia of a mild degree may be beneficial.

More money is needed to care for patients with cancer

Article

Full-text available

Oct 1997

Editor—The redistribution of NHS funding to primary care is causing severe problems in cancer units and centres. Members of clinical directorates and regional cancer centres are seeing rapidly increasing numbers of patients, often while coping with reduced budgets. The main target for budget reductions is often the money spent on cytotoxic chemotherapy. Potent but expensive new cytotoxic agents, which are generally agreed to be effective, are available. As a result of recent contract negotiations their use has in effect not been …

Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke t-PA Stroke Study Group

Article

Apr 1996
J NEUROSURG ANESTH

Hyperglycemia decreases acute neuronal ischemic changes after middle cerebral artery occlusion in cats

Article

Apr 1989

Hyperglycemia has been reported to worsen the tolerance of the brain to ischemia, and it has therefore been recommended that patients undergoing neurosurgical procedures not receive glucose-containing solutions. However, whereas most animal studies have used global ischemia models, most neurosurgical procedures are associated with risks of focal rather than global ischemia. We therefore studied the effects of glucose administration in an animal model of focal cerebral ischemia. We anesthetized 20 cats with halothane (0.85% end tidal in oxygen), and a focal cerebral ischemic lesion was produced by clip ligation of the left middle cerebral artery using a transorbital approach. Hyperglycemia (10 cats, mean +/- SEM plasma glucose concentration 561 +/- 36 mg/dl) was established before ligation by infusion of 50% glucose in 0.45% saline; the control group (10 cats, mean +/- SEM plasma glucose concentration 209 +/- 28 mg/dl) received 0.45% saline only. Total fluid administered, mean arterial blood pressure, body temperature, and arterial blood gas values did not differ between the two groups 0, 2, and 6 hours after ligation. The cats were killed 6 hours after ligation, and the area of severe ischemic neuronal damage was determined by microscopic examination of a coronal section at the level of the optic chiasm. The mean +/- SEM area of left cortical severe ischemic neuronal damage was 12 +/- 2% of the left cortex in the hyperglycemic group compared with 28 +/- 5% in the control group (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

NINDS rt-PA Stroke Study Group.Tissue plasminogen activator for acute ischemic stroke. New Engl J Med 333: 1581−1587

Article

Dec 1995
NEW ENGL J MED

Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke. METHODS: The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS: RESULTS: In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed (global odds ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P = 0.30). CONCLUSIONS: Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.

Intravenous Thrombolysis With Recombinant Tissue Plasminogen Activator for Acute Hemispheric Stroke

Article

Oct 1995

Werner Hacke

Objective. —To evaluate the efficacy and safety of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke.Design. —Randomized, prospective, multicenter, double-blind, placebo-controlled clinical trial.Setting. —A total of 75 hospitals in 14 European countries.Patients. —A total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT).Intervention. —Patients were randomized to treatment with 1.1 mg per kilogram of body weight of rt-PA (alteplase) or placebo within 6 hours from the onset of symptoms.Outcome Measures. —Primary end points included Barthel Index (BI) and modified Rankin Scale (RS) at 90 days. Secondary end points included combined BI and RS, Scandinavian Stroke Scale (SSS) at 90 days, and 30-day mortality. Tertiary end points included early neurologic recovery (SSS) and duration of in-hospital stay. Safety parameters included mortality and incidence of intracranial or extracranial hemorrhage.Results. —The distribution of demographic variables was similar among patients in the rt-PA and placebo treatment arms in both the intention-to-treat (ITT) analysis and the explanatory analysis for the target population (TP). A total of 109 patients (17.4%) were included in the trial despite major protocol violations but excluded from the TP. There was no difference in the primary end points in the ITT analysis, while the TP analysis revealed a significant difference in the RS in favor of rt-PA—treated patients (P<.035). Of the secondary end points, the combined BI and RS showed a difference in favor of rt-PA—treated patients in both analyses (P<.001). Neurologic recovery at 90 days was significantly better for rt-PA—treated patients in the TP (P=.03). The speed of neurologic recovery assessed by the SSS was significantly better up to 7 days in the ITT analysis and up to 30 days for the TP in the rt-PA treatment arm. In-hospital stay was significantly shorter in the rt-PA treatment arm in both analyses. There were no statistically significant differences in the mortality rate at 30 days or in the overall incidence of intracerebral hemorrhages among the rt-PA and placebo treatment arms in either analysis. However, the occurrence of large parenchymal hemorrhages was significantly more frequent in the rt-PA—treated patients.Conclusions. —Intravenous thrombolysis in acute ischemic stroke is effective in improving some functional measures and neurologic outcome in a defined subgroup of stroke patients with moderate to severe neurologic deficit and without extended infarct signs on the initial CT scan. However, the identification of this subgroup is difficult and depends on recognition of early major CT signs of early infarction. Therefore, since treating ineligible patients is associated with an unacceptable increase of hemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients.(JAMA. 1995;274:1017-1025)

Hyperglycaemia after acute stroke

Article

Sep 1997

Editor—Christopher J Weir and colleagues conclude from their study of a cohort of 750 non-diabetic patients with stroke that hyperglycaemia (plasma glucose concentration >8 mmol/l) during the acute phase has an adverse influence on outcome and that this is independent of severity of stroke.1 Stroke severity was assessed in a limited way using only the Oxfordshire community stroke project classification and time to resolution of symptoms (≤72 hours or >72 hours), both of which are relatively inaccurate measures. When two variables are closely correlated—for example, stroke severity and glucose concentration—the one that is most accurately measured (glucose concentration) will always emerge as the strongest explanatory variable in multiple regression even if it is, in fact, less important.2 We have produced a series of validated models to predict the probability of survival and disability using the 530 patients from the Oxfordshire community stroke project who were seen within 30 days of their stroke.3 A history of diabetes mellitus and the presence of acute hyperglycaemia (glucose concentration >12 mmol/l) were two of about 20 variables that were entered into these models, in addition to several measures related to stroke severity (eye, motor, and verbal components of the Glasgow coma score; arm power; and ability to walk). Although diabetes mellitus was an adverse and independent predictor of death (relative hazard 2.01; 95% confidence interval 1.36 to 2.99), hyperglycaemia was not (1.66; 0.93 to 2.97). Neither of these variables was an independent predictor of death or disability (modified Rankin score >2) at six months. We repeated our analyses using only the 249 patients seen within 72 hours of onset with no known history of diabetes; we redefined hyperglycaemia as glucose concentration >8mmol/l to allow direct comparison with the results of Weir and colleagues. Once more, hyperglycaemia was not an independent predictor of either death (relative hazard 1.02; 0.62 to 1.66) or death or disability (odds ratio 1.61; 0.38 to 6.75). We would therefore disagree that hyperglycaemia is an independent prognostic factor in acute stroke. We would, however, agree that a large randomised trial of glucose control in the acute phase of stroke is necessary to clarify the clinical management of these patients. Many guidelines recommend that hyperglycaemia should be treated aggressively with insulin infusions4; we are not aware of a single completed randomised trial addressing this issue, and so it remains unclear whether the risks of such an approach—for example, hypoglycaemia—outweigh any possible benefits. References1.↵Weir CJ, Murray GD, Dyker AG, Lees KR.Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long term follow up study.BMJ 1997;314: 1303-6. (3 May.)

Stroke After Thrombolysis : Mortality and Functional Outcomes in the GUSTO-I Trial

Article

Nov 1995

Background Stroke is the most feared complication of thrombolysis for acute myocardial infarction because of the resulting mortality and disability. We analyzed the incidence, timing, and outcomes of stroke in an international trial. Methods and Results Patients were randomly assigned to one of four thrombolytic strategies. Neurological events were confirmed clinically and anatomically and were adjudicated by a blinded committee. Stroke survivors, categorized by residual deficit and disability, assessed their quality of life with a time trade-off technique. Multivariable regression identified patient characteristics associated with intracranial hemorrhage. Overall, 1.4% of the patients had a stroke (93% anatomic documentation). The risk ranged from 1.19% with streptokinase/subcutaneous heparin therapy to 1.64% with combination thrombolytic therapy ( P =.007). Primary intracranial hemorrhage rates ranged from 0.46% with streptokinase/subcutaneous heparin to 0.88% with combination therapy ( P <.001). Of all strokes, 41% were fatal, 31% were disabling, and 24% were nondisabling, with no significant treatment-related differences. Stroke subtype affected prognosis: 60% of patients with primary intracranial hemorrhage died and 25% were disabled versus 17% dead and 40% disabled with nonhemorrhagic infarctions. Patients with moderate or severe residual deficits showed significantly decreased quality of life. Advanced age, lower weight, prior cerebrovascular disease or hypertension, systolic and diastolic blood pressures, randomization to tissue plasminogen activator, and an interaction between age and hypertension were significant predictors of intracranial hemorrhage. Conclusions Stroke remains a rare but catastrophic complication of thrombolysis. Additional studies should assess the net clinical benefit of thrombolysis in high-risk subgroups, particularly the elderly and patients with prior cerebrovascular events.

Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke

Article

Jul 1992
ANN NEUROL

An open angiography-based, dose rate escalation study on the effect of intravenous infusion of recombinant tissue plasminogen activator(rt-PA) on cerebral arterial recanalization in patients with acute focal cerebral ischemia was performed at 16 centers. Arterial occlusions consistent with acute ischemia in the carotid or vertebrobasilar territory in the absence of detectable intracerebal hemorrhage were prerequisites for treatment. After the 60-minute rt-PA infusion, arterial perfusion was assesed by repeat angiography and computed tomography scans were performed at 24 hours to assess hemorrhagic transformation, Of 139 patients with symptoms of focal ischemia, 80.6% (112) had complete occlusion of the primary vessel at a mean of 5.4 ± 1.7 hours after symptom onset. No dose rate response of cerebral arterial recanalization was observed in 93 patients who completed the rt-PA infusion. Middle cerebral artery division (M2) and branch (M3) occlusions were more likely to undergo recanalization by 60 minutes than were internal carotid artery occlusions. Hemorrhagic infarction occured in 20.2% and parenchymatous hematoma in 10.6% of patients over all dose rates, while neurological worsening accompanied hemorrhagic transformation (hemorrhagic infarction and parenchymatous hematoma) in 9.6% of patients. All findings were within prospective safety guidelines. No dose rate correlation with hemorrhagic infarction, parenchymatous hematoma, or both was seen. Hemorrhagic transformation occured significantly more frequently in patients receiving treatment at least 6 hours after symptom onset. No relationship between hemorrhagic transformation and recanalization was observed. This study indicates that site of occlusion, time to recanalization, and time to treatment are important variables in acute stroke intervention with this agent.

Wagner RW, Kleinholz M, de Courten-Myers GM & Myers RE.Hyperglycemic versus normoglycemic stroke: topography of brain metabolites, intracellular pH, and infarct size. J Cereb Blood Flow Metab 12: 213−222

Article

Apr 1992

Hyperglycemia aggravates brain pathologic outcome following middle cerebral artery (MCA) occlusion in cats. We presently determined if hyperglycemia during occlusion leads to high lactic acid accumulations in the ischemic MCA territory. We measured brain metabolite concentrations in 14 MCA territory sites at 0.5 and 4 h following occlusion in hyper- (20 mM) and normoglycemic (5 mM) cats and correlated these results with previous brain pathologic findings. Hyper- versus normoglycemia during MCA occlusion resulted in significantly higher lactate concentrations in the ischemic territory and more numerous loci with lactates greater than 17 mumol/g. At 0.5 h of occlusion, ATP levels were lower in normoglycemic cats, while at 4 h, ATP was similarly reduced (40%) in both glycemia groups. At 4 h, PCr was more reduced in hyperglycemics secondary to a greater brain tissue acidosis. Carbohydrate substrates at 0.5 h were more markedly depleted in normoglycemics, likely limiting lactate accumulation (34.3% versus only 5.0% of sites in hyperglycemics with glucose less than 0.5 mumol/g). Although lactate was markedly elevated at both 0.5 and 4 h in hyperglycemic ischemic territories, clip release at 4 versus 0.5 h yields a significantly poorer brain pathologic outcome. Correspondingly, intracellular pH, calculated from the creatine kinase equilibrium, was more markedly depressed at 4 than at 0.5 h of occlusion, demonstrating a time-dependent dissociation between tissue lactate and hydrogen ion accumulations. The present findings show that following MCA occlusion (a) hyperglycemia increases the magnitude and topographic extent of marked tissue lactic acidosis, (b) infarct size following 0.5 h of clip release correlates more closely with tissue acidosis than with lactate concentrations, (c) ischemic tissue ATP concentrations correlate poorly with infarct size, (d) normoglycemia limits lactate accumulation during focal ischemia because tissue glucose is depleted, and (e) early during ischemia, tissue buffering or antiport mechanisms may prevent marked increases in intracellular hydrogen ion activity.

Hemorrhagic infarct conversion in experimental stroke

Article

Mar 1992
ANN EMERG MED

This study investigated the relations between hemorrhagic infarction and occlusion, release, levels of glycemia, brain energy state, and lactate content after cerebrovascular occlusion. Prospective, controlled laboratory investigation. One hundred six pentobarbital-anesthetized cats. The middle cerebral artery was occluded with a Yasargil clip transorbitally either temporarily (0.5, four, and eight hours) or permanently. Normoglycemic and hyperglycemic animals were closely monitored for eight hours. Brain pathology was assessed after two weeks' survival or at the time of spontaneous animal death. Topographic brain metabolite studies were carried out after four hours of middle cerebral artery occlusion. Morphometric quantitation of cerebral hemorrhage and infarction and fluorometric determinations of blood and brain tissue, glucose, glycogen, lactate, adenosine triphosphate, and phosphocreatine from 16 topographic brain sites were carried out. Twenty-one of 82 (25.6%) animals evaluated neuropathologically showed hemorrhagic infarcts. Occluding the artery in hyperglycemic animals caused fivefold more frequent and 25-fold more extensive hemorrhage into infarcts than in normoglycemic animals. Temporary occlusion with clip release after four hours in hyperglycemic animals caused the most extensive hemorrhage into infarcts. Most hemorrhages into infarcts (81%) took place in animals that died within a few hours after they experienced ischemia and that showed infarction and marked edema of the entire middle cerebral artery territory. Linear regression analyses demonstrated a close relation between hemorrhage into infarcts and near-total energy depletion (adenosine triphosphate, less than 0.3 microM/g; phosphocreatine, less than 0.5 microM/g) in brain sites that showed extremely high tissue lactate concentrations (more than 30 microM/g). The biochemical changes that correlated with hemorrhage into infarcts were more marked than those with infarcts without hemorrhage. Hyperglycemia and restoration of blood flow to ischemic territories were strong risk factors for hemorrhagic infarct conversion. Concomitant tissue metabolic changes suggest that marked tissue energy depletion accompanied by acidosis damages brain vessels and renders them penetrable for edema fluid and, ultimately, red blood cell extravasation.

Hyperglycemia at ischemic stroke onset as prognostic factor

Article

Jul 1991

To find out whether the high blood glucose values sometimes found in the first stage of ischemic stroke have any prognostic value, we considered 76 patients hospitalized within 24 h of an acute cerebral infarction, documented by CT brain scan and/or necropsy, whose fasting blood glucose was recorded before any treatment was given. The patients were sorted into 3 groups: diabetics, normoglycemic non-diabetics and hyperglycemic nondiabetics. On the CT findings cases with large cortical and/or subcortical infarcts were analyzed separately from those with lacunar infarcts. The clinical symptoms on admission proved to be more severe (p less than 0.02) and 30-day mortality higher (p less than 0.02) among the hyperglycemic non-diabetics, who also showed a highly significant (p less than 0.00001) preponderance of large cortical and subcortical infarcts over lacunar infarcts. Multivariate analysis, which took account of variables of known relevance to the prognosis of cerebral infarction (age, sex, arterial hypertension, severity of the clinical pattern, type of brain lesion), confirmed the statistically discriminant power, in terms of mortality, of belonging to the hyperglycemic nondiabetic group. The results of the study confirm that hyperglycemia at stroke onset in nondiabetic patients is an adverse prognostic factor and suggest that it may be a reaction to stress, depending on the size of the infarcted area.

Effect of plasma glucose on infarct size in focal cerebral ischemia-reperfusion

Article

Jul 1991

Although hyperglycemia has been shown to consistently exacerbate ischemia brain injury following global or diffuse cerebral ischemia, the effect of hyperglycemia in unilateral focal cerebral ischemia remains controversial. Recent advances in thrombolytic therapy have enhanced the clinical significance of postischemic reperfusion. We studied the effect of plasma glucose on ischemic brain injury in a newly developed focal cerebral ischemia-reperfusion model. Rats allowed free access to food until ischemic insult developed intra- and postischemic hyperglycemia and cortical infarction. Rats fasted for 24 hours had blunted hyperglycemic responses. Infarct volumes were correspondingly smaller. The protective effect of fasting was partially abolished by glucose loading during ischemia to induce intra-ischemic hyperglycemia. Glucose loading immediately or 3 hours after focal cerebral ischemia did not significantly alter the protective effect of fasting. Insulin treatment in fed rats before ischemia also reduced hyperglycemic responses and infarct volume. Timing of insulin treatment was also critical in the reduction of ischemic injury. These findings indicate that plasma glucose during the period of ischemia is an important determinant of brain injury in focal cerebral ischemia-reperfusion and there is a therapeutic window for normalization of plasma glucose to be efficacious.

Acid-base change during complete brain ischemia

Article

Dec 1990

We examined the proposal that preischemic hyperglycemia causes exaggerated brain damage by decreasing intracellular or extracellular pH to below a specified threshold value. We also provide a critical appraisal of two related hypotheses. The first is that hyperglycemia enhances brain damage by causing excessive intraglial acidosis; the second, that the critical degree of acidosis is reached not during the ischemia but when recirculation is instituted. The following conclusions are drawn. First, the evidence is inconclusive in favor of marked compartmentation of H+ during ischemia, based on a discontinuous delta lactate/delta PCO2 relation and on direct intracellular pH measurements. In fact, results obtained with identical techniques in normoglycemic animals suggest that the acid compartment assumed to be glia is very small and may be of another origin. Second, although recirculation may give rise to a further increase in either extracellular or intracellular acidosis under certain conditions, this acidosis is not a prerequisite for increased tissue damage or infarction. Third, a critical appraisal of reports supports the contention that enhanced damage is triggered below a specified threshold pH value. In complete or near-complete ischemia, this value corresponds to a tissue lactate content of 17-20 mM.kg-1 wet wt. No correlation exists between subthreshold values for delta lactate and the severity of tissue damage. Furthermore, hyperglycemia cannot be expected to enhance damage if conditions prevent lactate from reaching threshold values or if they uncouple changes in lactate and pH.

Effect of hyperglycemia on neuronal changes in a rabbit model of focal cerebral ischemia

Article

Apr 1990

In clinical medicine, cerebral ischemia is frequently due to a focal, rather than global, insult. The effect of hyperglycemia in focal cerebral ischemia is not well defined. We studied the effect of hyperglycemia on neuropathologic changes in a rabbit model of focal cerebral ischemia. Rabbits were randomized to receive saline (n = 12) or glucose (n = 12) infusions. The left anterior cerebral and left internal carotid arteries were clipped after the infusion began. After 6 hours of occlusion, the area of severe ischemic neuronal damage in the left neocortex and striatum on two standard sections of brain was calculated and expressed as a percentage of the total area of the left cortex or striatum. The mean +/- SEM cortical area of severe ischemic neuronal damage was 22.1 +/- 2.8% in the glucose-treated rabbits and 34.0 +/- 4.6% in the saline-treated rabbits (p less than 0.05). The cortical area of severe ischemic neuronal damage was inversely correlated with plasma glucose concentration at the time of arterial clipping (p less than 0.05). We conclude that hyperglycemia is associated with decreased histologic neuronal injury in this model of focal cerebral ischemia and may be protective when cerebral ischemia occurs from a focal insult.

Fatal strokes in hyperglycemic cats

Article

Jan 1990

Hyperglycemia is associated with three- to fourfold larger infarcts than normoglycemia following permanent middle cerebral artery occlusion in cats. We investigated the effects of glycemia on brain outcome when middle cerebral artery blood flow was restored (clip release) after 4 hours of occlusion. Seven of 13 hyperglycemic (22 mM) and one of 12 normoglycemic (6 mM) anesthetized cats developed total middle cerebral artery territory infarcts and hemispheric edema and died of brainstem compression. The remaining six and 11 cats recovered fully and later showed no or only small infarcts. Compared with permanent occlusion, restoration of blood flow after 4 hours reduced infarct volume in all normoglycemic and hyperglycemic cats that survived, but caused a much higher proportion (54% vs. 17%) of hyperglycemic and, for the first time, one normoglycemic cat, to die of infarct extension, hemorrhagic infarct conversion, and total territory edema. Thus, clip release after 4 hours caused some cats to show reduced and others to show augmented tissue damage. Rendering cats hyperglycemic substantially worsened their outcome after reperfusion by increasing their death rate from total territory edema sevenfold. Our results demonstrate that risk/benefit analyses for recanalization efforts in humans should take serum glucose concentrations into account.

Zasslow MA, Pearl RG, Shuer LM, Steinberg GK, Lieberson RE & Larson CP.Hyperglycemia decreases acute neuronal ischemic changes after middle cerebral artery occlusion in cats. Stroke 20: 519−523

Article

May 1989

Hyperglycemia reduces the extent of cerebral infarction in rats

Article

May 1987

Although hyperglycemia is known to exacerbate neuronal injury in the setting of reversible brain ischemia, its effect on irreversible thrombotic infarction is less well understood. In this study, unilateral thrombotic infarction was induced photochemically in the parietal cortex of Wistar rats. Seven days later, brains were perfusion-fixed for light microscopy. Infarct areas were measured by computer-assisted planimetry on multiple coronal sections at 250-micron intervals; these data were integrated to yield infarct volumes. Fasted, normoglycemic rats were compared with hyperglycemic rats that had received 1.2-1.5 ml of 50% dextrose i.p. 15 minutes prior to the induction of infarction. Infarct volume averaged 12.5 +/- 4.0 mm3 (mean +/- SD) in rats (n = 14) with plasma glucose levels of 72-184 mg/dl; this differed statistically from the average volume of 9.3 +/- 3.3 mm3 observed in rats (n = 13) with elevated plasma glucose (range 264-607 mg/dl). Spearman rank correlation analysis confirmed a significant correlation of larger infarct volumes with lower plasma glucose levels. In contrast, rats receiving mannitol i.p. to produce an osmotic load comparable with that of the dextrose-pretreated animals showed larger infarct volumes than saline-treated controls. The small but definite beneficial effect of hyperglycemia in this end-arteriolar thrombotic infarction model is possibly attributable to improved local energy metabolism at the periphery of the lesion during the early period of lesion expansion.

Hyperglycemia enlarges infarct size in cerebrovascular occlusion in cats

Article

Jun 1988

We investigated the influence of serum glucose concentration on infarct size following middle cerebral artery occlusion in cats. These animals were deprived of food for 48 hours and infused with 1) saline for 1 hour before and 8 hours after occlusion (n = 8), 2) 10% glucose solution for 1 hour before and 6 hours after occlusion and saline for 2 additional hours (n = 8), or 3) 10% glucose for 1 hour before and saline for 8 hours after occlusion (n = 5). Nineteen cats killed after 2 weeks' survival were subjected to morphometric infarct size determinations. Eight normoglycemic and 11 hyperglycemic cats exhibited infarcts affecting 10.2 +/- 3.4% and 29.5 +/- 6.5% (mean +/- SEM) of their middle cerebral artery territories, respectively (p less than 0.02). Cats of the two hyperglycemic groups showed similarly sized infarcts. However, two of eight (25%) of cats with preocclusion and postocclusion hyperglycemia died 8 and 24 hours after occlusion with infarction of the entire middle cerebral artery territory, marked hemispheral edema, and brainstem compression. Our results demonstrate that serum glucose concentration at the time of large cerebral vessel occlusion influences stroke outcome.

Transient focal ischemia in hyperglycemic rats is associated with increased cerebral infarction

Article

May 1987
BRAIN RES

Maiken Nedergaard

To study whether transient ischemia is influenced by hyperglycemia, the middle cerebral artery was occluded for 5, 10 and 15 min in normo- and hyperglycemic rats. Five-minute ischemia induced minor lesions in both groups. After 10-min ischemia a significant greater infarct volume was found in hyperglycemia compared with normoglycemia (29 +/- 9 mm3 vs 4 +/- 4 mm3, P less than 0.001). Fifteen-minute artery occlusion induced even more damage in both hyper- and normoglycemia (63 +/- 20 mm3 vs 13 +/- 12 mm3, P less than 0.006). The lateral part of striatum was infarcted in all hyperglycemic animals exposed to 10 or 15 min of ischemia. In the same area selective neuronal injury occurred in 6 out of 9 normoglycemic animals. The findings show that hyperglycemia increases brain damage during transient ischemia by conversion of selective neuronal injury into cerebral infarction.

Focal ischemia of the rat brain, with special reference to the influence of plasma glucose concentration

Article

Feb 1987

Focal cerebral ischemia was induced by occlusion of the right middle cerebral artery in hypoglycemic, normoglycemic, as well as in acute and chronic diabetic rats. The brain damage was studied after 4 days. The volume of infarction was decreased in hypoglycemia (29 +/- 19 mm3 (mean +/- SD) versus 58 +/- 35 mm3, P less than 0.0046), unaltered in acute diabetes (61 +/- 45 mm3), and increased in chronic diabetes (91 +/- 22 mm3, P less than 0.0463). The cortex adjacent to the infarct showed selective neuronal injury affecting the cortical layers 2 and 3. The damage was enhanced by hypoglycemia and prevented in most of the diabetic animals. The findings indicate that different mechanisms cause infarction and selective neuronal injury outside infarcts, but that both are influenced by the plasma glucose concentration.

Infarct Rim: Effect of Hyperglycemia on Direct Current Potential and [14C]2-Deoxyglucose Phosphorylation

Article

Nov 1986

Focal ischemia was produced by occlusion of the right middle cerebral artery (MCA) in normo- and hyperglycemic rats. In the cortical infarct rim, regional [14C]2-deoxyglucose [( 14C]2-DG) phosphorylation was correlated to spontaneous transient changes in extracellular potassium recorded as direct current (DC) potential deflections. In normoglycemic rats the DC potential showed transient but recurrent deflections in the first hours following MCA occlusion. The 2-DG phosphorylation was elevated by 200% in the same area. In contrast, hyperglycemic rats had no, or a single, deflection of the DC potential in the rim, and the 2-DG phosphorylation remained normal. The same pattern was obtained by application of 3 M KCl to the exposed cortex. In normoglycemia potassium application resulted in recurrent deflections of the DC potential, and 2-DG phosphorylation increased in most parts of the hemisphere. Hyperglycemic animals had a nearly stable DC potential, and 2-DG phosphorylation increased only in the tissue area situated directly below the site of potassium application. The results indicate that metabolism in the cortical infarct rim is stimulated by spontaneous and recurrent changes in extracellular potassium--a phenomenon that may be related to spreading depression--and that the metabolism remained normal in the same area in hyperglycemic animals owing to an inhibition of transient increases of extracellular potassium.

Berger, L. & Hakim, A. M. The association of hyperglycemia with cerebral edema in stroke. Stroke 17, 865-871

Article

Sep 1986

A retrospective review of stroke patients admitted to our hospital revealed 39 patients diagnosed as suffering an acute completed ischemic stroke who also had had fasting (AC) serum glucose determinations and sequential computer tomography (CT) studies. The patients were divided into three groups on the basis of mean AC serum glucose: Group 1 (n = 12) mean serum AC glucose greater than 150 mg/dl; Group 2 (n = 13) mean serum AC glucose 100-150 mg/dl; and Group 3 (n = 14) mean serum AC glucose less than 100 mg/dl. CT scans performed on each patient were studied for the presence of midline shift and/or ventricular compression, which were interpreted as evidence of cerebral edema. The three groups were comparable with respect to mean age, average mean arterial blood pressure and initial infarct size. Our results show that in Group 1, 42% of the patients died within the first week following their CVA with clinical evidence of transtentorial herniation confirmed by CT or autopsy. In contrast, none of the Group 3 patients died and only one showed radiological evidence for cerebral edema. Group 2 patients showed intermediate mortality and evidence of cerebral edema. These trends were statistically significant at p less than 0.005. In addition, the combined hyperglycemic group (1 and 2) had a significantly higher rate of development of hypodensity on CT (p less than 0.05) than the normoglycemic group. Our findings suggest that patients with hyperglycemia in association with their CVA develop more pronounced cerebral edema and have a worse clinical outcome. Possible pathophysiological mechanisms that may underlie this observation are discussed.

Influence of In Vitro Lactic Acidosis and Hypercapnia on Respiratory Activity of Isolated Rat Brain Mitochondria

Article

Oct 1984

Respiratory activity and the ADP/O ratio of isolated rat brain mitochondria were measured following incubation with varying concentrations of lactic acid in reaction media buffered either with bicarbonate and CO2 or with phosphate alone, at a pH of 7.1. Increasing lactic acid levels caused a progressive decrease in substrate-, phosphate-, and ADP-stimulated (State 3) respiration and ADP/O ratios. Fifteen millimolar lactic acid, pH 6.4, caused approximately 50% inhibition of State 3 respiration (with malate + glutamate as substrate). At lower pH values (5.3-6.1), addition of ADP caused little or no increase in O2 consumption; i.e., ATP formation ceased. Addition of lactic acid at constant pH moderately affected respiratory control ratios but did not change State 3 respiration or ADP/O ratios. Thus, the effect of lactic acid was related to the pH change. Increasing CO2 concentrations in the reaction medium had similar effects on mitochondrial respiration, indicating that changes in extramitochondrial pH rather than in transmembrane H+ gradients determined the respiratory alterations. Following a 5-min incubation of mitochondria with lactic acid, pH 6.1, there was an incomplete recovery of State 3 respiration and respiratory control ratios. It is concluded that mitochondrial respiration is inhibited by a decrease in pH which, if excessive, may lead to a permanent suppression of ATP production. These results may, at least partly, explain the deleterious effects of enhanced lactic acidosis in brain ischemia.

Brain lactic acidosis and ischemic cell damage: Quantitative ultrastructural changes in capillaries of rat cerebral cortex

Article

Feb 1983

Excessive tissue lactic acidosis has earlier been shown to aggravate structural damage of both neurons and glial cells in the rat cerebral cortex. To study the reactions of cortical capillaries, light- and electronmicroscopic morphometry was used. Rats were subjected to severe incomplete ischemia (cerebral blood flow below 5% of normal) for 30 min by clamping their carotid arteries and by lowering the blood pressure. Lactate production during ischemia was modified by preischemic administration of either saline (low lactic acidosis group) or glucose (high lactic acidosis group). In the animals with low lactic acidosis, only minimal vascular changes were seen after both 5 min and 90 min recirculation. In the high lactic acidosis group, the endothelial cells were swollen after 5 min of recirculation, and the changes grew markedly worse during 90 min of recirculation. Nuclear chromatin coarsened and mitochondria swelled up. Morphometry showed that the lumen narrowed as a result of endothelial swelling. In spite of variable degree of perivascular astrocytic edema, the outer capillary diameter was little changed in the experimental groups. It seems likely that endothelial swelling hampers postischemic circulation in incomplete ischemia accompanied by high lactic acidosis.

Pulsinelli WA, Levy DE, Sigsbee B, Scherer P, Plum F.Increased damage after ischemic stroke in patients with hyperglycemia with or without diabetes mellitus. Am J Med 74: 540-544

Article

May 1983
AM J MED

Animal experiments employing controlled degrees of cerebral ischemia have demonstrated that elevated blood-brain glucose concentrations greatly enhance the extent and degree of subsequent brain damage. The question of whether or not a similar relationship applies in man was examined by retrospectively segregating patients admitted with the diagnosis of ischemic stroke into diabetic (n = 35) and nondiabetic (n = 72) groups. A separate nondiabetic population with ischemic stroke was prospectively analyzed by dividing patients into those with an admission blood glucose level above (n = 14) or below (n = 17) 120 mg/dl. The neurologic status at discharge was used to stratify outcome as good, fair, or poor in the retrospective study. The ability or inability to return to work was used to separate good and poor outcomes in the prospective study. Neurologic outcome in diabetic patients with stroke was significantly worse (p less than 0.05) than in nondiabetic patients, and the diabetic patients had a greater (p less than 0.05) number of stroke-related deaths. In the prospective study, neurologic outcome also was worse with high blood sugar levels, only 43 percent of the patients with blood glucose values above 120 mg/dl returned to work, whereas 76 percent of those with lower blood sugar values regained employment (p = 0.061).

Deferoxamine Reduces Early Metabolic Failure Associated With Severe Cerebral Ischemic Acidosis in Dogs

Article

May 1995

Postischemic metabolic injury may be mediated by acidosis and tissue bicarbonate depletion, with consequent-iron mobilization and oxygen radical formation during reperfusion. We have previously shown that reducing intracellular pH to below 5.7 and bicarbonate ion to below 1 to 2 mmol/L during hyperglycemic ischemia produces a profound secondary deterioration of brain ATP and cerebral blood flow during reperfusion. This study tested the hypothesis that pretreatment with free deferoxamine ameliorates metabolic decay and delayed hypoperfusion after global hyperglycemic ischemia. In addition, deferoxamine conjugated to a high-molecular-weight starch was administered to determine the importance of an intravascular site of action. Iron-loaded deferoxamine was used to determine whether the iron chelation properties of deferoxamine are important to postischemic viability as distinguished from the agent's significant radical scavenging potential. Cerebral ATP, phosphocreatine, and pH were measured by 31P magnetic resonance spectroscopy in anesthetized dogs. Tissue bicarbonate concentration was calculated from the Henderson-Hasselbalch equation. Incomplete cerebral ischemia was produced by intracranial pressure elevation for 30 minutes with plasma glucose at 540 +/- 15 mg/dL. Free deferoxamine, saline vehicle, hydroxyethyl starch-conjugated deferoxamine, hydroxyethyl starch vehicle, and deferoxamine loaded with equimolar ferric chloride were administered intravenously in five groups of dogs. The dose of deferoxamine was 50 mg/kg before ischemia, 50 mg/kg at the onset of reperfusion, and 50 mg/kg over the 180-minute reperfusion period. Ischemic hemispheric blood flow (mean, 6 to 8 mL/min per 100 g), intracellular pH (5.7 to 6.0), and bicarbonate levels (1 to 2 mmol/L) were similar in all groups. During reperfusion, cerebral pH and bicarbonate recovered only in the free-deferoxamine group. Both ATP and phosphocreatine initially increased in all groups, but recovery was sustained only in the free-deferoxamine group. Secondary losses of energy phosphates and cerebral oxygen consumption were observed in all other groups, accompanied by progressive reduction of perfusion. These data support the hypothesis that iron catalyzed oxygen radical production plays an important role in acidosis-mediated mechanisms of ischemic brain injury. The results with free and iron-loaded deferoxamine suggest that iron scavenging is an important, but not necessarily the principal, component of this mechanism. The poor recovery seen with conjugated deferoxamine indicates that the beneficial action of deferoxamine is not localized within the intravascular compartment.

Fibrinolytic therapy for acute embolic stroke: Intravenous, intracarotid, and intra-arterial local approaches

Article

Mar 1995

To clarify the efficacy and limitations of the intra-arterial local infusion of a high-dose fibrinolytic agent for acute embolic stroke, we analyzed the results of 44 patients and compared them with those of 51 patients treated with intracarotid (18 patients) or intravenous (33 patients) infusion therapy. Ten megaunits of recombinant tissue plasminogen activator or 24 x 10(4) IU of urokinase were administered through a microcatheter placed into or proximal to an embolus for 20 minutes. When arterial recanalization was not achieved, a second or third infusion was performed. The rates of complete and partial recanalization just after the local infusion were 52 and 32%, respectively. They were high in middle cerebral and basilar artery occlusion and low in internal carotid artery occlusion (69, 78, and 20%, respectively). In our use, there was no difference between tissue plasminogen activator and urokinase in restoring blood flow. The mean time interval from onset to recanalization in patients with middle cerebral artery occlusion showing marked improvement was 4.8 hours, and it was 5.8 hours with basilar artery occlusion. The size of infarction was reduced, and the outcome was good in patients with complete recanalization achieved. The incidence of hemorrhagic infarction within 24 hours was 22%, and only one patient clinically deteriorated. In the intracarotid infusion group (20 x 10(4) IU of urokinase for 30 min), only two patients showed partial recanalization without clinical improvement. The incidence of hemorrhagic infarction was 28%. The outcome in this group and the intravenous infusion group (18 x 10(4) IU of urokinase a day for 1 wk) was poor compared with that in the local infusion group showing complete recanalization. This preliminary study appears to suggest that intra-arterial local fibrinolytic therapy could be a new strategy for acute embolic stroke.

Tirilazad Pretreatment Improves Early Cerebral Metabolic and Blood Flow Recovery from Hyperglycemic Ischemia

Article

Jan 1995

Acidosis may augment cerebral ischemic injury by promoting lipid peroxidation. We tested the hypothesis that when acidosis is augmented by hyperglycemia, pretreatment with the 21-aminosteroid tirilazad mesylate (U74006F), a potent inhibitor of lipid peroxidation in vitro, improves early cerebral metabolic recovery. In a randomized, blinded study, anesthetized dogs received either tirilazad mesylate (1 mg/kg plus 0.2 mg/kg/h; n = 8) or vehicle (n = 8). Hyperglycemia (400-500 mg/dl) was produced prior to 30 min of global incomplete cerebral ischemia. Intracellular pH and high energy phosphates were measured by phosphorus magnetic resonance spectroscopy. During ischemia, microsphere-determined CBF decreased to 8 +/- 4 ml min-1 100 g-1 and intracellular pH decreased to 5.6 +/- 0.2 in both groups. During the first 20 min of reperfusion, ATP partially recovered in the vehicle group to 57 +/- 21% of baseline, but then declined progressively in association with elevated intracranial pressure. By 30 min, ATP recovery was greater in the tirilazad group (77 +/- 35 vs. 36 +/- 19%), although postischemic hyperemia was similar. By 45 min, the tirilazad group had a higher intracellular pH (6.5 +/- 0.5 vs. 5.9 +/- 0.6) and a lower intracranial pressure (18 +/- 6 vs. 52 +/- 24 mm Hg). By 180 min, blood flow and ATP were undetectable in seven of eight vehicle-treated dogs, whereas ATP was > 67% and pH was > 6.7 in six of eight tirilazad-treated dogs. Thus, tirilazad acts during early reperfusion to prevent secondary metabolic decay associated with severe acidotic ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of acid-base changes on the intracellular calcium concentration of neurons in primary culture

Article

Feb 1994

The influence of changes in intra- and extracellular pH (pHi and pHe, respectively) on the cytosolic, free calcium concentration ([Ca2+]i) of neocortical neurons was studied by microspectrofluorometric techniques and the fluorophore fura-2. When, at constant pHe, pHi was lowered with the NH4Cl prepulse technique, or by a transient increase in CO2 tension, [Ca2+]i invariably increased, the magnitude of the rise being proportional to ΔpHi. Since similar results were obtained in Ca2+-free solutions, the results suggest that the rise in [Ca2+]i was due to calcium release from intracellular stores. The initial alkaline transient during NH4Cl exposure was associated with a rise in [Ca2+]i. However, this rise seemed to reflect influx of Ca2+ from the external solution. Thus, in Ca2+-free solution NH4Cl exposure led to a decrease in [Ca2+]i. This result and others suggest that, at constant pHe, intracellular alkalosis reduces [Ca2+]i, probably by enhancing sequestration of calcium. When cells were exposed to a CO2 transient at reduced pHe, Ca2+ rose initially but then fell, often below basal values. Similar results were obtained when extracellular HCO 3-concentration was reduced at constant CO2 tension. Unexpectedly, such results were obtained only in Ca2+-containing solutions. In Ca2+-free solutions, acidosis always raised [Ca2+]i. It is suggested that a lowering of pHe stimulates extrusion of Ca2+ by ATP-driven Ca2+/2H+ antiport.

Individual risk assessment for intracranial hemorrhage during thrombolytic therapy.

Article

Dec 1993

Thrombolytic therapy improves outcome in patients with myocardial infarction but is associated with an increased risk of intracranial haemorrhage. For some patients, this risk may outweigh the potential benefits of thrombolytic treatment. Using data from other studies, we developed a model for the assessment of an individual's risk of intracranial haemorrhage during thrombolysis. Data were available from 150 patients with documented intracranial haemorrhage and 294 matched controls. 49 patients with intracranial haemorrhage and 122 controls had been treated with streptokinase, whereas 88 cases and 148 controls had received alteplase. By multivariate analysis, four factors were identified as independent predictors of intracranial haemorrhage; age over 65 years (odds ratio 2.2 [95% Cl 1.4-3.5]), body weight below 70 kg (2.1 [1.3-3.2]), hypertension on hospital admission (2.0 [1.2-3.2]), and administration of alteplase (1.6 [1.0-2.5]). If the overall incidence of intracranial haemorrhage is assumed to be 0.75%, patients without risk factors who receive streptokinase have a 0.26% probability of intracranial haemorrhage. The risk is 0.96%, 1.32%, and 2.17% in patients with one, two, or three risk factors, respectively. We present a model for individual risk assessment that can be used easily in clinical practice.

Normoglycemia (Not Hypoglycemia) Optimizes Outcome from Middle Cerebral Artery Occlusion

Article

Mar 1994

We examined the effects of serum glucose concentration during middle cerebral artery (MCA) occlusion in the cat on death rates in animals that died from hemispheric edema and on infarct size in animals that survived. We occluded that MCA permanently in some groups and released the clip after 8 h in others. By injecting or infusing glucose solutions, saline, or insulin, we maintained six animal groups steadily either hyper-, normo-, or slightly hypoglycemic before and for 6 or 8 h after permanent or 8-h temporary MCA occlusion. Studies with these groups revealed a distinct optimal outcome with normoglycemic animals. In three additional groups, we altered the glycemia after permanent occlusion from hyper- to normo- or hypoglycemia and from normo- to hyperglycemia. Two of the three hypoglycemic groups (8-h reversible and permanent hyper- to hypoglycemic occlusions) yielded the worst outcomes in this study, with > 10x larger median infarcts than the best outcome group (normoglycemic permanent occlusion). Hyperglycemia also was detrimental and increased infarct size and mortality after permanent occlusion. Restoring the cerebral blood flow after 8 h of occlusion increased the death rate from hemispheric edema compared with a maintained occlusion. Following permanent MCA occlusion, converting from normo- to hyperglycemia or vice versa yielded outcomes intermediate between a sustained normo- or hyperglycemia. A regression analysis of the normo- and hyperglycemic groups and the two groups with glycemia altered after permanent occlusion showed a significant linear correlation between glycemia level at and 1 h after MCA occlusion and median infarct size.

Moderate hyperglycemia worsens acute blood-brain barrier injury after forebrain ischemia in rats

Article

Feb 1993

Clinical and experimental data indicate that hyperglycemia can aggravate the consequences of stroke and cerebral ischemia. The purpose of this study was to examine the effects of moderate hyperglycemia on the response of the blood-brain barrier to normothermic (37 degrees C) and hypothermic (30 degrees C) global forebrain ischemia. Sixteen rats underwent 20 minutes of four-vessel occlusion followed by 30 minutes of postischemic recirculation. We used the protein tracer horseradish peroxidase as an indicator of increased vascular permeability, and rats were perfusion-fixed for microscopic analysis. To produce moderate hyperglycemia, we gave an intraperitoneal injection of 50% dextrose 15 minutes before the ischemic insult. After normothermic brain ischemia, normoglycemic rats (plasma glucose level, 115 +/- 3 mg/dl) demonstrated extravasated horseradish peroxidase mainly restricted to the cerebral cortex. In contrast, more severe and widespread protein extravasation was documented throughout the neuraxis of hyperglycemic (plasma glucose level, 342 +/- 27) rats. Sites of protein leakage included the cerebral cortex, striatum, hippocampus, thalamus, and cerebellum. Foci of protein extravasation were associated with pial and large penetrating vessels. Intraischemic hypothermia significantly attenuated the blood-brain barrier consequences of hyperglycemic brain ischemia. Under normothermic ischemic conditions, hyperglycemia significantly worsens the degree of acute blood-brain barrier breakdown compared with normoglycemia. Postischemic blood-brain barrier disruption may play an important role in the pathogenesis of increased brain damage associated with systemic hyperglycemia.

Neuroprotection after focal cerebral ischaemia in hyperglycaemic and diabetic rats

Article

Oct 1995
NEUROSCI LETT

The effects of acute hyperglycaemia and streptozotocin-induced diabetes on infarct size were measured 48 h after middle cerebral artery occlusion (MCAO) in Fischer 344 rats. Both hyperglycaemia (+46%) and diabetes (+68%) increased infarct volume when compared to normoglycaemic rats. Insulin-treated diabetic rats exhibited an infarct size similar to that observed in normoglycaemic rats. Neuroprotection has been difficult to demonstrate in pathological conditions that increase infarct volume such as chronic arterial hypertension. However, administration of the non-competitive NMDA antagonist, dizocilpine (MK-801), after MCAO, reduced the volume of ischaemic damage (by 33-48%) in all groups. The present findings indicate (a) that the detrimental effects of experimental diabetes on infarct volume are largely attributed to hyperglycaemia; and (b) dizocilpine was as neuroprotective in hyperglycaemia and diabetic conditions as in normoglycaemic rats.

Amelioration of Impaired Cerebral Metabolism After Severe Acidotic Ischemia by Tirilazad Posttreatment in Dogs

Article

Feb 1996

Acidosis may contribute to ischemic injury by mobilizing iron because the iron chelator deferoxamine improves early metabolic recovery from hyperglycermic ischemia. Mobilized iron may then promote oxygen radical-induced lipid peroxidative injury during reperfusion. We tested the hypothesis that administration of the antioxidant tirilazad at the start of reperfusion improves early metabolic recovery after severe acidotic ischemia and ameliorates depletion of the endogenous antioxidant glutathione. In anesthetized dogs, arterial glucose concentration was increased to 500 to 600 mg/dL and global incomplete cerebral ischemia was produced for 30 minutes by ventricular fluid infusion to reduce perfusion pressure to 10 to 12 mm Hg. Metabolic recovery and intracellular pH were measured by phosphorus MR spectroscopy. In the first experiment, four groups of eight dogs each received either vehicle or 0.25, 1, or 2.5 mg/kg of tirilizad mesylate at reperfusion. Cerebral blood flow was measured with microspheres. In the second experiment, two groups of eight dogs each each received either vehicle or 2.5 mg/kg of tirilazad at reperfusion, and cortical glutathione was measured at 3 hours of reperfusion. Cerebral blood flow decreased to approximately 6 mL/min per 100 g and intracellular pH decreased to approximately 5.6 during ischemia in all groups. In the vehicle group, ATP recovery was transient and pH remained less than 6.0. Cerebral blood flow, O2 consumption, and ATP eventually declined to near-zero levels by 3 hours. Recovery was improved by tirilazad posttreatment in a dose-dependent fashion. At the highest dose, cerebral blood flow and O2 consumption were sustained near preischemic levels, and five of eight dogs had recovery of ATP greater than 50% and of pH greater than 6.7. Recovery of ATP and phosphocreatine became significantly greater than that in the vehicle group by 17 minutes of reperfusion despite similar levels of early hyperemia, indicating that the drug was acting before the onset of hypoperfusion. Cortical glutathione concentration in the vehicle group was 27% less than that in the tirilazad group and 34% less than that in nonischemic controls. Decreased depletion of the endogenous antioxidant glutathione is consistent with tirilazad acting as an antioxidant in vivo. Improvement in high-energy phosphate recovery 17 minutes after starting tirilazad infusion during reperfusion is consistent with an early onset of a functionally significant oxygen radical injury. Thus, severe acidosis appears to contribute to early ischemic injury through an oxygen radical mechanism sufficient to impede metabolic recovery.

Brain Capillary Tissue Plasminogen Activator in a Diabetes Stroke Model

Article

Apr 1996

Tissue plasminogen activator (TPA) is normally expressed in rat brain capillaries. This study examines the expression of TPA in brain capillaries of diabetic rats in relation to focal ischemic brain injury. Diabetes type 1 was induced by streptozotocin for 7 days. Acute hyperglycemia was induced by 50% dextrose. Expression of TPA in brain capillaries was determined by Western blot and reverse transcription-polymerase chain reaction analyses. Focal stroke was produced by 1 hour of reversible middle cerebral artery occlusion. Physiological variables and cerebral blood flow were monitored during occlusion and within 1 hour of reperfusion. Neurological and neuropathologic examinations were performed after 24 hours of reperfusion. All rats developed comparable hyperglycemia (approximately 15 mmol/L). A complete depletion of TPA protein and 6.5-fold decrease in TPA mRNA were found in brain capillaries of diabetic rats, in contrast to normal TPA capillary levels in hyperglycemic rats. The blood flow in the periphery of the ischemic core was significantly reduced during reperfusion by 52% to 62% (P<.001) in diabetic rats and by 23% to 25% (P<.05) in hyperglycemic rats. The neurological score was worsened by 3.2-fold (P<.0003) by diabetes and by 24% by hyperglycemia only. Significant 41% (P<.007) and 29% (P<.05) increases in infarct volume and 163% (P<.007) and 60% increases in edema volume were found in diabetic rats relative to control and hyperglycemic rats, respectively. Diabetes type 1, but not acute hyperglycemia, produces downregulation of TPA in rat brain capillaries. This TPA reduction is associated with impaired restoration of blood flow after an ischemic insult, poor neurological outcome, and enhanced ischemic brain injury.

Suppression of Plasminogen Activator Inhibitor-1 Release From Human Cerebral Endothelium by Plasminogen Activators: A Factor Potentially Predisposing to Intracranial Bleeding

Article

Sep 1996

Intracranial bleeding is the most catastrophic potential complication of treatment with thrombolytic agents. To identify potential factors that may contribute to this problem, we characterized elaboration by human brain endothelial cells of plasminogen activator inhibitor-1 (PAI-1) and measured PAI-1 mRNA levels. When human cerebral microvascular endothelial cells (HCMEC), pial arterial endothelial cells, and middle meningeal arterial endothelial cells were exposed to 10 to 1000 ng/mL recombinant tissue-type plasminogen activator (RTPA), urokinase-type plasminogen activator (UPA), or streptokinase/ plasminogen (37 U streptokinase plus 2 mumol/L plasminogen) for 24 hours, they exhibited concentration-dependent decreases in elaboration of PAI-1 of 65 +/- 3%, 48 +/- 3%, and 59 +/- 8%. UPA and streptokinase/plasminogen elicited decreases of 33 +/- 8% and 35 +/- 4%, respectively, that were specific with respect to the protease agonists as to total protein synthesis and cell type; ie, neither human umbilical vein endothelial cells nor cerebral pericytes exhibited inhibition of PAI-1 elaboration. No decrease in HCMEC PAI-1 elaboration was induced by coagulation factor XB (10 nmol/L). A 2.7 +/- 0.5-fold increase was induced by alpha-thrombin (10 nmol/L). PAI-1 secretion from HCMEC decreased within 4 hours of exposure to 100 ng/mL RTPA. In HCMEC exposed to RTPA for 8 hours, PAI-1 mRNA decreased from 176 +/- 20 to 43 +/- 2.2 pg/microgram RNA. These results indicate that brain endothelial cells exposed to RTPA exhibit paradoxically diminished elaboration of PAI-1. This property may render brain vasculature vulnerable to attack by serine proteases, thereby predisposing to injury and initiating an underlying subsequent intracerebral hemorrhage in patients given plasminogen activators for treatment of coronary thrombosis.

Chronic Nicotine Treatment Enhances Focal Ischemic Brain Injury and Depletes Free Pool of Brain Microvascular Tissue Plasminogen Activator in Rats

Article

Feb 1997

Effects of nicotine treatment (4.5 mg/kg of nicotine-free base/day administered s.c. by osmotic minipumps for 14 days) on focal ischemic stroke and expression of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in cerebral microvessels were studied in rats in vivo using a reversible (1 h) middle cerebral artery occlusion model. Plasma levels of nicotine and its major metabolite cotinine after 14 days of treatment were 88 and 364 ng/ml, respectively. Nicotine treatment resulted in 35-40% (p < 0.001) decrease in the blood flow in the periphery of the ischemic core during reperfusion, an increase in the neurologic score of 2.6-fold (p < 0.01), and 36% (p < 0.05) and 121% (p < 0.01) increases in the injury and edema volume in the pallium, respectively. A free pool of brain microvascular t-PA antigen was completely depleted by nicotine, while the expression of the PAI-1 antigen and/or PAI-1-t-PA complexes remained unchanged. The relative abundance of cerebromicrovascular t-PA mRNA transcript versus beta-actin mRNA transcript did not change with nicotine. It is concluded that chronic nicotine treatment impairs the restoration of blood flow, worsens the neurologic outcome, and enhances brain injury following an ischemic insult. These nicotine effects are associated with depletion of brain microvascular t-PA antigen.

Is hyperglycemia an independent predictor of poor outcome after acute stroke? Results of a long term follow up study

Article

May 1997

To determine whether raised plasma glucose concentration independently influences outcome after acute stroke or is a stress response reflecting increased stroke severity. Long-term follow up study of patients admitted to an acute stroke unit. Western Infirmary, Glasgow. 811 patients with acute stroke confirmed by computed tomography. Analysis was restricted to the 750 non-diabetic patients. Survival time and placement three months after stroke. 645 patients (86%) had ischaemic stroke and 105 patients (14%) haemorrhagic stroke. Cox's proportional hazards modelling with stratification according to Oxfordshire Community Stroke Project categories identified increased age (relative hazard 1.36 per decade; 95% confidence interval 1.21 to 1.53), haemorrhagic stroke (relative hazard 1.67; 1.22 to 2.28), time to resolution of symptoms > 72 hours (relative hazard 2.15; 1.15 to 4.05), and hyperglycaemia (relative hazard 1.87; 1.43 to 2.45) as predictors of mortality. The effect of glucose concentration on survival was greatest in the first month. Plasma glucose concentration above 8 mmol/l after acute stroke predicts a poor prognosis after correcting for age, stroke severity, and stroke subtype. Raised plasma glucose concentration is therefore unlikely to be solely a stress response and should arguably be treated actively. A randomised trial is warranted.

Hemorrhagic Transformation in Acute Ischemic Stroke : Potential Contributing Factors in the European Cooperative Acute Stroke Study

Article

Jun 1997

Recent studies suggest that thrombolytic therapy may be of benefit to patients with acute ischemic stroke. However, the treatment also carries a significant risk of hemorrhagic transformation (HT). The purpose of this study was to select potential contributors to HT. We provide an explanatory analysis of the European Cooperative Acute Stroke Study (ECASS) data. ECASS was a multicenter, placebo-controlled, randomized trial of recombinant tissue plasminogen activator in ischemic stroke, within 6 hours of symptom onset, which enrolled 620 patients. HTs were classified into either hemorrhagic infarction or parenchymal hemorrhage according to their CT scan appearance. We used logistic regression analysis to select potential contributing factors to each type of HT. The severity of initial clinical deficit (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.6 to 4.0) and the presence of early ischemic changes on CT scan (OR, 3.5; 95% CI, 2.3 to 5.3) were associated with increased risk of hemorrhagic infarction. Increasing age (in decades; OR, 1.3; 95% CI, 1.0 to 1.7) and treatment with recombinant tissue plasminogen activator (OR, 3.6; 95% CI, 2.1 to 6.1) were related to the risk of parenchymal hemorrhage. Since all potential contributing factors are readily discernible upon hospital admission, they should be used to improve selection of patients into future studies.

Hyperglycemia Delays Terminal Depolarization and Enhances Repolarization after Peri-Infarct Spreading Depression as Measured by Serial Diffusion MR Mapping

Article

Jun 1997

We investigated the effect of hyperglycemia on the initiation and propagation of spreading depression-like peri-infarct ischemic depolarization (SD) induced by focal cerebral ischemia in rats. Peri-infarct SD were monitored during the initial 15 minutes after remotely induced middle cerebral artery occlusion (MCAO) using serial diffusion weighted magnetic resonance imaging. Maps of the apparent diffusion coefficient (ADC) were calculated and ADC decreases were monitored over time. Hyperglycemic rats (n = 6) had a significant prolongation of the time from induction of MCAO to the start of the ADC decrease as compared with normoglycemic control rats. The time to the maximal ADC decrease was significantly delayed and recovery of transient ADC declines in the area adjacent to the ischemic core was significantly faster in hyperglycemic rats. We conclude that hyperglycemia delays the terminal depolarization in the ischemic core and supports a faster repolarization in severely mal-perfused penumbral tissue after SD, which reflects the increased availability of energy substrates in the state of hyperglycemia.

Perfusion Deficit Parallels Exacerbation of Cerebral Ischemia/Reperfusion Injury in Hyperglycemic Rats

Article

Jun 1997

Magnetic resonance imaging (MRI) techniques were used to determine the effect of preexisting hyperglycemia on the extent of cerebral ischemia/reperfusion injury and the level of cerebral perfusion. Middle cerebral artery occlusion (MCAO) was induced by a suture insertion technique. Forty one rats were divided into hyperglycemic and normoglycemic groups with either 4 hours of continuous MCAO or 2 hours of MCAO followed by 2 hours of reperfusion. Diffusion-weighted imaging (DWI) was performed at 4 hours after MCAO to quantify the degree of injury in 6 brain regions. Relative cerebral blood flow (CBF) and cerebral blood volume (CBV) were estimated using gradient echo (GE) bolus tracking and steady-state spin echo (SE) imaging techniques, respectively. Brain injury correlated with the perfusion level measured in both SE CBV and dynamic GE CBF images. In the temporary MCAO model, mean lesion size in DWI was 118% larger and hemispheric CBV was reduced by 37% in hyperglycemic compared with normoglycemic rats. Hyperglycemia did not significantly exacerbate brain injury or CBV deficit in permanent MCAO models. We conclude that preexisting hyperglycemia increases acute postischemic MRI-measurable brain cellular injury in proportion to an associated increased microvascular ischemia.

Hyperglycaemia after acute stroke. Participants required for trial of treatment with glucose and insulin

Article

Oct 1997

Hyperglycaemia after acute stroke. May occur as result of neuroendocrine response

Article

Oct 1997

Serum Glucose Level and Diabetes Predict Tissue Plasminogen Activator Related Intracerebral Hemorrhage in Acute Ischemic Stroke

Abstract

No full-text available

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