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    Emergency Department hyperglycemia as a predictor of early mortality and worse functional outcome after intracerebral hemorrhage. Stead Latha G,Jain Anunaya,Bellolio M Fernanda,Odufuye Adetolu,Gilmore Rachel M,Rabinstein Alejandro,Chandra Raghav,Dhillon Ravneet,Manivannan Veena,Serrano Luis A,Yerragondu Neeraja,Palamari Balavani,Jain Minal,Decker Wyatt W Neurocritical care BACKGROUND:We have previously reported the association of hyperglycemia and mortality after ischemic stroke. This study attempts to answer the hypothesis, if hyperglycemia at arrival, is associated with early mortality and functional outcome in patients with acute non-traumatic intracerebral hemorrhage (ICH). METHODS:The study cohort consisted of 237 patients who presented to the ED with ICH and had blood glucose measured on ED presentation. The presence of hyperglycemia on presentation was correlated with outcome measures including volume of hematoma, intraventricular extension of hematoma (IVE), stroke severity, functional outcome at discharge, and date of death. RESULTS:Of the cohort of 237 patients, a total of 47 patients had prior history of Diabetes Mellitus (DM). Median blood glucose at presentation was 140 mg/dl (Inter-quartile range 112-181 mg/dl). DM patients had higher glucose levels on arrival (median 202 mg/dl for DM vs. 132.5 mg/dl for non-DM, P < 0.0001). Higher blood glucose at ED arrival was associated with early mortality in both non-diabetics and diabetics (P < 0.0001). Higher blood glucose was associated with poor functional outcome in non-DM patients(P < 0.0001) but not in DM patients (P = 0.268). In the logistic regression model, after adjustment for stroke severity, hematoma volume, and IVE of hemorrhage, higher initial blood glucose was a significant predictor of death (P = 0.0031); as well as bad outcome in non-DM patients (P = 0.004). CONCLUSIONS:Hyperglycemia on presentation in non-diabetic patients is an independent predictor of early mortality and worse functional outcome in patients with intracerebral hemorrhage. 10.1007/s12028-010-9355-0
    Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage. Song Eun-Chol,Chu Kon,Jeong Sang-Wuk,Jung Keun-Hwa,Kim Seong-Hoon,Kim Manho,Yoon Byung-Woo Stroke BACKGROUND AND PURPOSE:Hyperglycemia has a deleterious effect on brain ischemia. However, the effect of hyperglycemia in intracerebral hemorrhage (ICH) is not well known. We investigated the effect of hyperglycemia on the development of brain edema and perihematomal cell death in ICH. METHODS:Hyperglycemia was induced by intraperitoneal injection of streptozotocin (60 mg/kg) in adult Sprague-Dawley male rats. ICH was induced by stereotaxic infusion of 0.23 U of collagenase into the left striatum. Seventy-two hours after ICH, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining was performed for perihematomal cell death. We also measured brain water content to evaluate edema formation. RESULTS:The serum glucose level of the hyperglycemic group was 394.0+/-180.3 mg/dL (n=31), and that of the normoglycemic group was 97.5+/-27.4 mg/dL (n=31). The size of hemorrhage was similar between groups, without any significant difference (n=8 in each group). The brain water content of hyperglycemic rats (n=17) increased in both lesioned (81.0+/-0.5%) and nonlesioned hemispheres (78.7+/-0.6%) compared with the normoglycemic group (n=17; lesioned: 78.9+/-0.8%; nonlesioned: 77.3+/-1.1%). In the hyperglycemic group, more TUNEL-positive cells were found in the perihematomal regions (n=6). CONCLUSIONS:Hyperglycemia caused more profound brain edema and perihematomal cell death in experimental ICH. 10.1161/01.STR.0000088060.83709.2C
    The influence of diabetes and hyperglycemia on clinical course after intracerebral hemorrhage. Passero Stefano,Ciacci Giuseppe,Ulivelli Monica Neurology OBJECTIVE:To determine whether diabetes and admission hyperglycemia in nondiabetic patients influence outcome and the occurrence of cerebral and medical complications after intracerebral hemorrhage (ICH). METHODS:The study sample included 764 patients with ICH. The effects of diabetes and admission hyperglycemia were examined in relation to 30-day and 3-month mortality using Cox regression models controlling for potential confounders. The analysis was conducted for the entire sample of patients and repeated in comatose and noncomatose patients. RESULTS:Among comatose patients, neither diabetes nor admission hyperglycemia contributed significant predictive information, as nearly all patients died. In noncomatose patients, diabetes was an independent predictor of 30-day (odds ratio [OR] 1.31; 95% CI 1.08 to 1.58) and 3-month (OR 1.30; 95% CI 1.08 to 1.56) mortality and was associated with a greater incidence of infectious (OR 1.24; 95% CI 1.03 to 1.49) and cerebral (OR 1.42; 95% CI 1.10 to 1.83) complications. Among nondiabetic patients with Glasgow Coma Scale score of >8, hyperglycemia was an independent predictor of 30-day (OR 1.29; 95% CI 1.05 to 1.58) and 3-month (OR 1.27; 95% CI 1.05 to 1.53) mortality and was associated with a greater incidence of cerebral complications (OR 1.47; 95% CI 1.12 to 2.94). CONCLUSIONS:Both diabetes and admission hyperglycemia in nondiabetic patients are predictors of poor outcome after supratentorial ICH. This may be related to the greater incidence of cerebral and infectious complications in diabetic patients and of cerebral complications in hyperglycemic nondiabetic patients. 10.1212/01.wnl.0000094326.30791.2d
    Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein. Liu Jia,Gao Ben-Bo,Clermont Allen C,Blair Price,Chilcote Tamie J,Sinha Sukanto,Flaumenhaft Robert,Feener Edward P Nature medicine Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia augments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis. 10.1038/nm.2295
    Hyperglycemia promotes tissue plasminogen activator-induced hemorrhage by Increasing superoxide production. Won Seok Joon,Tang Xian Nan,Suh Sang Won,Yenari Midori A,Swanson Raymond A Annals of neurology OBJECTIVE:Risk of intracerebral hemorrhage is the primary factor limiting use of tissue plasminogen activator (tPA) for stroke. Clinical studies have established an association between admission hyperglycemia and the risk of hemorrhage with tPA use, independent of prior diabetes. Here we used an animal model of tPA-induced reperfusion hemorrhage to determine if this clinical association reflects a true causal relationship. METHODS:Rats underwent 90 minutes of focal ischemia, and tPA infusion was begun 10 minutes prior to vessel reperfusion. Glucose was administered during ischemia to generate blood levels ranging from 5.9 ± 1.8mM (normoglycemia) to 21 ± 2.3mM. In some studies, apocynin was administered to block superoxide production by nicotinamide adenine dinucleotide phosphate (NADPH). Brains were harvested 1 hour or 3 days after reperfusion to evaluate the effects of hyperglycemia and apocynin on oxidative stress, blood-brain barrier breakdown, infarct volume, and hemorrhage volume. RESULTS:Rats that were hyperglycemic during tPA infusion had diffusely increased blood-brain barrier permeability in the postischemic territory, and a 3- to 5-fold increase in intracerebral hemorrhage volumes. The hyperglycemic rats also showed increased superoxide formation in the brain parenchyma and vasculature during reperfusion. The effects of hyperglycemia on superoxide production, blood-brain barrier disruption, infarct size, and hemorrhage were all attenuated by apocynin. INTERPRETATION:These findings demonstrate a causal relationship between hyperglycemia and hemorrhage in an animal model of tPA stroke treatment, and suggest that this effect of hyperglycemia is mediated through an increase in superoxide production by NADPH oxidase. 10.1002/ana.22538
    Hyperglycemia exacerbates intracerebral hemorrhage via the downregulation of aquaporin-4: temporal assessment with magnetic resonance imaging. Chiu Cheng-Di,Chen Chiao-Chi V,Shen Chiung-Chyi,Chin Li-Te,Ma Hsin-I,Chuang Hao-Yu,Cho Der-Yang,Chu Chi-Hong,Chang Chen Stroke BACKGROUND AND PURPOSE:Intracerebral hemorrhage (ICH) is associated with high mortality and neurological deficits, and concurrent hyperglycemia usually worsens clinical outcomes. Aquaporin-4 (AQP-4) is important in cerebral water movement. Our aim was to investigate the role of AQP-4 in hyperglycemic ICH. METHODS:Hyperglycemia was induced by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg) in adult Sprague-Dawley male rats. ICH was induced by stereotaxic infusion of collagenase/heparin into the right striatum. One set of rats was repeatedly monitored by MRI at 1, 4, and 7 days after ICH induction so as to acquire information on the formation of hematoma and edema. Another set of rats was killed and brains were examined for differences in the degree of hemorrhage and edema, water content, blood-brain barrier destruction, and AQP-4 expression. RESULTS:Hyperglycemia ICH rats exhibited increased brain water content, more severe blood-brain barrier destruction, and greater vasogenic edema as seen on diffusion-weighted MRI. Significant downregulation of AQP-4 was observed in STZ-treated rats after ICH as compared with non-STZ-treated rats. Apoptosis was greater on day 1 after ICH in STZ-treated rats. CONCLUSIONS:The expression of AQP-4 in the brain is downregulated in hyperglycemic rats as compared with normoglycemic rats after ICH. This change is accompanied by increased vasogenic brain edema and more severe blood-brain barrier destruction. 10.1161/STROKEAHA.113.675983
    Hyperglycemia Is Associated with Island Sign in Patients with Intracerebral Hemorrhage. Zhang Fan,Li Hao,Qian Juan,Zhang Si,Tao Chuanyuan,You Chao,Yang Mu World neurosurgery OBJECTIVES:The prognostic value of admission serum glucose for early hematoma growth in patients with intracranial hemorrhage remains controversial. Island sign is a novel imaging predictor for early hematoma growth, implying multifocal active bleeding. The aim of this study is to investigate the potential associations between hyperglycemia and early hematoma expansion in patients with intracranial hemorrhage with or without island sign. PATIENTS AND METHODS:Clinical characteristics and radiologic parameters were retrospectively obtained from the electronic medical record. Admission blood glucose was measured within 24 hours from disease onset. Hematoma expansion and island sign were estimated by 2 experienced reviewers from initial and follow-up computed tomography scans. Multivariate logistic regression analyses were used to explore the associations of hematoma expansion and island sign on other clinical variables. RESULTS:In total, 187 patients were enrolled in current study; 61 patients were presented to have early hematoma expansion, whereas 32 exhibited island sign. The average blood glucose level was 7.64 mmol/L among all patients. The multivariate logistic regression analyses revealed that the time from ictus to initial computed tomography scan, Glasgow Coma Scale score on admission, hematoma volume, island sign, and hyperglycemia were associated with hematoma expansion, whereas only admission serum glucose and hematoma size were associated with island sign. CONCLUSIONS:Admission serum glucose is associated with hematoma growth and prevalence of island sign, respectively. These results indicated that elevated blood glucose level plays a pathological role in active bleeding. Further studies concerning exact molecular signal pathway are urgently required. 10.1016/j.wneu.2018.07.251
    Prognostic Significance of Hyperglycemia in Acute Intracerebral Hemorrhage: The INTERACT2 Study. Saxena Anubhav,Anderson Craig S,Wang Xia,Sato Shoichiro,Arima Hisatomi,Chan Edward,Muñoz-Venturelli Paula,Delcourt Candice,Robinson Thompson,Stapf Christian,Lavados Pablo M,Wang Jiguang,Neal Bruce,Chalmers John,Heeley Emma, Stroke BACKGROUND AND PURPOSE:We aimed to determine associations of baseline blood glucose and diabetes mellitus with clinical outcomes in participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). METHODS:INTERACT2 was an international prospective, open, blinded end point, randomized controlled trial of 2839 patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure randomly assigned to intensive (target systolic blood pressure <140 mm Hg) or guideline-based (systolic blood pressure <180 mm Hg) BP management. Associations of hyperglycemia at presentation (>6.5 mmol/L) and combined and separate poor outcomes of death and major disability (scores of 3-6, 3-5, and 6, respectively, on the modified Rankin scale) at 90 days were determined in logistic regression models. RESULTS:In 2653 patients with available data, there were 1348 (61%) with hyperglycemia and 292 (11%) with diabetes mellitus. Associations of baseline blood glucose and poor outcome were strong and near continuous. After adjustment for baseline variables, the highest fourth (7.9-25.0 mmol/L) of blood glucose was significantly associated with combined poor outcome (adjusted odds ratio 1.35, 95% confidence interval 1.01-1.80; P trend 0.015). Diabetes mellitus also predicted poor outcome (adjusted odds ratio 1.46, 95% confidence interval 1.05-2.02; P=0.023), though more important for residual disability than death on separate analysis. CONCLUSIONS:Hyperglycemia and diabetes mellitus are independent predictors of poor outcome in patients with predominantly mild to moderate severity of intracerebral hemorrhage. These data support guideline recommendations for good glycemic control in patients with intracerebral hemorrhage. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079. 10.1161/STROKEAHA.115.011627