Association of Baseline Hyperglycemia With Outcomes of Patients With and Without Diabetes With Acute Ischemic Stroke Treated With Intravenous Thrombolysis: A Propensity Score–Matched Analysis From the SITS-ISTR Registry

Tsivgoulis, Georgios; Katsanos, Aristeidis H.; Mavridis, Dimitris; Lambadiari, Vaia; Roffe, Christine; MacLeod, Mary Joan; Ševčík, Petr; Cappellari, Manuel; Nevšímalová, Miroslava; Toni, Danilo; Ahmed, Niaz

doi:10.2337/db19-0440

Cited by 59 publications

(52 citation statements)

References 40 publications

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“…There is striking evidence that acute hyperglycemia at presentation with stroke is a marker of risk, both of poor functional outcome and of mortality 33 . Several studies have addressed the question of whether intervention to control glycemia might be of benefit in such patients.…”

Section: Acute Association Of Glycemia With Strokementioning

confidence: 99%

“…There is striking evidence that acute hyperglycemia at presentation with stroke is a marker of risk, both of poor functional outcome and of mortality. 33 Several studies have addressed the question of whether intervention to control glycemia might be of benefit in such patients. The Stroke Hyperglycemia Insulin Network Effort (SHINE) randomized clinical trial included adult patients with known diabetes whose blood glucose exceeded 110 mg/dL and those not known to have diabetes with glucose exceeding 150 mg/dL; there was no demonstrable difference in stroke outcome, but severe hypoglycemia (glucose <40 mg/dL) occurred in 2.6% of the intervention group but in none of those randomized to standard treatment.…”

Section: The Association Of Long-term Glycemia With Strokementioning

confidence: 99%

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Diabetes and stroke: An important complication

Bloomgarden

Chilton

2020

Journal of Diabetes

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Diabetes is associated with a plethora of metabolic changes which may underlie the propensity to development of stroke (Figure 1). 1 Insulin resistance has multiple drivers, is inextricably linked to type 2 diabetes, and is associated with coronary artery 2 and cerebrovascular 3 atherosclerosis. Insulin resistance is mediated by increased levels of bioactive lipids, including ceramides 4 and diacylglycerol, 5 playing a role in cell death in numerous tissues. 6 Hyperglycemia leads to formation of advanced glycation end products and to activation of the polyol pathway, protein kinase C pathway, and the polyadenosine diphosphate-ribose polymerase (PARP) and hexosamine pathways, all increasing oxidative stress, with formation of such reactive oxygen species as the hydroxyl radical, superoxide anion, peroxides, reducing endogenous antioxidants including superoxide dismutase, glutathione, and ascorbic acid and eventuating in oxidative damage of DNA, proteins, and lipids, causing cellular necrosis or apoptosis. 1 Hyperglycemia directly and indirectly increases circulating levels of T cells and macrophages as well as inflammatory and prothrombotic factors, reduces endothelial function, and leads to glycation and oxidation of lipoproteins, increasing their atherogenicity. 1 A specific mediator of oxidative stress involves activation of the transient receptor potential melastatin (TRMP) 2 calcium channel by ischemia/reperfusion injury, a pathway upregulated in diabetes and insulin-resistant states and mediating neuronal cell death in association with oxidative stress. 7 Diabetes leads to reductions in levels of key microRNAs, miRNA-126, miRNA-124, and miRNA-223, which are also downregulated in stroke and which have anti-inflammatory and neuroprotective effects. 8

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Section: Acute Association Of Glycemia With Strokementioning

confidence: 99%

Section: The Association Of Long-term Glycemia With Strokementioning

confidence: 99%

Diabetes and stroke: An important complication

Bloomgarden

Chilton

2020

Journal of Diabetes

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“…Hyperglycemia is associated with poor prognosis in various ICU patients 2,3,8,10) . Hyperglycemia is a predictor associated with poor neurological prognosis in patients with neurological diseases such as ischemic stroke, intracerebral hemorrhage, and aneurysmal subarachnoid hemorrhage 5,9,13,16) . Indeed, hyperglycemia itself could be harmful to the brain 7) .…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, hyperglycemia is frequently accompanied in neurocritically ill patients 6,7) . Hyperglycemia is a significantly prognostic marker of poor neurological outcome of patients with ischemic stroke or intracerebral hemorrhage 1,5,13,16) . However, there are limited reports of neurological prognosis according to hyperglycemia in neurocritially ill patients 12,17) .…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of Early Hyperglycemia in Neurocritically Ill Patients

Han

Lee

Ryu

2020

J Neurointensive Care

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Objective To evaluate the relationship of early hyperglycemia and neurological prognosis in neurocritically ill patients. Methods This was a retrospective study of adult patients admitted to the neurosurgical intensive care unit (ICU) from January 2010 to July 2019. Primary outcome was neurological status at 6-month follow-up assessed with the Glasgow Outcome Scale (GOS, 1 to 5). Results A total of 202 patients were analyzed in this study. Of them, 70 (34.7%) patients had early hyperglycemia (≥200 mg/dL within 48 hours after ICU admission). Brain tumor (39.6%) and subarachnoid hemorrhage (17.8%) were the most common reasons for ICU admission. Ninety-three (46.0%) patients had favorable neurological outcomes (GOS of 4 or 5). Poor neurological outcome was more common in the early hyperglycemia group than in the non-hypoglycemia group (71.4% vs. 44.7%, p<0.001). In addition, 90-day mortality rate was significantly higher for patients with early hyperglycemia than that for patients without hyperglycemia (17.1% vs. 8.3%, p=0.011). Multivariable logistic regression analysis revealed that age (adjusted odd ratio [OR]: 1.04, 95% confidence interval (CI): 1.020-1.066), Acute Physiology and Chronic Health Evaluation II score on ICU admission (adjusted OR: 1.06, 95% CI: 1.003-1.113), and early hyperglycemia (adjusted OR: 2.32, 95% CI: 1.188-4.528) were significantly associated with poor neurological outcomes in neurocritically ill patients (Hosmer-Lemeshow Chi-squared = 5.43, df=8, p=0.711). Conclusions In this study, early hyperglycemia could be a significant predictor for neurological outcome in neurocritically ill patients.

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“…This may stem from an imbalance between the risks and benefits of intravenous tissue plasminogen activator (tPA). In this connection, comprehensive analyses of clinical and experimental evidences demonstrates that post-stroke hyperglycemia may work as a critical interfering factor to reduce the efficacy of reperfusion therapies and increase the possibility of neurovascular complications (Tsivgoulis et al, 2019). The high prevalence of hyperglycemia in admitted stroke patients, either that associated with pre-existing diabetes (30%) simply that of stress hyperglycemia (50%) (Allport et al, 2006;Furie & Ay, 2018) coupled with the limitations in glucose normalization in the acute stroke setting (Bruno et al, 2014;Johnston et al, 2019), demands for adjunctive therapies to supplement in thrombolytics.…”

Section: Introductionmentioning

confidence: 99%

Verapamil is an adjunct therapy to reduce tPA toxicity in hyperglycemic stroke: implication of TXNIP/NLRP3 inflammasome

Ismael¹,

Nasoohi²,

Yoo³

et al. 2020

Preprint

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Background and Purpose: Thrombolytic therapy has remained utterly challenging in hyperglycemic patients for poor prognosis and increased hemorrhagic conversions. We have recently shown that tissue plasminogen activator (tPA)-induced cerebrovascular damage is associated with thioredoxin interacting protein (TXNIP) upregulation, which has an established role in the detrimental effects of hyperglycemia. In the present work, we investigated whether verapamil, as an established TXNIP inhibitor may provide protection against hyperglycemic stroke and tPA-induced blood-brain barrier (BBB) disruption. Experimental approach: Acute hyperglycemia was induced by intraperitoneal administration of 20% glucose 15 min prior to transient middle cerebral artery occlusion (tMCAO). Verapamil (0.15 mg/kg) or saline was intravenously infused with tPA at hyperglycemic reperfusion, 1 h post tMCAO. After 24 h of ischemia/reperfusion (I/R), mice were tested for neurobehavioral deficits followed by evaluation of infarct size, edema, and microbleeding. Alterations in TXNIP, inflammatory mediators, and BBB markers were further analyzed using immunoblotting or immunostaining techniques. Key results: As an adjunctive therapy, verapamil significantly reduced tPA-induced BBB leakage, matrix metallopeptidase 9 (MMP-9), and tight junction protein deregulation, all leading to less hemorrhagic conversions. Importantly, verapamil strongly reversed tPA-induced TXNIP/NRRP3 (NOD-like receptor pyrin domain-containing-3) inflammasome activation, along with reduced infarct area. This concurred with a remarkable decrease in high mobility group box protein 1 (HMGB-1)/ nuclear factor kappa B (NF-κB) stimulation leading to less priming of NLRP3 inflammasome. Conclusion and implication: This preclinical evidence supporting verapamil as a safe adjunctive therapy in thrombolytic approaches, underlines TXNIP's detrimental role in BBB disruption in metabolic distress.

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Association of Baseline Hyperglycemia With Outcomes of Patients With and Without Diabetes With Acute Ischemic Stroke Treated With Intravenous Thrombolysis: A Propensity Score–Matched Analysis From the SITS-ISTR Registry

Cited by 59 publications

References 40 publications

Diabetes and stroke: An important complication

Diabetes and stroke: An important complication

Prognostic Value of Early Hyperglycemia in Neurocritically Ill Patients

Verapamil is an adjunct therapy to reduce tPA toxicity in hyperglycemic stroke: implication of TXNIP/NLRP3 inflammasome

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