Nebulization of Low-Dose S-Nitrosoglutathione in Diabetic Stroke Enhances Benefits of Reperfusion and Prevents Post-Thrombolysis Hemorrhage

The COVID-19 pandemic has escalated the occurrence of hypoxia including thrombotic stroke worldwide, for which nitric oxide (NO) therapy seems very promising and translatable. Therefore, various modes/routes of NO-delivery are now being tested in different clinical trials for safer, faster, and more effective interventions against ischemic insults. Intravenous (IV) infusion of S-Nitrosoglutathione (GSNO), the major endogenous molecular pool of NO, has been reported to protect against mechanical cerebral ischemia-reperfusion (IR); however, it has been never tested in any kind of “clinically” relevant thromboembolic stroke models with or without comorbidities and in combination with the thrombolytic reperfusion therapy. Moreover, “IV-effects” of higher dose of GSNO following IR-injury have been contradicted to augment stroke injury. Herein, we tested the hypothesis that nebulization of low-dose GSNO will not alter blood pressure (BP) and will mitigate stroke injury in diabetic mice via enhanced cerebral blood flow (CBF) and brain tissue oxygenation (PbtO2). GSNO-nebulization (200 μg/kgbwt) did not alter BP, but augmented the restoration of CBF, improved behavioral outcomes and reduced stroke injury. Moreover, GSNO-nebulization increased early reoxygenation of brain tissue/PbtO2 as measured at 6.5 h post-stroke following thrombolytic reperfusion, and enervated unwanted effects of late thrombolysis in diabetic stroke. We conclude that the GSNO-nebulization is safe and effective for enhancing collateral microvascular perfusion in the early hours following stroke. Hence, nebulized-GSNO therapy has the potential to be developed and translated into an affordable field therapy against ischemic events including strokes, particularly in developing countries with limited healthcare infrastructure.

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Monitoring of brain tissue oxygenation during aneurysm surgery: prediction of procedure-related ischemic events

Journal of Neurosurgery ◽

10.3171/jns.2003.98.3.0515 ◽

2003 ◽

Vol 98 (3) ◽

pp. 515-523 ◽

Cited By ~ 39

Author(s):

Andreas Jödicke ◽

Felix Hübner ◽

Dieter-Karsten Böker

Keyword(s):

Brain Tissue ◽

Tissue Oxygenation ◽

Arterial Occlusion ◽

Aneurysm Surgery ◽

Characteristic Analysis ◽

Anterior Circulation ◽

Brain Tissue Oxygenation ◽

Content Type ◽

Ischemic Events ◽

Fine Print

Object. The aim of this study was to evaluate the feasibility of monitoring brain tissue oxygenation (PO2) during aneurysm surgery for the detection of procedure-related ischemia. Methods. Between 1997 and 1998, PO2 was monitored prospectively in a cohort of 40 patients (42 recordings) during aneurysm surgery in the anterior circulation within the vascular territory of the aneurysm-bearing artery. The position of the probe used to measure oxygenation levels was verified on computerized tomography (CT) scanning on the 1st postoperative day. Because of the mislocation of one probe and the malfunction of another, data from only 38 patients (40 recordings) were suitable for analysis. Relative changes from baseline to absolute nadir values of intraoperative PO2 were correlated with simultaneously recorded somatosensory evoked potentials (SSEPs), and cardiovascular and ventilatory parameters. The frequency of ischemic events was evaluated with the aid of CT on the 1st postoperative day as a substitute parameter for intraoperative ischemia. Clinical outcome was evaluated 30 days postoperatively based on the Glasgow Outcome Scale. Except for three, all patients underwent surgery for treatment of a symptomatic aneurysm. Mean baseline PO2 was 23.9 mm Hg (range 2–67.2 mm Hg) before clip application. A relative decrease in PO2 (20% decrease in value compared with baseline) occurred in 12 patients and was a sensitive indicator for the risk of ischemia during temporary arterial occlusion, but was less predictive of nonocclusive ischemia (sensitivity 0.5; positive predictive value [PPV] 0.42; p > 0.05). Results of receiver operating characteristic analysis demonstrated a postclipping PO2 nadir of 15 mm Hg as a dichotomizing threshold for the prediction of ischemia. This threshold rendered an improved sensitivity (0.9) and PPV (0.56) for procedure-related ischemia (p = 0.0003). The results of utility analysis revealed this monitoring parameter to be clinically diagnostic. Only PO2 monitoring, and not SSEP at the tibial nerve, was predictive of ischemia within the anterior cerebral artery territory. Conclusions. Using 15 mm Hg as a dichotomizing threshold, intraoperative PO2 monitoring enables one to identify patients at risk for procedure-related ischemia during aneurysm surgery and surpasses SSEP monitoring. This newly defined threshold based on intraoperative PO2 monitoring provides a basis for studies on treatments for procedure-related ischemia during aneurysm surgery.

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Faculty Opinions recommendation of Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2082971.2577054 ◽

2010 ◽

Author(s):

Jonathan Rhodes

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Tissue ◽

Cerebral Perfusion Pressure ◽

Cerebral Perfusion ◽

Tissue Oxygenation ◽

Perfusion Pressure ◽

Brain Tissue Oxygenation ◽

Pressure Reactivity ◽

Cerebrovascular Pressure Reactivity

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Faculty Opinions recommendation of Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2082971.1671069 ◽

2010 ◽

Author(s):

Nicolas Bruder

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Tissue ◽

Cerebral Perfusion Pressure ◽

Cerebral Perfusion ◽

Tissue Oxygenation ◽

Perfusion Pressure ◽

Brain Tissue Oxygenation ◽

Pressure Reactivity ◽

Cerebrovascular Pressure Reactivity

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Protective effect of uridine 5'-triphosphate on brain tissue after cerebral ischemia-reperfusion injury in rats

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2010.00608 ◽

2010 ◽

Vol 30 (6) ◽

pp. 608-611

Author(s):

Mou-li TIAN ◽

Hai-jing SUN ◽

Xin GAO ◽

Hui-jie NING ◽

Xue-yin SHI

Keyword(s):

Cerebral Ischemia ◽

Protective Effect ◽

Reperfusion Injury ◽

Brain Tissue ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury

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Optimal antithrombotic regimen in patients with cardiogenic shock on ImpellaTM mechanical support: less might be more

European Heart Journal ◽

10.1093/ehjci/ehaa946.1843 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

C Vandenbriele ◽

L Dannenberg ◽

M Monteagudo-Vela ◽

T Balthazar ◽

D Metzen ◽

...

Keyword(s):

Cardiogenic Shock ◽

Low Dose ◽

Cox Regression ◽

Mechanical Support ◽

Bleeding Events ◽

Heparin Group ◽

Cox Regression Analysis ◽

Dose Heparin ◽

Low Dose Heparin ◽

Ischemic Events

Abstract Background Bleeding and ischemic complications are the main cause of morbidity and mortality in critically ill cardiogenic shock patients, supported by short-term percutaneous mechanical circulatory support (pMCS) devices. Hence, finding the optimal antithrombotic regimen is challenging. Bleeding not only occurs because of heparin and antiplatelet therapy (both required in the prevention of pump and acute stent thrombosis) but also because of device- and disease related coagulopathy. To prevent clotting-related device failure, most centers target full therapeutic heparin anticoagulation levels in left ventricular (LV) Impella™ supported patients in analogy with Veno-Arterial Extracorporeal Membrane Oxygenation. We aimed to investigate the safety (related to bleeding and thrombotic complications) of targeting low-dose versus therapeutic heparin levels in left Impella™-supported cardiogenic shock patients on dual antiplatelet therapy (DAPT). Methods In this hypothesis generating pilot study, we investigated 114 patients supported for at least two days by LV Impella™ mechanical support due to cardiogenic shock at three tertiary ICUs, highly specialized in mechanical support. Low-dose heparin (aPTT 40–60s or anti-Xa 0.2–0.3) was compared to standard of care (aPTT 60–80s or anti-Xa 0.3–0.5). Major adverse cardio- and cerebrovascular events (MACCE; composite of death, myocardial infarction, stroke/transient ischemic attack) and BARC bleeding (bleeding academic research consortium classification) during 30 day follow-up were assessed. Inverse probability of treatment weighting (IPTW) analysis was calculated with age, gender, arterial hypertension, diabetes mellitus, smoking, chronic kidney disease, previous stroke, previous myocardial infarction, previous coronary arterial bypass grafting, hypercholesterolemia and DAPT as matching variables. COX regression analysis was conducted to test for robustness. Results IPTW revealed 52 patients in the low-dose heparin group and 62 patients in the therapeutic group. Mean age of patients after IPTW was 62±16 years in the intermediate and 62±13 years in the therapeutic group (p=0.99). 25% and 42.2% were male (p=0.92). Overall bleeding events and major (BARC3b) bleeding events were higher in the therapeutic heparin group (overall bleeding: Hazard ratio [HR]=2.58, 95% confidence interval [CI] 1.2–5.5; p=0.015; BARC 3b: HR=4.4, 95% CI 1.4–13.6, p=0.009). Minor bleeding (BARC3a) as well as MACCE and its single components (ischemic events) did not differ between both groups. These findings were robust in the COX regression analysis. Conclusion In this pilot analysis, low-dose heparin in 114 LV Impella™ cardiogenic shock patients was associated with less bleeding without increased ischemic events, adjusted for DAPT. Reducing the target heparin levels in critically ill patients supported by LV Impella™ might improve the outcome of this precarious group. These findings need to be validated in randomized clinical trials. Funding Acknowledgement Type of funding source: None

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Effect of atorvastatin on the angiogenic responsiveness of coronary endothelial cells in normal and streptozotocin (STZ) induced diabetic rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2013-0391 ◽

2014 ◽

Vol 92 (4) ◽

pp. 338-349 ◽

Cited By ~ 7

Author(s):

Kiranj K. Chaudagar ◽

Anita A. Mehta

Keyword(s):

Endothelial Cells ◽

Low Dose ◽

Ischemia Reperfusion ◽

Late Phase ◽

Diabetic Rats ◽

Lipid Lowering ◽

Diabetic Rat ◽

High Dose ◽

Atorvastatin Treatment ◽

Coronary Endothelial Cells

Atorvastatin, a lipid lowering agent, possesses various pleiotropic vasculoprotective effects, but its role in coronary angiogenesis is still controversial. Our objective was to study the effects of atorvastatin on the angiogenic responsiveness of coronary endothelial cells (cEC) from normal and diabetic rats. Male Wistar rats were distributed among 9 groups; (i) normal rats, (ii) 30 day diabetic rats, (iii) 60 day diabetic rats, (iv) normal rats administered a low dose of atorvastatin (1 mg/kg body mass, per oral (p.o.), for 15 days); (v) 30 day diabetic rats administered a low dose of atorvastatin; (vi) 60 day diabetic rats administered a low dose of atorvastatin; (vii) normal rats administered a high dose of atorvastatin (5 mg/kg, p.o., for 15 days); (viii) 30 day diabetic rats administered a high dose of atorvastatin; (ix) 60 day diabetic rats administered a high dose of atorvastatin. Each group was further divided into 2 subgroups, (i) sham ischemia–reperfusion and (ii) rats hearts that underwent ischemia–reperfusion. Angiogenic responsiveness the and nitric oxide (NO) releasing properties of the subgroups of cECs were studied using a chorioallantoic membrane assay and the Griess method, respectively. Atorvastatin treatment significantly increased VEGF-induced angiogenic responsiveness and the NO-releasing properties of cECs from all of the subgroups, compared with their respective non-treated subgroups except for the late-phase diabetic rat hearts that underwent ischemia–reperfusion, and the high dose of atorvastatin treatment groups. These effects of atorvastatin were significantly inhibited by pretreatment of cECs with l-NAME, wortmannin, and chelerythrine. Thus, treatment with a low dose of atorvastatin improves the angiogenic responsiveness of the cECs from normal and diabetic rats, in the presence of VEGF, via activation of eNOS–NO release.

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