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Nitrite pharmacokinetics, safety and efficacy after experimental ventricular fibrillation cardiac arrest.

ABSTRACT: INTRODUCTION:Besides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics (PK). Therefore, to define the optimal use of this agent, studies on the PK of nitrite in experimental ventricular fibrillation (VF) are needed. We tested the hypothesis that nitrite administered after resuscitation from VF is detectable in cerebrospinal fluid (CSF), brain and other organ tissues, produces no adverse hemodynamic effects, and improves neurologic outcome in rats. METHODS:After return of spontaneous circulation (ROSC) of 5?min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8??M, 0.13?mg/kg) or placebo as a 5?min infusion beginning at 5?min after CA. Additionally, sham groups with and without nitrite treatment were also studied. Whole blood nitrite levels were serially measured. After 15?min, CSF, brain, heart and liver tissue were collected. In a second series, using a randomized and blinded treatment protocol, rats were treated with nitrite or placebo after arrest. Neurological deficit scoring (NDS) was performed daily and eight days after resuscitation, fear conditioning testing (FCT) and brain histology were assessed. RESULTS:In an initial series of experiments, rats (n?=?21) were randomized to 4 groups: VF-CPR and nitrite therapy (n?=?6), VF-CPR and placebo therapy (n?=?5), sham (n?=?5), or sham plus nitrite therapy (n?=?5). Whole blood nitrite levels increased during drug infusion to 57.14?±?10.82??M?at 11?min post-resuscitation time (1?min after dose completion) in the VF nitrite group vs. 0.94?±?0.58??M in the VF placebo group (p?

SUBMITTER: Uray T

PROVIDER: S-EPMC6957908 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Nitrite pharmacokinetics, safety and efficacy after experimental ventricular fibrillation cardiac arrest.

Uray Thomas T Empey Philip E PE Drabek Tomas T Stezoski Jason P JP Janesko-Feldman Keri K Jackson Travis T Garman Robert H RH Kim Francis F Kochanek Patrick M PM Dezfulian Cameron C

Nitric oxide : biology and chemistry 20190914

<h4>Introduction</h4>Besides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics ( ...[more]

PMID: 31526855

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Project description:BACKGROUND:Quantitative measures of the ventricular fibrillation (VF) ECG waveform can assess myocardial physiology and predict cardiac arrest outcomes, making these measures a candidate to help guide resuscitation. Chest compressions are typically paused for waveform measure calculation because compressions cause ECG artifact. However, such pauses contradict resuscitation guideline recommendations to minimize cardiopulmonary resuscitation interruptions. We evaluated a comprehensive group of VF measures with and without ongoing compressions to determine their performance under both conditions for predicting functionally-intact survival, the study's primary outcome. METHODS:Five-second VF ECG segments were collected with and without chest compressions before 2755 defibrillation shocks from 1151 out-of-hospital cardiac arrest patients. Twenty-four individual measures and 3 combination measures were implemented. Measures were optimized to predict functionally-intact survival (Cerebral Performance Category score ?2) using 460 training cases, and their performance evaluated using 691 independent test cases. RESULTS:Measures predicted functionally-intact survival on test data with an area under the receiver operating characteristic curve ranging from 0.56 to 0.75 (median, 0.73) without chest compressions and from 0.53 to 0.75 (median, 0.69) with compressions ( P<0.001 for difference). Of all measures evaluated, the support vector machine model ranked highest both without chest compressions (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.73-0.78) and with compressions (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.72-0.78; P=0.75 for difference). CONCLUSIONS:VF waveform measures predict functionally-intact survival when calculated during chest compressions, but prognostic performance is generally reduced compared with compression-free analysis. However, support vector machine models exhibited similar performance with and without compressions while also achieving the highest area under the receiver operating characteristic curve. Such machine learning models may, therefore, offer means to guide resuscitation during uninterrupted cardiopulmonary resuscitation.

Project description:IntroductionDespite decades of improved strategy in conventional cardiopulmonary resuscitation (CCPR), survival rates of favorable neurological outcome after cardiac arrest (CA) remains poor. It is indicated that the survival rate of successful resuscitation of extracorporeal membrane oxygenation (ECMO) is superior to that of CCPR. But the effect of ECMO in heart is unclear. We aimed to investigate whether ECMO produces cardiac protection by ameliorating post-ischemia reperfusion myocardial injury and myocardial apoptosis.MethodsAfter undergoing 8-min untreated ventricle fibrillation (VF) and 6-min basic life support, 20 male pigs were ultimately used in this study and randomly divided into two groups: CCPR group (n = 10) and extracorporeal CPR (ECPR) group (n = 10). Hemodynamics and blood samples were obtained at baseline and 1, 2, 4, and 6 h during resuscitation. The successfully resuscitated pigs were sacrificed at 6 h after return of spontaneous circulation (ROSC), and the hearts were removed and analyzed under electron microscopy, and immunohistochemistry, quantitative real-time polymerase chain reaction, and immunofluorescence staining assay were performed to evaluate myocardial injury and myocardial apoptosis.ResultsThere were no significant differences at basic hemodynamic status between the two groups. The survival rate of ECPR was significantly higher than CCPR group (10/10 [100%] vs. 4/10 [40%], P = 0.04). Compared to CCPR group, ECPR group exhibited a better outcome in hemodynamic function. Cardiac function was significantly impaired after ROSC in both groups, but left ventricular ejection fraction (LVEF) was significantly elevated in ECPR group than CCPR group. The expression of myocardial injury biomarkers (CK-MB, cTNI, H-FABP), endothelial injury biomarker (sP-selectin), and cardiac function biomarker (BNP) were remarkably increased after ROSC in both groups, but low levels in ECPR group than in CCPR group. Cardiomyocytes injury was attenuated in ECPR group under transmission electron microscopy (TEM). Typical apoptotic nuclei of cardiomyocytes were significantly reduced and oxidative damage were attenuated in ECPR group.ConclusionsDuring prolonged VF-induced CA, ECPR contributes to improving hemodynamics, attenuating myocardial ischemia-reperfusion injury, ameliorating myocardial ultra structure, improving cardiac function, and elevating survival rate by preventing oxidative damage, regulating energy metabolism, inhibiting cardiomyocyte apoptosis.

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Nitrite pharmacokinetics, safety and efficacy after experimental ventricular fibrillation cardiac arrest.

Publications

Nitrite pharmacokinetics, safety and efficacy after experimental ventricular fibrillation cardiac arrest.

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