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Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase.

ABSTRACT: BACKGROUND:The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). METHODS:Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR-/-) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. RESULTS:GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P=0.045). CONCLUSIONS:CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

SUBMITTER: Hayashida K

PROVIDER: S-EPMC6361681 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase.

Hayashida Kei K Bagchi Aranya A Miyazaki Yusuke Y Hirai Shuichi S Seth Divya D Silverman Michael G MG Rezoagli Emanuele E Marutani Eizo E Mori Naohiro N Magliocca Aurora A Liu Xiaowen X Berra Lorenzo L Hindle Allyson G AG Donnino Michael W MW Malhotra Rajeev R Bradley Matthews O MO Stamler Jonathan S JS Ichinose Fumito F

Circulation 20190201 6

<h4>Background</h4>The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR).<h4>Methods</h4>Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR<sup>-/-</sup>) mice were subjected to potassium chloride-induced CA ...[more]

PMID: 30586713

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Project description:The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and prevention of reperfusion injury, as this holds the promise of restoring life to many patients for whom our current therapies fail.

Project description:Background and objectivesPatients on maintenance dialysis with in-hospital cardiac arrest have been reported to have worse outcomes relative to those not on dialysis; however, it is unknown if poor outcomes are related to the quality of resuscitation. Using the Get With The Guidelines-Resuscitation (GWTG-R) registry, we examined processes of care and outcomes of in-hospital cardiac arrest for patients on maintenance dialysis compared with nondialysis patients.Design, setting, participants, & measurementsWe used GWTG-R data linked to Centers for Medicare and Medicaid data to identify patients with ESKD receiving maintenance dialysis from 2000 to 2012. We then case-matched adult patients on maintenance dialysis to nondialysis patients in a 1:3 ratio on the basis of age, sex, race, hospital, and year of arrest. Logistic regression models with generalized estimating equations were used to assess the association of in-hospital cardiac arrest and outcomes by dialysis status.ResultsAfter matching, there were a total of 31,144 GWTG-R patients from 372 sites, of which 8498 (27%) were on maintenance dialysis. Patients on maintenance dialysis were less likely to have a shockable initial rhythm (20% versus 21%) and less likely to be within the intensive care unit at the time of arrest (46% versus 47%) compared with nondialysis patients; they also had lower composite scores for resuscitation quality (89% versus 90%) and were less likely to have defibrillation within 2 minutes (54% versus 58%). After adjustment, patients on maintenance dialysis had similar adjusted odds of survival to discharge (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 0.97 to 1.13), better acute survival (OR, 1.33; 95% CI, 1.26 to 1.40), and were more likely to have favorable neurologic status (OR, 1.12; 95% CI, 1.04 to 1.22) compared with nondialysis patients.ConclusionsAlthough there appears to be opportunities to improve the quality of in-hospital cardiac arrest care for among those on maintenance dialysis, survival to discharge was similar for these patients compared with nondialysis patients.

Project description:ObjectiveEthnic differences in sudden cardiac arrest resuscitation have not been fully explored and studies have yielded inconsistent results. We examined the association of ethnicity with factors affecting sudden cardiac arrest outcomes.MethodsRetrospective cohort study of 3551 white, 440 black and 297 Asian sudden cardiac arrest cases in Seattle and King County, Washington, USA.ResultsCompared with whites, blacks and Asians were younger, had lower socioeconomic status and were more likely to have diabetes, hypertension and end-stage renal disease (all p<0.001). Blacks and Asians were less likely to have a witnessed arrest (whites 57.6%, blacks 52.1%, Asians 46.1%, p<0.001) or receive bystander cardiopulmonary resuscitation (whites 50.9%, blacks 41.4%, Asians 47.1%, p=0.001), but had shorter average emergency medical services response time (mean in minutes: whites 5.18, blacks 4.75, Asians 4.85, p<0.001). Compared with whites, blacks were more likely to be found in pulseless electrical activity (blacks 20.9% vs whites 16.6%, p<0.001), and Asians were more likely to be found in asystole (Asians 41.1% vs whites 30.0%, p<0.001). One of the strongest predictors of resuscitation outcomes was initial cardiac rhythm with 25% of ventricular fibrillation, 4% of patients with pulseless electrical activity and 1% of patients with asystole surviving to hospital discharge (adjusted OR of resuscitation in pulseless electrical activity compared with ventricular fibrillation: 0.30, 95% CI 0.24 to 0.34, p<0.001, adjusted OR of resuscitation in asystole relative to ventricular fibrillation 0.21, 95% CI 0.17 to 0.26, p<0.001). Survival to hospital discharge was similar across all three ethnicities.ConclusionsWhile there were differences in some prognostic characteristics between blacks, whites and Asians, we did not detect a significant difference in survival following sudden cardiac arrest between the three ethnic groups. There was, however, an ethnic difference in presenting rhythm, with pulseless electrical activity more prevalent in blacks and asystole more prevalent in Asians.

Project description:BackgroundTraumatic arrests have historically had poor survival rates. Identifying salvageable patients and ideal management is challenging. We aimed to (1) describe the management and outcomes of prehospital traumatic arrests; (2) determine regional variation in survival; and (3) identify Advanced Life Support (ALS) procedures associated with survival.MethodsThis was a secondary analysis of cases from the Resuscitation Outcomes Consortium Epistry-Trauma and Prospective Observational Prehospital and Hospital Registry for Trauma (PROPHET) registries. Patients were included if they had a blunt or penetrating injury and received cardiopulmonary resuscitation. Logistic regression analyses were used to determine the association between ALS procedures and survival.ResultsWe included 2,300 patients who were predominately young (Epistry mean [SD], 39 [20] years; PROPHET mean [SD], 40 [19] years), males (79%), injured by blunt trauma (Epistry, 68%; PROPHET, 67%), and treated by ALS paramedics (Epistry, 93%; PROPHET, 98%). A total of 145 patients (6.3%) survived to hospital discharge. More patients with blunt (Epistry, 8.3%; PROPHET, 6.5%) vs. penetrating injuries (Epistry, 4.6%; PROPHET, 2.7%) survived. Most survivors (81%) had vitals on emergency medical services arrival. Rates of survival varied significantly between the 12 study sites (p = 0.048) in the Epistry but not PROPHET (p = 0.14) registries.Patients in the PROPHET registry who received a supraglottic airway insertion or intubation experienced decreased odds of survival (adjusted OR, 0.27; 95% confidence interval, 0.08-0.93; and 0.37; 95% confidence interval, 0.17-0.78, respectively) compared to those receiving bag-mask ventilation. No other procedures were associated with survival.ConclusionsSurvival from traumatic arrest may be higher than expected, particularly in blunt trauma and patients with vitals on emergency medical services arrival. Although limited by confounding and statistical power, no ALS procedures were associated with increased odds of survival.Level of evidencePrognostic study, level IV.

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Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase.

Publications

Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase.

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