Nitrite therapy is neuroprotective and safe in cardiac arrest survivors.
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ABSTRACT:
SUBMITTER: Dezfulian C
PROVIDER: S-EPMC4337393 | biostudies-literature | 2012 May
REPOSITORIES: biostudies-literature
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Nitrite therapy is neuroprotective and safe in cardiac arrest survivors.
Dezfulian Cameron C Alekseyenko Aleksey A Dave Kunjan R KR Raval Ami P AP Do Rose R Kim Francis F Perez-Pinzon Miguel A MA
Nitric oxide : biology and chemistry 20120330 4
Cardiac arrest results in significant mortality after initial resuscitation due in most cases to ischemia-reperfusion induced brain injury and to a lesser degree myocardial dysfunction. Nitrite has previously been shown to protect against reperfusion injury in animal models of focal cerebral and heart ischemia. Nitrite therapy after murine cardiac arrest improved 22 h survival through improvements in myocardial contractility. These improvements accompanied transient mitochondrial inhibition whic ...[more]
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Project description:BACKGROUND:Patients resuscitated from cardiac arrest have brain and cardiac injury. Recent animal studies suggest that the administration of sodium nitrite after resuscitation from 12min of asystole limits acute cardiac dysfunction and improves survival and neurologic outcomes. It has been hypothesized that low doses of IV sodium nitrite given during resuscitation of out of hospital cardiac arrest (OHCA) will improve survival. Low doses of sodium nitrite (e.g., 9.6mg of sodium nitrite) are safe in healthy individuals, however the effect of nitrite on blood pressure in resuscitated cardiac arrest patients is unknown. METHODS:We performed a single-center, pilot trial of low dose sodium nitrite (1 or 9.6mg dose) vs. placebo in hospitalized out-of-hospital cardiac arrest patient to determine whether nitrite administration reduced blood pressure and whether whole blood nitrite levels increased in response to nitrite administration. RESULTS:This is the first reported study of sodium nitrite in cardiac arrest patients. Infusion of low doses of sodium nitrite in comatose survivors of OHCA (n=7) compared to placebo (n=4) had no significant effects on heart rate within 30min after infusion (70±20 vs. 78±3 beats per minute, p=0.18), systolic blood pressure (103±20 vs 108±15mmHg, p=0.3), or methemoglobin levels (0.92±0.33 vs. 0.70±0.26, p=0.45). Serum nitrite levels of 2-4?M were achieved within 15min of a 9.6mg nitrite infusion. CONCLUSIONS:Low dose sodium nitrite does not cause significant hemodynamic effect in patients with OHCA, which suggests that nitrite can be delivered safely in this critically ill patient population. Higher doses of sodium nitrite are necessary in order to achieve target serum level of 10?M.
| S-EPMC5774860 | biostudies-literature
Project description:Nitrite acts as an ischemic reservoir of nitric oxide (NO) and a potent S-nitrosating agent which reduced histologic brain injury after rat asphyxial cardiac arrest (ACA). The mechanism(s) of nitrite-mediated neuroprotection remain to be defined. We hypothesized that nitrite-mediated brain mitochondrial S-nitrosation accounts for neuroprotection by reducing reperfusion reactive oxygen species (ROS) generation. Nitrite (4 ?mol) or placebo was infused IV after normothermic (37°C) ACA in randomized, blinded fashion with evaluation of neurologic function, survival, brain mitochondrial function, and ROS. Blood and CSF nitrite were quantified using reductive chemiluminescence and S-nitrosation by biotin switch. Direct neuroprotection was verified in vitro after 1 and 4 h neuronal oxygen glucose deprivation measuring neuronal death with inhibition studies to examine mechanism. Mitochondrial ROS generation was quantified by live neuronal imaging using mitoSOX. Nitrite significantly reduced neurologic disability after ACA. ROS generation was reduced in brain mitochondria from nitrite- versus placebo-treated rats after ACA with congruent preservation of brain ascorbate and reduction of ROS in brain sections using immuno-spin trapping. ATP generation was maintained with nitrite up to 24 h after ACA. Nitrite rapidly entered CSF and increased brain mitochondrial S-nitrosation. Nitrite reduced in vitro mitochondrial superoxide generation and improved survival of neurons after oxygen glucose deprivation. Protection was maintained with inhibition of soluble guanylate cyclase but lost with NO scavenging and ultraviolet irradiation. Nitrite therapy results in direct neuroprotection from ACA mediated by reductions in brain mitochondrial ROS in association with protein S-nitrosation. Neuroprotection is dependent on NO and S-nitrosothiol generation, not soluble guanylate cyclase.
| S-EPMC5247267 | biostudies-literature
Project description:IntroductionBesides 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.MethodsAfter return of spontaneous circulation (ROSC) of 5 min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8 μM, 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.ResultsIn 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 μM at 11 min post-resuscitation time (1 min after dose completion) in the VF nitrite group vs. 0.94 ± 0.58 μM in the VF placebo group (p < 0.001). There was a significant difference between the treatment and placebo groups in nitrite levels in blood between 7.5 and 15 min after CPR start and between groups with respect to nitrite levels in CSF, brain, heart and liver. In a second series (n = 25 including 5 shams), 19 out of 20 animals survived until day 8. However, NDS, FCT and brain histology did not show any statistically significant difference between groups.ConclusionsNitrite, administered early after ROSC from VF, was shown to cross the blood brain barrier after a 5 min VF cardiac arrest. We characterized the PK of intravenous nitrite administration after VF and were able to demonstrate nitrite safety in this feasibility study.
| S-EPMC6957908 | biostudies-literature
Project description:PurposeTo assess outcomes and predictors of long-term myocardial dysfunction after cardiac arrest (CA) of cardiac origin.MethodsWe retrospectively included consecutive, single-center, prospective-registry patients who survived to hospital discharge for adult out-of-hospital and in-hospital CA of cardiac origin in 2005-2019. The primary objective was to collect the 1-year New York Heart Association Functional Class (NYHA-FC) and major adverse cardiovascular events (MACE).ResultsOf 135 patients, 94 (72%) had their NYHA-FC determined after 1 year, including 75 (75/94, 80%) who were I, 17 (17/94, 18%) II, 2 (2/94, 2%) III, and none IV. The echocardiographic left ventricular ejection fraction was abnormal in 87/130 (67%) patients on day 1, 52/123 (42%) at hospital discharge, and 17/52 (33%) at 6 months. During the median follow-up of 796 [283-1975] days, 38/119 (32%) patients experienced a MACE. These events were predominantly related to acute heart failure (13/38) or ischemic cardiovascular events (16/38), with acute coronary syndrome being the most prevalent among them (8/16). Pre-CA cardiovascular disease was a risk factor for 1-year NYHA-FC > I (P = 0.01), absence of bystander cardiopulmonary resuscitation was significantly associated with NYHA-FC > I at 1 year.ConclusionMost patients had no heart-failure symptoms a year after adult out-of hospital or in-hospital CA of cardiac origin, and absence of bystander cardiopulmonary resuscitation was the only treatment component significantly associated with NYHA-FC > I at 1 year. Nearly a third experienced MACE and the most common types of MACE were ischemic cardiovascular events and acute heart failure. Early left ventricular dysfunction recovered within 6 months in half the patients with available values.
| S-EPMC10582774 | biostudies-literature
Project description:Background:Cognitive deficits may detract from quality of life after cardiac arrest. Their pattern and prevalence are not well documented. We used the Computer Assessment of Mild Cognitive Impairment (CAMCI), the Montreal Cognitive Assessment (MOCA) and the 41 Cent Test (41CT) to assess cognitive impairment in cardiac arrest survivors and examine the exams' diagnostic accuracy. We hypothesized that the scores of these exams would indicate the presence of cognitive impairment in arrest survivors, that the overall scores on the three study assessments would correlate with one another, and that the 41CT, MOCA, and executive function element of the CAMCI would vary independently from other non-executive CAMCI components, reflecting executive function impairment after cardiac arrest.Methods:Four researchers administered the CAMCI, MOCA, and/or the 41CT to cardiac arrest survivors after discharge from the intensive care unit between 2010 and 2015. Physicians screened patients with the Mini-Mental State Exam to determine when this cognitive testing was feasible, generally when the patient was able to score 20-25 points on the MMSE. We performed pairwise correlations between the different subscales' and tests' scores.Results:One hundred and fourteen participants completed the CAMCI, of which 38 (33.3%) participants additionally completed the MOCA and 41CT. The median (IQR) percentile score for CAMCI for all 114 participants was 33.5 (18.3, 49.8), which corresponds to moderately low risk of impairment. The median (IQR) for the MOCA was 22.0 (19, 24.8) out of a possible 30, which is considered indicative of abnormal cognitive function, and for the 41CT was 6 (5, 7) out of a possible 7 points when all 38 participants were included. MOCA correlated strongly with the overall CAMCI score (r=0.71); the CAMCI correlated moderately strongly with the 41CT (r=0.62) and the MOCA and 41CT were moderately strongly correlated with each other (r=0.56). When all 114 CAMCI scores were considered, the Executive Accuracy subscale was strongly correlated with the overall CAMCI score (r=0.81).Conclusion:The CAMCI detects cognitive impairment after cardiac arrest. The MOCA correlates strongly with the overall CAMCI and the executive function subscale of the CAMCI. The 41CT as appears less effective than the MOCA in detecting cognitive deficits.
| S-EPMC7702001 | biostudies-literature
Project description:OBJECTIVE:Cardiac catheterisation and implantable cardioverter defibrillator (ICD) insertion are increasingly common following cardiac arrest survival. However, much of the evidence for the benefit is observational, leaving open the possibility that biased patient selection confounds the association between these invasive procedures and improved outcome. We evaluated the likelihood of selection bias in the association between cardiac catheterisation or ICD placement and outcome by measuring long-term outcomes overall and in a cause-specific approach that separated cardiac mortality from non-cardiac mortality. METHODS:We performed a multivariable survival analysis of a clinical cohort between 2005 and 2013, with follow-up through 2015. We included patients who had out-of-hospital or inhospital cardiac arrest that survived to discharge, and evaluated the association between cardiac catheterisation or ICD insertion and all-cause, cardiovascular and non-cardiovascular mortality. RESULTS:Among 678 patients who survived cardiac arrest, we observed lower all-cause mortality among patients who underwent cardiac catheterisation (adjusted HR (aHR) 0.40; P<0.01) or ICD insertion (aHR 0.55; P<0.01). However, cause-specific analysis showed that the benefits of cardiac catheterisation and ICD insertion resulted from reduced non-cardiac causes of death (cardiac catheterisation: aHR 0.24, P<0.01; ICD: aHR 0.58, P<0.01), while reduced cardiac cause of death was not associated with cardiac catheterisation (cardiac catheterisation: aHR 0.75, P=0.33). CONCLUSIONS:There is evidence of selection bias in the secondary prevention survival benefit attributable to cardiac catheterisation for patients who survive cardiac arrest. Observational studies that consider its effects on all-cause mortality likely overestimate the potential benefit of this procedure.
| S-EPMC6063756 | biostudies-literature
Project description:BackgroundAmong cardiac arrest survivors, about half remain comatose 72 h following return of spontaneous circulation (ROSC). Prognostication of poor neurological outcome in this population may result in withdrawal of life-sustaining therapy and death. The objective of this article is to provide recommendations on the reliability of select clinical predictors that serve as the basis of neuroprognostication and provide guidance to clinicians counseling surrogates of comatose cardiac arrest survivors.MethodsA narrative systematic review was completed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Candidate predictors, which included clinical variables and prediction models, were selected based on clinical relevance and the presence of an appropriate body of evidence. The Population, Intervention, Comparator, Outcome, Timing, Setting (PICOTS) question was framed as follows: "When counseling surrogates of comatose adult survivors of cardiac arrest, should [predictor, with time of assessment if appropriate] be considered a reliable predictor of poor functional outcome assessed at 3 months or later?" Additional full-text screening criteria were used to exclude small and lower-quality studies. Following construction of the evidence profile and summary of findings, recommendations were based on four GRADE criteria: quality of evidence, balance of desirable and undesirable consequences, values and preferences, and resource use. In addition, good practice recommendations addressed essential principles of neuroprognostication that could not be framed in PICOTS format.ResultsEleven candidate clinical variables and three prediction models were selected based on clinical relevance and the presence of an appropriate body of literature. A total of 72 articles met our eligibility criteria to guide recommendations. Good practice recommendations include waiting 72 h following ROSC/rewarming prior to neuroprognostication, avoiding sedation or other confounders, the use of multimodal assessment, and an extended period of observation for awakening in patients with an indeterminate prognosis, if consistent with goals of care. The bilateral absence of pupillary light response > 72 h from ROSC and the bilateral absence of N20 response on somatosensory evoked potential testing were identified as reliable predictors. Computed tomography or magnetic resonance imaging of the brain > 48 h from ROSC and electroencephalography > 72 h from ROSC were identified as moderately reliable predictors.ConclusionsThese guidelines provide recommendations on the reliability of predictors of poor outcome in the context of counseling surrogates of comatose survivors of cardiac arrest and suggest broad principles of neuroprognostication. Few predictors were considered reliable or moderately reliable based on the available body of evidence.
| S-EPMC10241762 | biostudies-literature
Project description:Little is known about the long-term outcomes in elderly survivors of in-hospital cardiac arrest. We determined rates of long-term survival and readmission among survivors of in-hospital cardiac arrest and examined whether these outcomes differed according to demographic characteristics and neurologic status at discharge.We linked data from a national registry of inpatient cardiac arrests with Medicare files and identified 6972 adults, 65 years of age or older, who were discharged from the hospital after surviving an in-hospital cardiac arrest between 2000 and 2008. Predictors of 1-year survival and of readmission to the hospital were examined.One year after hospital discharge, 58.5% of the patients were alive, and 34.4% had not been readmitted to the hospital. The risk-adjusted rate of 1-year survival was lower among older patients than among younger patients (63.7%, 58.6%, and 49.7% among patients 65 to 74, 75 to 84, and ?85 years of age, respectively; P<0.001), among men than among women (58.6% vs. 60.9%, P=0.03), and among black patients than among white patients (52.5% vs. 60.4%, P=0.001). The risk-adjusted rate of 1-year survival was 72.8% among patients with mild or no neurologic disability at discharge, as compared with 61.1% among patients with moderate neurologic disability, 42.2% among those with severe neurologic disability, and 10.2% among those in a coma or vegetative state (P<0.001 for all comparisons). Moreover, 1-year readmission rates were higher among patients who were black, those who were women, and those who had substantial neurologic disability (P<0.05 for all comparisons). These differences in survival and readmission rates persisted at 2 years. At 3 years, the rate of survival among survivors of in-hospital cardiac arrest was similar to that of patients who had been hospitalized with heart failure and were discharged alive (43.5% and 44.9%, respectively; risk ratio, 0.98; 95% confidence interval, 0.95 to 1.02; P=0.35).Among elderly survivors of in-hospital cardiac arrest, nearly 60% were alive at 1 year, and the rate of 3-year survival was similar to that among patients with heart failure. Survival and readmission rates differed according to the demographic characteristics of the patients and neurologic status at discharge. (Funded by the American Heart Association and the National Heart, Lung, and Blood Institute.).
| S-EPMC3652256 | biostudies-literature
Project description:BackgroundMild therapeutic hypothermia is recommended for comatose patients resuscitated from cardiac arrest. However, the prevalence of delirium and its associated risk factors have not been assessed in survivors of cardiac arrest treated with therapeutic hypothermia.ObjectiveTo determine the prevalence of and risk factors for delirium among survivors of cardiac arrest who were treated with therapeutic hypothermia.MethodsA retrospective observational study of patients treated with therapeutic hypothermia after cardiac arrest from 2007 through 2014. Baseline demographic data and daily delirium assessments throughout the intensive care unit stay were obtained. The association between duration of delirium and various risk factors was assessed.ResultsOf 251 patients, 107 (43%) awoke from coma. Among the 107 survivors, all had at least 1 day of delirium during their intensive care unit stay. Median number of days of delirium was 4.0 (interquartile range, 2.0-7.5). Multivariable analysis revealed that age (odds ratio, 1.72; 95% CI, 1.0-2.95; P = .05), time from cardiopulmonary resuscitation to return of spontaneous circulation (odds ratio 1.52; 95% CI, 1.11-2.07; P = .01), and total dose of prewarming propofol (odds ratio, 0.02; 95% CI, 0.00-0.48; P = .02) were associated with duration of delirium.ConclusionsAll survivors of cardiac arrest treated with mild therapeutic hypothermia had at least 1 day of delirium. Age and time from initiation of cardiopulmonary resuscitation to return of spontaneous circulation were associated with prolonged delirium, whereas exposure to propofol was protective against delirium. These findings are limited to this unique cohort and may not be generalizable to different populations.
| S-EPMC5240926 | biostudies-literature
Project description:Long-term outcome studies after pediatric cardiac arrest (CA) are few. They require a CA registry and dedicated outcome teams. Learning about the long-term outcomes is very important for developing prognostication guidelines, improving post-cardiac care, counseling caregivers about the future of their child, and creating opportunities for therapeutic intervention studies to improve outcomes. Few PICUs worldwide provide a multidisciplinary follow-up program as routine practice at an outpatient clinic with standardized measurements, using validated instruments including neuropsychological assessments by psychologists. The primary goal of such a follow-up program should be to provide excellent care to children and their caregivers, thereby resulting in a high attendance. Pediatric psychologists, neurologists and pediatricians/pediatric intensivists should ideally be involved to screen for delayed development and psychosocial problems and offer appropriate care at the same time. Preferably, outcomes should consist of evaluation of morbidity (physical and neuropsychological), functional health and Health Related Quality Of Life (QoL) of the patient and their caregivers.
| S-EPMC10847941 | biostudies-literature