Increased Survival Time With SS-31 After Prolonged Cardiac Arrest in Rats.
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ABSTRACT:
SUBMITTER: Zhang W
PROVIDER: S-EPMC6081272 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
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Increased Survival Time With SS-31 After Prolonged Cardiac Arrest in Rats.
Zhang Wei W Tam Jonathan J Shinozaki Koichiro K Yin Tai T Lampe Joshua W JW Becker Lance B LB Kim Junhwan J
Heart, lung & circulation 20180207 3
<h4>Background</h4>Cardiac arrest is one of the leading causes of death with a very high mortality rate. No therapeutic drug that can be administered during resuscitation has been reported. Mitochondrial dysfunction is believed to play an important role for the pathogenesis of cardiac arrest. SS-31, a tetra-peptide, has been shown to protect mitochondria from ischaemia/reperfusion injury. Therefore, we tested whether SS-31 improves rat survival after prolonged cardiac arrest.<h4>Methods</h4>Rats ...[more]
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Project description:BackgroundDespite the benefits of extracorporeal cardiopulmonary resuscitation (ECPR) in cohorts of selected patients with cardiac arrest (CA), extracorporeal membrane oxygenation (ECMO) includes an artificial oxygenation membrane and circuits that contact the circulating blood and induce excessive oxidative stress and inflammatory responses, resulting in coagulopathy and endothelial cell damage. There is currently no pharmacological treatment that has been proven to improve outcomes after CA/ECPR. We aimed to test the hypothesis that administration of hydrogen gas (H2) combined with ECPR could improve outcomes after CA/ECPR in rats.MethodsRats were subjected to 20 min of asphyxial CA and were resuscitated by ECPR. Mechanical ventilation (MV) was initiated at the beginning of ECPR. Animals were randomly assigned to the placebo or H2 gas treatment groups. The supplement gas was administered with O2 through the ECMO membrane and MV. Survival time, electroencephalography (EEG), brain functional status, and brain tissue oxygenation were measured. Changes in the plasma levels of syndecan-1 (a marker of endothelial damage), multiple cytokines, chemokines, and metabolites were also evaluated.ResultsThe survival rate at 4 h was 77.8% (7 out of 9) in the H2 group and 22.2% (2 out of 9) in the placebo group. The Kaplan-Meier analysis showed that H2 significantly improved the 4 h-survival endpoint (log-rank P = 0.025 vs. placebo). All animals treated with H2 regained EEG activity, whereas no recovery was observed in animals treated with placebo. H2 therapy markedly improved intra-resuscitation brain tissue oxygenation and prevented an increase in central venous pressure after ECPR. H2 attenuated an increase in syndecan-1 levels and enhanced an increase in interleukin-10, vascular endothelial growth factor, and leptin levels after ECPR. Metabolomics analysis identified significant changes at 2 h after CA/ECPR between the two groups, particularly in D-glutamine and D-glutamate metabolism.ConclusionsH2 therapy improved mortality in highly lethal CA rats rescued by ECPR and helped recover brain electrical activity. The underlying mechanism might be linked to protective effects against endothelial damage. Further studies are warranted to elucidate the mechanisms responsible for the beneficial effects of H2 on ischemia-reperfusion injury in critically ill patients who require ECMO support.
| S-EPMC8594155 | biostudies-literature
Project description:Neuroinflammation has been recognized as a major cause for neurocognitive diseases. Although the hippocampus has been considered an important region for cognitive dysfunction, the influence of hippocampal neuroinflammation on brain functional connectivity (FC) has been rarely studied. In this study, lipopolysaccharide (LPS) was used to induce systemic inflammation and neuroinflammation in the aged rat brain, while elamipretide (SS-31) was used for treatment. Systemic and hippocampal inflammation were determined using ELISA, while astrocyte responses during hippocampal neuroinflammation were determined by interleukin 1 beta (IL-1β)/tumor necrosis factor alpha (TNFα) double staining immunofluorescence. Oxidative stress was determined by reactive oxidative species (ROS), electron transport chain (ETC) complex, and superoxide dismutase (SOD). Short- (<7 days) and long-term (>30 days) learning and spatial working memory were tested by the Morris water maze (MWM). Resting-state functional magnetic resonance imaging (rs-fMRI) was used to analyze the brain FC by placing seed voxels on the left and right hippocampus. Compared with the vehicle group, rats with the LPS exposure showed an impaired MWM performance, higher oxidative stress, higher levels of inflammatory cytokines, and astrocyte activation in the hippocampus. The neuroimaging examination showed decreased FC on the right orbital cortex, right olfactory bulb, and left hippocampus on day 3, 7, and 31, respectively, after treatment. In contrast, rats with SS-31 treatment showed lower levels of inflammatory cytokines, less astrocyte activation in the hippocampus, and improved MWM performance. Neuroimaging examination showed increased FC on the left-parietal association cortex (L-PAC), left sensory cortex, and left motor cortex on day 7 with the right flocculonodular lobe on day 31 as compared with those without SS-31 treatment. Our study demonstrated that inhibiting neuroinflammation in the hippocampus not only reduces inflammatory responses in the hippocampus but also improves the brain FC in regions related to the hippocampus. Furthermore, early anti-inflammatory treatment with SS-31 has a long-lasting effect on reducing the impact of LPS-induced neuroinflammation.
| S-EPMC7956963 | biostudies-literature
Project description:During cardiac arrest (CA), myocardial perfusion is solely dependent on cardiopulmonary resuscitation (CPR) although closed-chest compressions only provide about 10-20% of normal myocardial perfusion. The study was conducted in a whole animal CPR model to determine whether CPR-generated oxygen delivery preserves or worsens mitochondrial function. Male Sprague-Dawley rats (400-450 g) were randomly divided into four groups: (1) BL (instrumentation only, no cardiac arrest), (2) CA(15) (15 min cardiac arrest without CPR), (3) CA(25) (25 min cardiac arrest without CPR) and (4) CPR (15 min cardiac arrest, followed by 10 min CPR). The differences between groups were evaluated by measuring mitochondrial respiration, electron transport chain (ETC) complex activities and mitochondrial ultrastructure by transmission electron microscopy (TEM). The CA(25) group had the greatest impairment of mitochondrial respiration and ETC complex activities (I-III). In contrast, the CPR group was not different from the CA(15) group regarding all measures of mitochondrial function. Complex I was more susceptible to ischemic injury than the other complexes and was the major determinant of mitochondrial dysfunction. Observations of mitochondrial ultrastructure by TEM were compatible with the biochemical results. The findings suggest that, despite low blood flow and oxygen delivery, CPR is able to preserve heart mitochondrial function and viability during ongoing global ischemia. Preservation of complex I activity and mitochondrial function during cardiac arrest may be an important mechanism underlying the beneficial effects of CPR which have been shown in clinical studies.
| S-EPMC2783672 | biostudies-literature
Project description:IMPORTANCE:Delay in administration of the first epinephrine dose is associated with decreased survival among adults after in-hospital, nonshockable cardiac arrest. Whether this association is true in the pediatric in-hospital cardiac arrest population remains unknown. OBJECTIVE:To determine whether time to first epinephrine dose is associated with outcomes in pediatric in-hospital cardiac arrest. DESIGN, SETTING AND PARTICIPANTS:We performed an analysis of data from the Get With the Guidelines-Resuscitation registry. We included US pediatric patients (age <18 years) with an in-hospital cardiac arrest and an initial nonshockable rhythm who received at least 1 dose of epinephrine. A total of 1558 patients (median age, 9 months [interquartile range [IQR], 13 days-5 years]) were included in the final cohort. EXPOSURE:Time to epinephrine, defined as time in minutes from recognition of loss of pulse to the first dose of epinephrine. MAIN OUTCOMES AND MEASURES:The primary outcome was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation (ROSC), survival at 24 hours, and neurological outcome. A favorable neurological outcome was defined as a score of 1 to 2 on the Pediatric Cerebral Performance Category scale. RESULTS:Among the 1558 patients, 487 (31.3%) survived to hospital discharge. The median time to first epinephrine dose was 1 minute (IQR, 0-4; range, 0-20; mean [SD], 2.6 [3.4] minutes). Longer time to epinephrine administration was associated with lower risk of survival to discharge in multivariable analysis (multivariable-adjusted risk ratio [RR] per minute delay, 0.95 [95% CI, 0.93-0.98]). Longer time to epinephrine administration was also associated with decreased risk of ROSC (multivariable-adjusted RR per minute delay, 0.97 [95% CI, 0.96-0.99]), decreased risk of survival at 24 hours (multivariable-adjusted RR per minute delay, 0.97 [95% CI, 0.95-0.99]), and decreased risk of survival with favorable neurological outcome (multivariable-adjusted RR per minute delay, 0.95 [95% CI, 0.91-0.99]). Patients with time to epinephrine administration of longer than 5 minutes (233/1558) compared with those with time to epinephrine of 5 minutes or less (1325/1558) had lower risk of in-hospital survival to discharge (21.0% [49/233] vs 33.1% [438/1325]; multivariable-adjusted RR, 0.75 [95% CI, 0.60-0.93]; P?=?.01). CONCLUSIONS AND RELEVANCE:Among children with in-hospital cardiac arrest with an initial nonshockable rhythm who received epinephrine, delay in administration of epinephrine was associated with decreased chance of survival to hospital discharge, ROSC, 24-hour survival, and survival to hospital discharge with a favorable neurological outcome.
| S-EPMC6191294 | biostudies-literature
Project description:Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer a glimpse of the protein interaction landscape of SS-31 and provide mechanistic insight relevant to SS-31 mitochondrial therapy.
| S-EPMC7334473 | biostudies-literature
Project description:Background The ambulance response time in out-of-hospital cardiac arrest (OHCA) has doubled over the past 30 years in Sweden. At the same time, the chances of surviving an OHCA have increased substantially. A correct understanding of the effect of ambulance response time on the outcome after OHCA is fundamental for further advancement in cardiac arrest care. Methods and Results We used data from the SRCR (Swedish Registry of Cardiopulmonary Resuscitation) to determine the effect of ambulance response time on 30-day survival after OHCA. We included 20 420 cases of OHCA occurring in Sweden between 2008 and 2017. Survival to 30 days was our primary outcome. Stratification and multiple logistic regression were used to control for confounding variables. In a model adjusted for age, sex, calendar year, and place of collapse, survival to 30 days is presented for 4 different groups of emergency medical services (EMS)-crew response time: 0 to 6 minutes, 7 to 9 minutes, 10 to 15 minutes, and >15 minutes. Survival to 30 days after a witnessed OHCA decreased as ambulance response time increased. For EMS response times of >10 minutes, the overall survival among those receiving cardiopulmonary resuscitation before EMS arrival was slightly higher than survival for the sub-group of patients treated with compressions-only cardiopulmonary resuscitation. Conclusions Survival to 30 days after a witnessed OHCA decreases as ambulance response times increase. This correlation was seen independently of initial rhythm and whether cardiopulmonary resuscitation was performed before EMS-crew arrival. Shortening EMS response times is likely to be a fast and effective way of increasing survival in OHCA.
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Project description:Neuro-cognitive disabilities are a well-recognized complication of hypothermic circulatory arrest. We and others have reported that prolonged cardiac arrest (CA) produces neuronal death and microglial proliferation and activation that are only partially mitigated by hypothermia. Microglia, and possibly other cells, are suggested to elaborate tumor necrosis factor alpha (TNF-?), which can trigger neuronal death cascades and exacerbate edema after CNS insults. Minocycline is neuroprotective in some brain ischemia models in part by blunting the microglial response. We tested the hypothesis that minocycline would attenuate neuroinflammation as reflected by brain tissue levels of TNF-? after hypothermic CA in rats. Rats were subjected to rapid exsanguination, followed by a 6 min normothermic CA. Hypothermia (30 °C) was then induced by an aortic saline flush. After a total of 20 min CA, resuscitation was achieved via cardiopulmonary bypass (CPB). After 5 min reperfusion, minocycline (90 mg kg?1; n = 6) or vehicle (PBS; n = 6) was given. Hypothermia (34 °C) was maintained for 6 h. Rats were sacrificed at 6 or 24 h. TNF-? was quantified (ELISA) in four brain regions (cerebellum, CEREB; cortex, CTX; hippocampus, HIP; striatum, STRI). Naïve rats (n = 6) and rats subjected to the same anesthesia and CPB but no CA served as controls (n = 6). Immunocytochemistry was used to localize TNF-?. Naïve rats and CPB controls had no detectable TNF-? in any brain region. CA markedly increased brain TNF-?. Regional differences were seen, with the highest TNF-? levels in striatum in CA groups (10-fold higher, P < 0.05 vs. all other brain regions). TNF-? was undetectable at 24 h. Minocycline attenuated TNF-? levels in CTX, HIP and STRI (P < 0.05). TNF-? showed unique co-localization with neurons. In conclusion, we report region-dependent early increases in brain TNF-? levels after prolonged hypothermic CA, with maximal increases in striatum. Surprisingly, TNF-? co-localized in neurons and not microglia. Minocycline attenuated TNF-? by approximately 50% but did not totally ablate its production. That minocycline decreased brain TNF-? levels suggests that it may represent a therapeutic adjunct to hypothermia in CA neuroprotection. University of Pittsburgh IACUC 0809278B-3.
| S-EPMC3952024 | biostudies-literature
Project description:To investigate the effects of the combination of extracorporeal cardiopulmonary resuscitation and thrombolytic therapy on the recovery of vital organ function after prolonged cardiac arrest.Laboratory investigation.University laboratory.Pigs.Animals underwent 30-minute untreated ventricular fibrillation cardiac arrest followed by extracorporeal cardiopulmonary resuscitation for 6 hours. Animals were allocated into two experimental groups: t-extracorporeal cardiopulmonary resuscitation (t-ECPR) group, which received streptokinase 1 million units, and control extracorporeal cardiopulmonary resuscitation (c-ECPR), which did not receive streptokinase. In both groups, the resuscitation protocol included the following physiologic targets: mean arterial pressure greater than 70 mm Hg, cerebral perfusion pressure greater than 50 mm Hg, PaO2 150 ± 50 torr (20 ± 7 kPa), PaCO2 40 ± 5 torr (5 ± 1 kPa), and core temperature 33°C ± 1°C. Defibrillation was attempted after 30 minutes of extracorporeal cardiopulmonary resuscitation.A cardiac resuscitability score was assessed on the basis of success of defibrillation, return of spontaneous heart beat, weanability from extracorporeal cardiopulmonary resuscitation, and left ventricular systolic function after weaning. The addition of thrombolytic to extracorporeal cardiopulmonary resuscitation significantly improved cardiac resuscitability (3.7 ± 1.6 in t-ECPR vs 1.0 ± 1.5 in c-ECPR). Arterial lactate clearance was higher in t-ECPR than in c-ECPR (40% ± 15% vs 18% ± 21%). At the end of the experiment, the intracranial pressure was significantly higher in c-ECPR than in t-ECPR. Recovery of brain electrical activity, as assessed by quantitative analysis of electroencephalogram signal, and ischemic neuronal injury on histopathologic examination did not differ between groups. Animals in t-ECPR group did not have increased bleeding complications, including intracerebral hemorrhages.In a porcine model of prolonged cardiac arrest, t-ECPR improved cardiac resuscitability and reduced brain edema, without increasing bleeding complications. However, early electroencephalogram recovery and ischemic neuronal injury were not improved.
| S-EPMC4948940 | biostudies-literature
Project description:National efforts to measure hospital performance in treating cardiac arrest have focused on case survival, with the hope of improving survival after cardiac arrest. However, it is plausible that hospitals with high case-survival rates do a poor job of preventing cardiac arrests in the first place.To describe the association between inpatient cardiac arrest incidence and survival rates.Within a large, national registry, we identified hospitals with at least 50 adult in-hospital cardiac arrest cases between January 1, 2000, and November 30, 2009. We used multivariable hierarchical regression to evaluate the correlation between a hospital's cardiac arrest incidence rate and its case-survival rate after adjusting for patient and hospital characteristics.The correlation between a hospital's incidence rate and case-survival rate for cardiac arrest.Of 102,153 cases at 358 hospitals, the median hospital cardiac arrest incidence rate was 4.02 per 1000 admissions (interquartile range, 2.95-5.65 per 1000 admissions), and the median hospital case-survival rate was 18.8% (interquartile range, 14.5%-22.6%). In crude analyses, hospitals with higher case-survival rates also had lower cardiac arrest incidence (r, -0.16; P = .003). This relationship persisted after adjusting for patient characteristics (r, -0.15; P = .004). After adjusting for potential mediators of this relationship (ie, hospital characteristics), the relationship between incidence and case survival was attenuated (r, -0.07; P = .18). The one modifiable hospital factor that most attenuated this relationship was a hospital's nurse-to-bed ratio (r, -0.12; P = .03).Hospitals with exceptional rates of survival for in-hospital cardiac arrest are also better at preventing cardiac arrests, even after adjusting for patient case mix. This relationship is partially mediated by measured hospital attributes. Performance measures focused on case-survival rates seem an appropriate first step in quality measurement for in-hospital cardiac arrest.
| S-EPMC4181325 | biostudies-literature
Project description:Background Patients suffering from an out-of-hospital cardiac arrest are often transported to the closest hospital. Although it has been suggested that these patients be transported to cardiac resuscitation centers, few jurisdictions have acted on this recommendation. To better evaluate the evidence on this subject, a systematic review and meta-analysis of the currently available literature evaluating the association between the destination hospital's capability (cardiac resuscitation center or not) and resuscitation outcomes for adult patients suffering from an out-of-hospital cardiac arrest was performed. Methods and Results PubMed, EMBASE , and the Cochrane Library databases were first searched using a specifically designed search strategy. Both original randomized controlled trials and observational studies were considered for inclusion. Cardiac resuscitation centers were defined as having on-site percutaneous coronary intervention and targeted temperature management capability at all times. The primary outcome measure was survival. Twelve nonrandomized observational studies were retained in this review. A total of 61 240 patients were included in the 10 studies that could be included in the meta-analysis regarding the survival outcome. Being transported to a cardiac resuscitation center was associated with an increase in survival (odds ratio=1.95 [95% confidence interval 1.47-2.59], P<0.001). Conclusions Adult patients suffering from an out-of-hospital cardiac arrest transported to cardiac resuscitation centers have better outcomes than their counterparts. When possible, it is reasonable to transport these patients directly to cardiac resuscitation centers (class II a, level of evidence B, nonrandomized). Clinical Trial Registration URL : www.crd.york.ac.uk/PROSPERO/ . Unique identifier: CRD 42018086608.
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