Asphyxial Cardiac Arrest Research Articles

Therapeutic hypothermia promotes cerebral blood flow recovery and brain homeostasis after resuscitation from cardiac arrest in a rat model

Laboratory and clinical studies have demonstrated that therapeutic hypothermia (TH), when applied as soon as possible after resuscitation from cardiac arrest (CA), results in better neurological outcome. This study tested the hypothesis that TH would promote cerebral blood flow (CBF) restoration and its maintenance after return of spontaneous circulation (ROSC) from CA. Twelve Wistar rats resuscitated from 7-min asphyxial CA were randomized into two groups: hypothermia group (7 H, n = 6), treated with mild TH (33–34℃) immediately after ROSC and normothermia group (7 N, n = 6,37.0 ± 0.5℃). Multiple parameters including mean arterial pressure, CBF, electroencephalogram (EEG) were recorded. The neurological outcomes were evaluated using electrophysiological (information quantity, IQ, of EEG) methods and a comprehensive behavior examination (neurological deficit score, NDS). TH consistently promoted better CBF restoration approaching the baseline levels in the 7 H group as compared with the 7 N group. CBF during the first 5–30 min post ROSC of the two groups was 7 H:90.5% ± 3.4% versus 7 N:76.7% ± 3.5% (P < 0.01). Subjects in the 7 H group showed significantly better IQ scores after ROSC and better NDS scores at 4 and 24 h. Early application of TH facilitates restoration of CBF back to baseline levels after CA, which in turn results in the restoration of brain electrical activity and improved neurological outcome.

A comparison of therapeutic hypothermia and genetic mitochondrial permeability transition pore inhibition in a murine model of cardiac arrest

Recent evidence suggests that therapeutic hypothermia limits the severity of the post-cardiac arrest syndrome by inhibiting mitochondrial permeability transition pore (mPTP) opening through a Cyclophilin-D (CypD) dependent mechanism. We sought to compare the effects of genetic loss of CypD (CypD-KO) and therapeutic hypothermia on resuscitability and survival after cardiac arrest (CA). Adult mice underwent 5 minutes of asphyxial CA followed by resuscitation. Animals were assigned to one of the 5 following groups: Sham, Control (Ctrl): normothermic CA in wild-type mice, CypD-KO: normothermic CA in CypD-KO mice, therapeutic hypothermia (TH): CA in wild-type mice with fast hypothermia induced by external cooling at the onset of cardiac massage (33 °C for 1 hour) and CypD-KO + TH. Two hours after CA, left ventricle-shortening fraction, blood levels of S100B protein (a marker of brain injury) and troponin Ic, were assessed. Additional mice were included in the same 5 groups for survival follow-up. Baseline characteristics and characteristics of CA were similar among groups. Rate of restoration of spontaneous circulation (ROSC) was significantly higher in CypD-KO and TH groups compared to controls ( P < 0.05). Time to ROSC was significantly shorter in CypD-KO mice versus wild-type mice ( P < 0.05). Genetic loss of CypD and therapeutic hypothermia prevented to a similar extent CA-induced myocardial dysfunction, increase in S100B, troponin Ic and death within 24 hours after CA ( P < 0.05 versus Ctrl). Only therapeutic hypothermia applied to either wild-type or CypD-KO animals improved survival at day 7 ( P < 0.05 versus non-hypothermic groups). There were no additive beneficial effects in the combination of genetic loss of CypD and therapeutic hypothermia. In our CA model, genetic inhibition of CypD improved resuscitability and early cardiac dysfunction but, unlike therapeutic hypothermia, failed to improve 7-day survival.

Glibenclamide Prevents Water Diffusion Abnormality in the Brain After Cardiac Arrest in Rats.

Glibenclamide (GBC) improves neurological outcome after cardiac arrest (CA) in rats. In this study, we sought to elucidate the mechanism responsible for the neuroprotective effects of GBC by using a high-field MRI system. Male Sprague-Dawley rats were subjected to 10-min asphyxial CA followed by cardiopulmonary resuscitation (CPR). Diffusion-weighted imaging (DWI) as well as conventional T2-weighted imaging was conducted prior to CA and at 24, 48, and 72h after resuscitation. Afterward, histological examination was performed. Twelve rats were randomized to receive GBC (n=6) or vehicle (n=6) at 15min after return of spontaneous circulation, while four rats were set as sham control. Rats that underwent CA/CPR and received vehicle exhibited distinct neurological deficit, which was alleviated by GBC treatment. Marked water diffusion abnormality as demonstrated by hyperintense DWI in vulnerable regions of the brain was detected after CA/CPR, with the most prominent hyperintense DWI observed in the hippocampal CA1 region at 72h. Consistently, histological examination revealed neuronal swelling, dendritic injury, and activation of astrocytes and microglia in the hippocampal CA1 region in vehicle-treated rats. Correlation analysis revealed that the ADC values in the hippocampus were significantly correlated with the histological findings (all p<0.05). These results suggest that the neuroprotective effects of GBC after CA was exerted, as least in part, through prevention of water diffusion abnormality, namely brain edema.

Adrenergic Blockade Bi-directionally and Asymmetrically Alters Functional Brain-Heart Communication and Prolongs Electrical Activities of the Brain and Heart during Asphyxic Cardiac Arrest.

Sudden cardiac arrest is a leading cause of death in the United States. The neurophysiological mechanism underlying sudden death is not well understood. Previously we have shown that the brain is highly stimulated in dying animals and that asphyxia-induced death could be delayed by blocking the intact brain-heart neuronal connection. These studies suggest that the autonomic nervous system plays an important role in mediating sudden cardiac arrest. In this study, we tested the effectiveness of phentolamine and atenolol, individually or combined, in prolonging functionality of the vital organs in CO2-mediated asphyxic cardiac arrest model. Rats received either saline, phentolamine, atenolol, or phentolamine plus atenolol, 30 min before the onset of asphyxia. Electrocardiogram (ECG) and electroencephalogram (EEG) signals were simultaneously collected from each rat during the entire process and investigated for cardiac and brain functions using a battery of analytic tools. We found that adrenergic blockade significantly suppressed the initial decline of cardiac output, prolonged electrical activities of both brain and heart, asymmetrically altered functional connectivity within the brain, and altered, bi-directionally and asymmetrically, functional, and effective connectivity between the brain and heart. The protective effects of adrenergic blockers paralleled the suppression of brain and heart connectivity, especially in the right hemisphere associated with central regulation of sympathetic function. Collectively, our results demonstrate that blockade of brain-heart connection via alpha- and beta-adrenergic blockers significantly prolonged the detectable activities of both the heart and the brain in asphyxic rat. The beneficial effects of combined alpha and beta blockers may help extend the survival of cardiac arrest patients.

Standardized model of porcine resuscitation using a custom-made resuscitation board results in optimal hemodynamic management

AimStandardized modeling of cardiac arrest and cardiopulmonary resuscitation (CPR) is crucial to evaluate new treatment options. Experimental porcine models are ideal, closely mimicking human-like physiology. However, anteroposterior chest diameter differs significantly, being larger in pigs and thus poses a challenge to achieve adequate perfusion pressures and consequently hemodynamics during CPR, which are commonly achieved during human resuscitation. The aim was to prove that standardized resuscitation is feasible and renders adequate hemodynamics and perfusion in pigs, using a specifically designed resuscitation board for a pneumatic chest compression device. Methods and resultsA “porcine-fit” resuscitation board was designed for our experiments to optimally use a pneumatic compression device (LUCAS® II, Physio-Control Inc.), which is widely employed in emergency medicine and ideal in an experimental setting due to its high standardization. Asphyxial cardiac arrest was induced in 10 German hybrid landrace pigs and cardiopulmonary resuscitation was performed according to ERC/AHA 2015 guidelines with mechanical chest compressions. Hemodynamics were measured in the carotid and pulmonary artery. Furthermore, arterial blood gas was drawn to assess oxygenation and tissue perfusion.The custom-designed resuscitation board in combination with the LUCAS® device demonstrated highly sufficient performance regarding hemodynamics during CPR (mean arterial blood pressure, MAP 46 ± 1 mmHg and mean pulmonary artery pressure, mPAP of 36 ± 1 mmHg over the course of CPR). MAP returned to baseline values at 2 h after ROSC (80 ± 4 mmHg), requiring moderate doses of vasopressors. Furthermore, stroke volume and contractility were analyzed using pulse contour analysis (106 ± 3 ml and 1097 ± 22 mmHg/s during CPR). Blood gas analysis revealed CPR-typical changes, normalizing in the due course. Thermodilution parameters did not show persistent intravascular volume shift. ConclusionStandardized cardiopulmonary resuscitation is feasible in a porcine model, achieving adequate hemodynamics and consecutive tissue perfusion of consistent quality.

Utilizing the Modified T-Maze to Assess Functional Memory Outcomes After Cardiac Arrest

Background: Evaluating mild to moderate cognitive impairment in a global cerebral ischemia (i.e. cardiac arrest) model can be difficult due to poor locomotion after surgery. For example, rats who undergo surgical procedures and are subjected to the Morris water maze may not be able to swim, thus voiding the experiment. New Method: We established a modified behavioral spontaneous alternation T-maze test. The major advantage of the modified T-maze protocol is its relatively simple design that is powerful enough to assess functional learning/memory after ischemia. Additionally, the data analysis is simple and straightforward. We used the T-maze to determine the rats' learning/memory deficits both in the presence or absence of mild to moderate (6 min) asphyxial cardiac arrest (ACA). Rats have a natural tendency for exploration and will explore the alternate arms in the T-maze, whereas hippocampal-lesioned rats tend to adopt a side-preference resulting in decreased spontaneous alternation ratios, revealing the hippocampal-related functional learning/memory in the presence or absence of ACA. Results: ACA groups have higher side-preference ratios and lower alternations as compared to control. Comparison with Existing Method(s): The Morris water and Barnes maze are more prominent for assessing learning/memory function. However, the Morris water maze is more stressful than other mazes. The Barnes maze is widely used to measure reference (long-term) memory, while ACA-induced neurocognitive deficits are more closely related to working (short-term) memory. Conclusions: We have developed a simple, yet effective strategy to delineate working (short-term) memory via the T-maze in our global cerebral ischemia model (ACA).

Utilizing the Modified T-Maze to Assess Functional Memory Outcomes After Cardiac Arrest.

Evaluating mild to moderate cognitive impairment in a global cerebral ischemia (i.e. cardiac arrest) model can be difficult due to poor locomotion after surgery. For example, rats who undergo surgical procedures and are subjected to the Morris water maze may not be able to swim, thus voiding the experiment. New Method: We established a modified behavioral spontaneous alternation T-maze test. The major advantage of the modified T-maze protocol is its relatively simple design that is powerful enough to assess functional learning/memory after ischemia. Additionally, the data analysis is simple and straightforward. We used the T-maze to determine the rats' learning/memory deficits both in the presence or absence of mild to moderate (6 min) asphyxial cardiac arrest (ACA). Rats have a natural tendency for exploration and will explore the alternate arms in the T-maze, whereas hippocampal-lesioned rats tend to adopt a side-preference resulting in decreased spontaneous alternation ratios, revealing the hippocampal-related functional learning/memory in the presence or absence of ACA. ACA groups have higher side-preference ratios and lower alternations as compared to control. Comparison with Existing Method(s): The Morris water and Barnes maze are more prominent for assessing learning/memory function. However, the Morris water maze is more stressful than other mazes. The Barnes maze is widely used to measure reference (long-term) memory, while ACA-induced neurocognitive deficits are more closely related to working (short-term) memory. We have developed a simple, yet effective strategy to delineate working (short-term) memory via the T-maze in our global cerebral ischemia model (ACA).

Interfacial Nanoprecipitation toward Stable and Responsive Microbubbles and Their Use as a Resuscitative Fluid

AbstractA new approach has been developed to prepare stable microbubbles (MBs) by interfacial nanoprecipitation of bioabsorbable polymers at air/liquid interfaces. This facile method offers robust control over the morphology and chemophysical properties of MBs by simple chemical modifications. This approach is amenable to large‐scale manufacturing, and is useful to develop functional MBs for advanced biomedical applications. To demonstrate this, a MB‐based intravenous oxygen carrier was created that undergoes pH‐triggered self‐elimination. Intravenous injection of previous MBs increased the risk of pulmonary vascular obstruction. However, we show, for the first time, that our current design is superior, as they 1) yielded no evidence of acute risks in rodents, and 2) improved the survival in a disease model of asphyxial cardiac arrest (from 0 to 100 %), a condition that affects more than 100 000 in‐hospital patients, and carries a mortality of about 90 %.

Interfacial Nanoprecipitation toward Stable and Responsive Microbubbles and Their Use as a Resuscitative Fluid.

A new approach has been developed to prepare stable microbubbles (MBs) by interfacial nanoprecipitation of bioabsorbable polymers at air/liquid interfaces. This facile method offers robust control over the morphology and chemophysical properties of MBs by simple chemical modifications. This approach is amenable to large-scale manufacturing, and is useful to develop functional MBs for advanced biomedical applications. To demonstrate this, a MB-based intravenous oxygen carrier was created that undergoes pH-triggered self-elimination. Intravenous injection of previous MBs increased the risk of pulmonary vascular obstruction. However, we show, for the first time, that our current design is superior, as they 1) yielded no evidence of acute risks in rodents, and 2) improved the survival in a disease model of asphyxial cardiac arrest (from 0 to 100 %), a condition that affects more than 100 000 in-hospital patients, and carries a mortality of about 90 %.

The relationship between low survival and acute increase of tumor necrosis factor α expression in the lung in a rat model of asphyxial cardiac arrest.

Cardiac arrest (CA) is sudden loss of heart function and abrupt stop in effective blood flow to the body. The patients who initially achieve return of spontaneous circulation (RoSC) after CA have low survival rate. It has been known that multiorgan dysfunctions after RoSC are associated with high morbidity and mortality. Most previous studies have focused on the heart and brain in RoSC after CA. Therefore, the aim of this research was to perform serological, physiological, and histopathology study in the lung and to determine whether or how pulmonary dysfunction is associated with low survival rate after CA. Experimental animals were divided into sham-operated group (n=14 at each point in time), which was not subjected to CA operation, and CA-operated group (n=14 at each point in time), which was subjected to CA. The rats in each group were sacrificed at 6 hours, 12 hours, 24 hours, and 2 days, respectively, after RoSC. Then, pathological changes of the lungs were analyzed by hematoxylin and eosin staining, Western blot and immunohistochemistry for tumor necrosis factor α (TNF-α). The survival rate after CA was decreased with time past. We found that histopathological score and TNF-α immunoreactivity were significantly increased in the lung after CA. These results indicate that inflammation triggered by ischemia-reperfusion damage after CA leads to pulmonary injury/dysfunctions and contributes to low survival rate. In addition, the finding of increase in TNF-α via inflammation in the lung after CA would be able to utilize therapeutic or diagnostic measures in the future.

Cerebral microcirculatory alterations and the no-reflow phenomenon in vivo after experimental pediatric cardiac arrest

Decreased cerebral blood flow (CBF) after cardiac arrest (CA) contributes to secondary ischemic injury in infants and children. We previously reported cortical hypoperfusion with tissue hypoxia early in a pediatric rat model of asphyxial CA. In order to identify specific alterations as potential therapeutic targets to improve cortical hypoperfusion post-CA, we characterize the CBF alterations at the cortical microvascular level in vivo using multiphoton microscopy. We hypothesize that microvascular constriction and disturbances of capillary red blood cell (RBC) flow contribute to cortical hypoperfusion post-CA. After resuscitation from 9 min asphyxial CA, transient dilation of capillaries and venules at 5 min was followed by pial arteriolar constriction at 30 and 60 min (19.6 ± 1.3, 19.3 ± 1.2 µm at 30, 60 min vs. 22.0 ± 1.2 µm at baseline, p < 0.05). At the capillary level, microcirculatory disturbances were highly heterogeneous, with RBC stasis observed in 25.4% of capillaries at 30 min post-CA. Overall, the capillary plasma mean transit time was increased post-CA by 139.7 ± 51.5%, p < 0.05. In conclusion, pial arteriolar constriction, the no-reflow phenomenon and increased plasma transit time were observed post-CA. Our results detail the microvascular disturbances in a pediatric asphyxial CA model and provide a powerful platform for assessing specific vascular-targeted therapies.

Metabolomics profiling reveals different patterns in an animal model of asphyxial and dysrhythmic cardiac arrest

Cardiac arrest (CA) is not a uniform condition and its pathophysiology strongly depends on its cause. In this work we have used a metabolomics approach to study the dynamic metabolic changes occurring in the plasma samples of a swine model following two different causes of CA, namely asphyxia (ACA) and ventricular fibrillation (VFCA). Plasma samples were collected at baseline and every minute during the experimental phases. In order to identify the metabolomics profiles characterizing the two pathological entities, all samples were analysed by 1H NMR spectroscopy and LC-MS/MS spectrometry.The metabolomics fingerprints of ACA and VFCA significantly differed during the peri-arrest period and the resuscitation phase. Major alterations were observed in plasma concentrations of metabolites related to tricarboxylic acid (TCA) cycle, urea cycle, and anaplerotic replenishing of TCA. ACA animals showed significant metabolic disturbances during the asphyxial and CA phases, while for VFCA animals this phenomenon resulted shifted at the resuscitation phase. Interestingly, starting from the asphyxial phase, the ACA animals were stratified in two groups based on their metabolomics profiles that resulted to be correlated with the clinical outcome. Succinate overproduction was observed in the animals with the worse outcome, suggesting a potential prognostic role for this metabolite.

Abstract 21321: Heart Rate During Pulseless Electrical Activity as a Marker for Successful Resuscitation and Neurological Outcome in a Rodent Model of Cardiac Arrest

Introduction: During cardiac arrest (CA), a major goal of responders is to ascertain the likelihood of successful cardiopulmonary resuscitation (CPR) and optimize efforts accordingly to achieve return of spontaneous circulation (ROSC). Pulseless electrical activity (PEA), a common form of CA in inpatient settings, often allows monitoring of heart rate (HR) immediately preceding cardiopulmonary resuscitation (CPR). We were interested in assessing the role of HR during PEA in outcome of CPR. To evaluate this in a controlled setting, we used a rodent model of asphyxial CA with electrocardiogram (ECG) recordings and neurological testing. We hypothesized that more severe bradycardia may be associated with failure to achieve ROSC and worse neurological outcome if ROSC is achieved. Methods: Adult male Wistar rats (n=25) were anesthetized, intubated, and placed under mechanical ventilation. Needle electrodes were inserted into the rats to obtain continuous ECG data. Rats then underwent 8 minutes of asphyxial CA followed by CPR accompanied with intravenous epinephrine and bicarbonate injections. Neurological deficit scale (NDS) testing was conducted at 24hrs post-ROSC. Results: Of 25 rats that underwent CA, 4 failed to achieve ROSC. HR was measured after 7.5 minutes of asphyxia (i.e. 30 sec. prior to CPR), when the systolic blood pressure was &lt;10-20mmHg, which is presumed to be a “pulseless” equivalent in humans. Rats failing to achieve ROSC had a significantly lower HR in comparison to rats achieving ROSC (26.6±8.4 vs. 46.2±16.9; p&lt; 0.05). Interestingly, among survivors, HR immediately pre-CPR was inversely correlated with NDS scores (r=-0.655, p&lt; 0.05). No association was found between groups in pre-CA arterial blood gas measurements (e.g. pH, CO2, electrolytes). Conclusions: In a rodent asphyxial model of CA mimicking a PEA state, rats failing to achieve ROSC had lower HR immediately prior to CPR. However, in rats achieving ROSC, slower pre-CPR HR is associated with better neurological outcome. These findings appear to be independent of respiratory acidosis. We propose a model and future experimentation that may help define underlying mechanisms. Validation is needed in human studies to assess potential translational implications in a clinical setting.

Abstract 21158: Ultra-Short Caloric Restriction Prior to Cardiac Arrest and Resuscitation Leads to Improved Survival and Neurological Outcome in a Rodent Model

Introduction: Caloric restriction (CR) has been widely shown to have both cardioprotective and neuroprotective properties. However, nearly all studies have investigated chronic CR with mechanisms linked to the upregulation of SIRT-1 and BDNF. Minimal to no focus has been placed on the potential benefits of transient CR in models of brain injury, including stroke. Furthermore, the effects of transient CR in cardiac arrest-induced global cerebral ischemia have not been evaluated. We investigated the effects of overnight (~14-hour) CR on survival and neurological outcome in a rodent model of cardiac arrest (CA). Methods: Adult male Wistar rats (n=28) were divided into 75% CR (n=14) and non-CR (n=14) groups 14hrs prior to rats undergoing intubation, mechanical ventilation, cannulation of femoral vessels, and 8 minutes of asphyxial CA followed by cardiopulmonary resuscitation (CPR). Blood glucose was measured before CA. We conducted neurological deficit scale (NDS) behavioral testing at 4hrs, 24hrs, 48hrs, and 72hrs post-CA. The NDS score ranges from 0 (dead) to 80 (normal). Rats were euthanized after 72hrs and tissue was collected for protein analysis via Western blot. Results: CR, in comparison to no-CR, resulted in significant reduction of mortality (0% vs. 28.6%; Kaplan-Meier log-rank test, p&lt; 0.05). Of those that survived, NDS scores improved significantly in the CR group at 4hrs (32.8±6.1 vs. 24.5±3.3; p&lt;0.05), 24hrs (66.5±8.4 vs. 57.0±7.9; p&lt; 0.05), 48hrs (73.1±4.7 vs. 61.3±12.5; p&lt; 0.05), and 72hrs (76.3±3.3 vs. 73.14±12.2; p&lt; 0.05). CR also significantly lowered pre-CA glucose levels (151.0±22.1 vs. 220.7±17.5; p&lt; 0.05). Western blot analysis yielded no significant difference in BDNF and SIRT-1 expression in brain regions of CR vs. non-CR rats. Conclusions: Our results demonstrate that ultra-short CR (~14 hours) significantly improves survival and neurological outcome after CA/CPR. Interestingly, these improvements appear to be independent of BDNF or SIRT-1 pathways, commonly linked to chronic CR. While ultra-short CR improved glycemic control in rats, further investigation into the underlying molecular mechanisms are imperative to explore potential translational and therapeutic implications, including for patients at high risk of CA.

Valproic Acid Combined With Postcardiac Arrest Hypothermic-Targeted Temperature Management Prevents Delayed Seizures and Improves Survival in a Rat Cardiac Arrest Model

High-dose valproic acid in combination with hypothermic-targeted temperature management has been reported to synergistically improve neurologic outcomes after cardiac arrest. This study investigated the potential synergistic mechanisms. Prospective, randomized, experimental study. University research institution. Male Long Evans rats. Rats resuscitated from asphyxial cardiac arrest were randomized to one of the three groups: normothermic-targeted temperature management (37°C ± 1°C), hypothermic-targeted temperature management (33° ± 1° × 24 hr + placebo infusion), hypothermic-targeted temperature management plus high-dose valproic acid (300 mg/kg IV × 1 initiated 5 min post return of spontaneous circulation and infused over 20 min) (hypothermic-targeted temperature management + valproic acid). Seventy-two-hour survival was significantly greater with hypothermic-targeted temperature management + valproic acid, compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p < 0.05). Survival with good neurologic function, neurodegeneration, expression of HSP70, phosphorylation of Akt and Erk1/2 were not significantly different between hypothermic-targeted temperature management and hypothermic-targeted temperature management + valproic acid. The prevalence of seizures during the first 72-hour postcardiac arrest was significantly lower with hypothermic-targeted temperature management + valproic acid compared to hypothermic-targeted temperature management and normothermic-targeted temperature management (p = 0.01). High-dose valproic acid combined with hypothermic-targeted temperature management prevents postcardiac arrest seizures and improves survival. It remains to be determined if the mechanism of seizure prevention is through the antiepileptic effect of valproic acid or direct neuroprotection. Overall, the combination of high-dose valproic acid and hypothermic-targeted temperature management remains a promising strategy to improve cardiac arrest outcomes.

Impact of age on cardiovascular function, inflammation, and oxidative stress in experimental asphyxial cardiac arrest.

Advanced age is an independent predictor of poor outcome after cardiac arrest (CA). From experimental studies of regional ischemia-reperfusion injury, advanced age is associated with larger infarct size, reduced organ function, and augmented oxidative stress. The objective of this study was to investigate the effect of age on cardiovascular function, oxidative stress, inflammation, and endothelial activation after CA representing global ischemia-reperfusion. Aged (26months) and young (5months) rats were subjected to 8min of asphyxia induced CA, resuscitated and observed for 360min. Left ventricular pressure-derived cardiac function was measured at baseline and 360min after CA. Blood samples obtained at baseline, 120min, and 360min after CA were analyzed for IL-1β, IL-6, IL-10, TNF-α, elastase, sE-selectin, sL-selectin, sI-CAM1, hemeoxygenase-1 (HO-1) and protein carbonyl. Tissue samples of brain, heart, kidney, and lung were analyzed for HO-1. Cardiac function, evaluated by dP/dtmax and dP/dtmin , was decreased after CA in both young and aged rats, with no group differences. Mean arterial pressure increased after CA in young, but not old rats. Aged rats showed significantly higher plasma levels of elastase and sE-selectin after CA, and there was a significant different development over time between groups for IL-6 and IL-10. Young rats showed higher levels of HO-1 in plasma and renal tissue after CA. In a rat model of asphyxial CA, advanced age is associated with an attenuated hyperdynamic blood pressure response and increased endothelial activation.

Gynostemma pentaphyllum is neuroprotective in a rat model of cardiopulmonary resuscitation.

Asphyxial cardiac arrest (ACA)-induced ischemia results in acute and delayed neuronal cell death. The early reperfusion phase is critical for the outcome. Intervention strategies directed to this period are promising to reduce ACA/resuscitation-dependent impairments. This study focused on the evaluation of the protective potential of an extract from Gynostemma pentaphyllum (GP), a plant used in traditional medicine with antioxidative, glucose lowering and neuroprotective activities, in an ACA rat model. We tested the following parameters: i) Basic systemic parameters such as pCO2 and blood glucose value within the first 30 min post-ACA; ii) mitochondrial response by determining activities of citrate synthase, respiratory chain complexes I + III and II + III, and the composition of cardiolipin 6 and 24 h post-ACA; iii) neuronal vitality of the CA1 hippocampal region by immunohistochemistry 24 h and 7 days post-ACA; and iv) cognitive function by a novel object recognition test 7 days post-ACA. GP, administered after reaching spontaneous circulation, counteracted the following: i) ACA-mediated increases in arterial CO2 tension and blood glucose values; ii) transient increase in the activity of the respiratory chain complexes II + III; iii) elevation in cardiolipin content; iv) hippocampal CA1 neurodegeneration, and v) loss of normal novelty-object seeking. The protective effects of GP were accompanied by side effects of the vehicle DMSO, such as the stimulation of citrate synthase activity in control animals, inhibition of cardiolipin synthesis in ACA animals and complex II + III activity in both control and ACA animals. The results emphasize the importance of the early post-resuscitation phase for the neurological outcome after ACA/resuscitation, and demonstrated the power of GP substitution as neuroprotective intervention. Moreover, the results underline the need of a careful handling of the popular vehicle DMSO.

Comparison of myocardial metabolism by using PET after resuscitation between ventricular fibrillation cardiac arrest and asphyxia cardiac arrest

Objective To characterize myocardial metabolism using positron emission tomography (PET) in porcine models of ventricular fibrillation cardiac arrest (VFCA) and asphyxiation cardiac arrest (ACA) after resuscitation. Methods Thirty-two healthy miniature pigs were randomized into two groups. The pigs of VFCA group (n=16) were subject to programmed electric stimulation to create a ventricular fibrillation cardiac arrest, and the pigs of ACA group (n=16) were subjected to endotracheal tube clamping to establish a cardiac arrest (CA). Once modeling was established, pigs with CA were left untreated for a period of 8 min. Two minutes following initiation of cardiopulmonary resuscitation (CPR), defibrillation was attempted until the restoration of spontaneous circulation (ROSC) was achieved or animals died. To assess myocardial metabolism, PET was performed before modeling, 4 hrs and 24hrs after ROSC. To analyze 18F-FDG myocardial uptake in PET, the maximum standardized uptake value (SUVmax) ) was measured. Results ROSC was obtained in 100% of pigs in VFCA group and only 50% in ACA group. The average survival time in VFCA pigs was significantly longer than that in ACA pigs (22.63±0.95) hvs. (8.75±2.54)h, P<0.01. VFCA pigs had better mean arterial pressure and cardiac output after ROSC than ACA pigs. Myocardial metabolism imaging using PET demonstrated that myocardial metabolism injuries after ACA were more severe and widespread than those after VFCA at 4 hrs and 24hrs after ROSC and SUVmax) was much higher in VFCA group than that in ACA group [4 h after ROSC: (1.9±0.3) vs. (1.0±0.4), P<0.01; 24 h after ROSC: (2.4±0.6) vs. (1.2±0.5), P<0.01]. Conclusions Compared with VFCA, ACA causes more severe cardiac metabolism dysfunction associated with less successful resuscitation and shorter survival time; therefore they should be treated as different pathological entities. Key words: Ventricular fibrillation; Asphyxia; Cardiac arrest; Return of spontaneous circulation; Myocardial metabolism; PET; Maxinum standardized uptake value; Survival time

Changes in histopathology and tumor necrosis factor-α levels in the hearts of rats following asphyxial cardiac arrest.

ObjectivePost cardiac arrest (CA) syndrome is associated with a low survival rate in patients who initially have return of spontaneous circulation (ROSC) after CA. The aim of this study was to examine the histopathology and inflammatory response in the heart during the post CA syndrome.MethodsWe induced asphyxial CA in male Sprague-Dawley rats and determined the survival rate of these rats during the post resuscitation phase.ResultsSurvival of the rats decreased after CA: 66.7% at 6 hours, 36.7% at 1 day, and 6.7% at 2 days after ROSC following CA. The rats were sacrificed at 6 hours, 12 hours, 1 day, and 2 days after ROSC, and their heart tissues were examined. Histopathological scores increased at 12 hours post CA and afterwards, histopathological changes were not significant. In addition, levels of tumor necrosis factor-α immunoreactivity gradually increased after CA.ConclusionThe survival rate of rats 2 days post CA was very low, even though histopathological and inflammatory changes in the heart were not pronounced in the early stage following CA.

Glycocalyx degradation leads to blood–brain barrier dysfunction and brain edema after asphyxia cardiac arrest in rats

The role of glycocalyx in blood–brain barrier (BBB) integrity and brain damage is poorly understood. Our study aimed to investigate the impacts of endothelial glycocalyx on BBB function in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Male Sprague-Dawley rats subjected to 8-min asphyxia CA/CPR. Compared to controls, glycocalyx was mildly injured by CA, severely disrupted by hyaluronidase (HAase) with CA, and mitigated by hydrocortisone (HC) with CA. More importantly, the disruption of glycocalyx caused by HAase treatment was associated with higher BBB permeability and aggravated brain edema at 24 h after return of spontaneous circulation, as well as lower survival rate and poorer neurologic outcome at seventh day. Reversely, less degradation of glycocalyx by HC treatment was accompanied by higher seven-day survival rate and better neurologic outcome. Mechanistically, HAase treatment further increased CA/CPR-induced activation of glia cells and expression of inflammatory factors, whereas HC decreased them in the brain cortex and hippocampus. Glycocalyx degradation results in BBB leakage, brain edema, and deteriorates neurologic outcome after asphyxia CA/CPR in rats. Preservation of glycocalyx by HC could improve neurologic outcome and reduce BBB permeability, apparently through reduced gene transcription-protein synthesis and inflammation.