Arrest Model Research Articles

Protection Against Post-resuscitation Acute Kidney Injury by N-Acetylcysteine via Activation of the Nrf2/HO-1 Pathway.

Background and ObjectiveAcute kidney injury (AKI), the common complication after cardiopulmonary resuscitation (CPR), seriously affects the prognosis of cardiac arrest (CA) patients. However, there are limited studies on post-resuscitation AKI. In addition, it has been demonstrated that N-acetylcysteine (N-AC) as an ROS scavenger, has multiorgan-protective effects on systemic and regional ischaemia-reperfusion injuries. However, no studies have reported its protective effects against post-resuscitation AKI and potential mechanisms. This study aimed to clarify the protective effects of N-AC on post-resuscitation AKI and investigate whether its potential mechanism was mediated by activating Nrf-2/HO-1 pathway in the kidney.MethodsWe established cardiac arrest models in rats. All animals were divided into four groups: the sham, control, N-AC, and ZnPP groups. Animals in each group except for the ZnPP group were assigned into two subgroups based on the survival time: 6 and 48 h. The rats in the control, N-AC, and ZnPP groups underwent induction of ventricular fibrillation (VF), 8 min untreated VF and cardiopulmonary resuscitation. Renal function indicators, were detected using commercial kits. Renal pathologic changes were assessed by haematoxylin–eosin (HE) staining. Oxidative stress and inflammatory responses were measured using the corresponding indicators. Apoptosis was evaluated using terminal uridine nick-end labeling (TUNEL) staining, and expression of proteins associated with apoptosis and the Nrf-2/HO-1 pathway was measured by western blotting.ResultsN-AC inhibited post-resuscitation AKI. We observed that N-AC reduced the levels of biomarkers of renal function derangement; improved renal pathological changes; and suppressed apoptosis, oxidative stress, and inflammatory response. Additionally, the production of ROS in the kidneys markedly decreased by N-AC. More importantly, compared with the control group, N-AC further upregulated the expression of nuclear Nrf2 and endogenous HO-1 in N-AC group. However, N-AC-determined protective effects on post-resuscitation AKI were markedly reversed after pretreatment of the HO-1 inhibitor zinc protoporphyrin (ZnPP).ConclusionsN-AC alleviated renal dysfunction and prolonged survival in animal models of CA. N-AC partially exerts beneficial renal protection via activation of the Nrf-2/HO-1 pathway. Altogether, all these findings indicated that N-AC as a common clinical agent, may have the potentially clinical utility to improve patients the outcomes in cardiac arrest.

Necrosulfonamide improves post-resuscitation myocardial dysfunction via inhibiting pyroptosis and necroptosis in a rat model of cardiac arrest

The systemic inflammatory response following global myocardial ischemia/reperfusion (I/R) injury is a critical driver of poor outcomes. Both pyroptosis and necroptosis are involved in the systemic inflammatory response and contribute to regional myocardial I/R injury. This study aimed to explore the effect of necrosulfonamide (NSA) on post-resuscitation myocardial dysfunction in a rat model of cardiac arrest. Sprague-Dawley rats were randomly categorized to Sham, CPR and CPR-NSA groups. For rats in the latter two groups, ventricular fibrillation was induced without treatment for 6 min, with cardiopulmonary resuscitation (CPR) being sustained for 8 min. Rats were injected with NSA (10 mg/kg in DMSO) or vehicle at 5 min following return of spontaneous circulation. Myocardial function was measured by echocardiography, survival and neurological deficit score (NDS) were recorded at 24, 48, and 72 h after ROSC. Western blotting was used to assess pyroptosis- and necroptosis-related protein expression. ELISAs were used to measure levels of inflammatory cytokine. Rats in the CPR-NSA group were found to exhibit superior post-resuscitation myocardial function, and better NDS values in the group of CPR-NSA. Rats in the group of CPR-NSA exhibited median survival duration of 68 ± 8 h as compared to 34 ± 21 h in the CPR group. After treatment with NSA, NOD-like receptor 3 (NLRP3), GSDMD-N, phosphorylated-MLKL, and phosphorylated-RIP3 levels in cardiac tissue were reduced with corresponding reductions in inflammatory cytokine levels. Administration of NSA significantly improved myocardial dysfunction succeeding global myocardial I/R injury and enhanced survival outcomes through protective mechanisms potentially related to inhibition of pyroptosis and necroptosis pathways.

The Use of Levosimendan after Out-of-Hospital Cardiac Arrest and Its Association with Outcome-An Observational Study.

Background: Levosimendan improves resuscitation rates and cardiac performance in animal cardiac arrest models. The aim of this study was to describe the use of levosimendan in out-of-hospital cardiac arrest (OHCA) patients and its association with outcome. Methods: A retrospective observational study of OHCA patients admitted to six intensive care units in Stockholm, Sweden, between 2010 and 2016. Patients treated with levosimendan within 24 h from admission were compared with those not treated with levosimendan. Propensity score matching and multivariable logistic regression analysis were used to assess the association between levosimendan treatment and 30-day mortality Results: Levosimendan treatment was initiated in 94/940 (10%) patients within 24 h. The proportion of men (81%, vs. 67%, p = 0.007), initial shockable rhythm (66% vs. 37%, p < 0.001), acute myocardial infarction, AMI (47% vs. 24%, p < 0.001) and need for vasoactive support (98% vs. 61%, p < 0.001) were higher among patients treated with levosimendan. After adjustment for age, sex, bystander cardiopulmonary resuscitation, witnessed status, initial rhythm and AMI, the odds ratio (OR) for 30-day mortality in the levosimendan group compared to the no-levosimendan group was 0.94 (95% Confidence interval [CI], 0.56–1.57, p = 0.82). Similar results were seen when using a propensity score analysis comparing patients with circulatory shock. Conclusions: In this observational study of OHCA patients, levosimendan was used in a limited patient group, most often in those with initial shockable rhythms, acute myocardial infarction and with a high need for vasopressors. In this limited patient cohort, levosimendan treatment was not associated with 30-day mortality. However, a better matching of patient factors and indications for use is required to derive conclusions on associations with outcome.

Protective effect of Tulbaghia violacea extract on cardiac damage: deep circulatory arrest rat model

Objectives: Total circulatory arrest (TCA) technique is a method used in cardiac surgery accompanied by cardiopulmonary bypass (CPB). It has been shown that Tulbaghia violacea extract increases antioxidant capacity, regulates blood pressure, decreases lipid peroxide, and reduces atherosclerosis. In this experimental study, we aimed to investigate the effect of T. violacea extract administration on serum oxidative stress parameters (Total antioxidant status [TAS], total oxidant status [TOS] and oxidative stress index [OSI] and deoxyribonucleic acid [DNA] damage level with 8-Hydroxy-2-Deoxyguanosine [8-OHdG]) and histopathological changes in the heart and other organs in rats with deep circulatory arrest model. Methods: In this study, 48 Wistar Albino adult rats, 24 female and 24 male, obtained from Harran University Experimental Animals Research Center were used. The average weight of female rats was 250-300 g, and the average weight of male rats was 450-500 g. These rats were randomly divided into four groups. 6 male and 6 female rats were used in each group (Group 1 = Sham, Group 2 = Injury, Group 3 = Treatment and Injury, Group 4 = Treatment). Results: As a result of this experimental study, the changes in the biochemical 8-OHdG, TOS, OSI and TAS levels of the groups were found to be statistically significant (p &amp;lt; 0.001). In the subgroup analyzes of the data, 8-OHdG level, which is an oxidative DNA damage marker in Group 2 was higher than the Group 1, Group 3 and Group 4 and there was a statistically significant difference (p &amp;lt; 0.001, p = 0.027 and p &amp;lt; 0.001; respectively). The TOS level of the injury group was higher than Group 1, Group 3 and Group 4 and there was a statistically significant difference (p &amp;lt; 0.001, p = 0.003 and p &amp;lt; 0.001; respectively). Conclusions: As a result of our study, we revealed that T. violacea extract has a protective effect on organ and tissue damage in the TCA model.

Automated aortic endovascular balloon volume titration prevents re-arrest immediately after return of spontaneous circulation in a swine model of nontraumatic cardiac arrest

ObjectivesEndovascular aortic occlusion as an adjunct to cardiopulmonary resuscitation (CPR) for non-traumatic cardiac arrest is gaining interest. In a recent clinical trial, return of spontaneous circulation (ROSC) was achieved despite prolonged no-flow times. However, 66% of patients re-arrested upon balloon deflation. We aimed to determine if automated titration of endovascular balloon volume following ROSC can augment diastolic blood pressure (DBP) to prevent re-arrest. MethodsTwenty swine were anesthetized and placed into ventricular fibrillation (VF). Following 7 minutes of no-flow VF and 5 minutes of mechanical CPR, animals were subjected to complete aortic occlusion to adjunct CPR. Upon ROSC, the balloon was either deflated steadily over 5 minutes (control) or underwent automated, dynamic adjustments to maintain a DBP of 60 mmHg (Endovascular Variable Aortic Control, EVAC). ResultsROSC was obtained in ten animals (5 EVAC, 5 REBOA). Sixty percent (3/5) of control animals rearrested while none of the EVAC animals rearrested (p = 0.038). Animals in the EVAC group spent a significantly higher proportion of the post-ROSC period with a DBP > 60 mmHg [median (IQR)] [control 79.7 (72.5–86.0)%; EVAC 97.7 (90.8–99.7)%, p = 0.047]. The EVAC group had a statistically significant reduction in arterial lactate concentration [7.98 (7.4–8.16) mmol/L] compared to control [9.93 (8.86–10.45) mmol/L, p = 0.047]. There were no statistical differences between the two groups in the amount of adrenaline (epinephrine) required. ConclusionIn our swine model of cardiac arrest, automated aortic endovascular balloon titration improved DBP and prevented re-arrest in the first 20 minutes after ROSC.

Methylene Blue Reduces Fluid Loading and Norepinephrine Requirements for Post-Resuscitation Syndrome in a Pig Model of Refractory Cardiac Arrest Resuscitated with Veno-Arterial ECMO.

Background: Refractory cardiac arrest management relies on extracorporeal cardiopulmonary resuscitation (ECPR), requiring the use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Circulatory flow recovery can be associated with an ischemia–reperfusion injury, leading to vasoplegia and vasopressor requirement. The aim of this work was to evaluate the impact on hemodynamics of a methylene blue bolus infusion in a porcine model of ischemic refractory cardiac arrest. Methods: Ischemic refractory cardiac arrest was induced in 20 pigs. After a low flow period of 30 min, VA-ECMO was initiated and the pigs were randomly assigned to the standard care group (norepinephrine + crystalloids) or methylene blue group (IV 2 mg·kg−1 bolus of methylene blue over 30 min + norepinephrine and crystalloids). Macrocirculatory parameters and lactate clearance were measured. Sublingual microcirculation was evaluated with sidestream dark field (SDF) imaging. The severity of the ischemic digestive lesions was assessed according to the histologic Chiu/Park scale. Results: Eighteen pigs were included. The total crystalloid load (5000 (6000–8000) mL vs. 17,000 (10,000–19,000) mL, p = 0.007, methylene blue vs. standard care group) and catecholamine requirements (0.31 (0.14–0.44) μg·kg−1·min−1 vs. 2.32 (1.17–5.55) μg·kg−1·min−1, methylene blue vs. standard care group, p = 0.004) were significantly reduced in the methylene blue group. There were no significant between-group differences in lactate clearance, sublingual capillary microvascular parameters assessed by SDF or histologic Chiu/Park scale. Conclusions: In our refractory cardiac arrest porcine model treated with ECPR, methylene blue markedly reduced fluid loading and norepinephrine requirements in comparison to standard care during the first 6 h of VA-ECMO.

Electroacupuncture attenuates brain injury through α7 nicotinic acetylcholine receptor-mediated suppression of neuroinflammation in a rat model of asphyxial cardiac arrest

We determined whether electroacupuncture (EA) ameliorated brain injury following asphyxial cardiac arrest (CA) and evaluated the role of the α7 nicotinic acetylcholine receptor (α7nAChR)-mediated anti-inflammatory pathway. In CA-induced rats, EA reduced brain injury and promoted behavioral recovery. Morris water maze escape latency time reduced after Baihui (GV20) and Shuigou (DU26) stimulation. EA reduced α7nAChR downregulation after cardiopulmonary resuscitation (CPR), reducing tumor necrosis factor alpha, interleukin-1, and interleukin-6 expression and ionized calcium binding adapter molecule 1 production. The α7nAChR antagonist methyllycaconitine reversed EA effect. EA stimulation of acupuncture points alleviated brain damage after CPR and reduced the inflammatory response via α7nAChR activation.

Hydrogen therapy after resuscitation improves myocardial injury involving inhibition of autophagy in an asphyxial rat model of cardiac arrest

Hydrogen (H2) therapy is a therapeutic strategy using molecular H2. Due to its ability to regulate cell homeostasis, H2 therapy has exhibited marked therapeutic effects on a number of oxidative stress-associated diseases. The present study investigated the effectiveness of H2 therapy in protecting against myocardial injury in a rat model of asphyxial cardiac arrest and cardiopulmonary resuscitation. Rats underwent 10-min asphyxia-induced cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), and were randomly divided into control and H2 therapy groups. After resuscitation, the H2 therapy group was administered room air mixed with 2% H2 gas for respiration. During CA/CPR, the arterial pressure and heart rate were measured every minute. Survival rate, cardiac function, myocardial injury biomarkers creatine kinase-MB and cardiac troponin-T, and histopathological changes were evaluated to determine the protective effects of H2 therapy in CA/CPR. Immunohistochemistry and western blot analysis were used to determine the expression levels of autophagy-associated proteins. In vitro, H9C2 cells were subjected to hypoxia/reoxygenation and H2-rich medium was used in H2 treatment groups. Western blotting and immunofluorescence were used to observe the expression levels of autophagy-associated proteins. Moreover, an adenovirus-monomeric red fluorescent protein-green fluorescent protein-LC3 construct was used to explore the dynamics of autophagy in the H9C2 cells. The results showed that H2 therapy significantly improved post-resuscitation survival and cardiac function. H2 therapy also improved mitochondrial mass and decreased autophagosome numbers in cardiomyocytes after resuscitation. The treatment inhibited autophagy activation, with lower expression levels of autophagy-associated proteins and decreased autophagosome formation in vivo and vitro. In conclusion, H2 gas inhalation after return of spontaneous circulation improved cardiac function via the inhibition of autophagy.

Post-Cardiac Arrest Syndrome Is Not Associated With an Early Bacterial Translocation.

The aim of this study was to investigate bacterial translocation and its possible role in the development of post-resuscitation inflammatory response following Cardio-Pulmonary Resuscitation (CPR) after cardiac arrest. Munich female swine were employed for a model of cardiac arrest via application of electrical current. After 7 min, CPR was initiated, and animals were either successfully return to spontaneous circulation (ROSC) within 40 min or not (no-ROSC). At the end of experimental period and prior to sacrifice, samples from the intestine, mesenteric lymph nodes (MLN), liver and portal vein blood were obtained. Evaluation of inflammation and gut permeability was performed; MLN, liver and portal vein samples were analyzed for 16 s rRNA detection and cytokine mRNA expression. A decreased expression of the tight junction protein Occludin, with higher levels of inflammation, greater epithelial disintegration, ulceration, loss of crypts and villi height were found in the intestines of the ROSC swine in comparison to no-ROSC. The macrophage surface antigen CD-14 staining was relatively more intense in the ROSC than in no-ROSC. Higher levels of TNF-α mRNA expression were present in the liver of the ROSC group. Finally, despite the inflammatory response and the gut mucosal alterations in ROSC group, no bacterial translocation was detected in liver, MLN and portal vein. We show that resuscitation from cardiac arrest induces inflammatory response and intestinal permeability in swine 4h after resuscitation, but not a bacterial translocation. Bacterial translocation is not an early phase phenomenon but probably part of the pathophysiologic sequelae.

Electrical design analyses studies on ultra high voltage air insulated surge arresters

Abstract Air Insulated substations (AIS) experience over-voltages like lightning, switching and temporary over-voltages. The voltage distribution across air insulated surge arrester (AISA) is highly non-uniform and its non-uniformity increases with increase of rated voltage. To achieve non-uniformity voltage factor within permissible limits, special grading shields like window based shields are proposed. In the present study, 420 / 800 kV surge arrester models with composite insulator housing have been considered to analyze voltage distribution across the metal-oxide (MO) blocks. The electrostatic field and voltage distribution analyses are carried out on AISA by considering various shield designs using numerical techniques. Instead of single grading shield, multiple voltage grading-cum-electric field controlled shields are adopted to achieve uniform electric field and optimized non-uniformity voltage factors in the order of ±8 % irrespective of rated voltage of surge arrester. An electrical model is also developed using PSPICE software to calculate voltage distribution across MO blocks. The validity of the network model developed through PSPICE is validated by comparing with the results obtained from numerical analysis. Different configurations of grading shields are proposed and effect of various parameters like rated voltage i.e. 420/800 kV, height of shield, diameter of shield and type of shield like high voltage, floating, LT shield etc. on non-uniformity voltage factor and electric field distribution of surge arrester are analyzed.

Novel capsaicin releasing system targeted protects ischemic brain from cardiac arrest

Objectiveas a fatal cardiovascular emergency, cardiac arrest causes cerebral ischemic injury as a main complication. Recently, capsaicin has attracted great attention for its activating effect on TRPV1 as well as various organ protective effects especially in brain. However, the poor water-solubility and extremely short biological half-life of capsaicin largely impedes the clinical use of it. Blood-brain barrier (BBB) consist another great challenge of application of capsaicin in ischemic brain. Methodsin this study, we employed the mesoporous iron oxide nanoparticles (MIONs) for carriers to load capsaicin. The nanoparticles were further modified with polyethylene glycol (PEG) and lactoferrin (LF). Resultsa novel capsaicin releasing system was developed (Capsaicin-MIPL), with controlled and slow releasing manner and brain targeted ability. The novel system showed excellent biocompatibility. Fluorescent nanoparticles were found to be localized in mice brain areas, with increased capsaicin levels in brain tissues. The protective effects of Capsaicin-MIPL were both investigated in the in vitro hypoxic neuron models and the in vivo cardiac arrest models, and significant neuroprotective effects were observed. ConclusionThis study offers a practical tool for controlled release of capsaicin in vivo especially in brain, and provides a novel method for cerebral protection after cardiac arrest.

Noninvasive Versus Invasive Brain Temperature Measurement During Targeted Temperature Management: A Preclinical Study in a Swine Cardiac Arrest Model.

We aimed to evaluate correlation and agreement between noninvasive brain temperature (TBN) and invasive brain temperature (TBI) measurement during targeted temperature management (TTM) in a swine cardiac arrest model. Defibrillation attempts were provided after 5 minutes of ventricular fibrillation and 12 minutes of cardiopulmonary resuscitation in five pigs. After return of spontaneous circulation, TTM was provided with induction and maintenance phases with a target temperature of 33°C for 6 hours and a rewarming phase with a rewarming rate of 1°C/h for 4 hours. TBN and TBI were measured using a double sensor method and an intracranial catheter, respectively. Pulmonary artery temperature (TP), esophageal temperature (TE), and rectal temperature (TR) were measured. Primary outcomes were correlation and agreement between TBN and TBI and secondary outcomes were correlation and agreement among TBN and other temperatures. The Pearson correlation coefficient (PCC) between TBN and TBI was 0.95 (p < 0.001) during the whole TTM phases. PCCs between TBN and TBI during the induction, maintenance, and rewarming phases were 0.91 (p < 0.001), 0.88 (p < 0.001), and 0.94 (p < 0.001) and 95% limits of agreement (LoAs) between TBN and TBI were (-0.27°C to 0.78°C), (-0.18°C to 0.54°C), and (-0.93°C to 0.88°C), respectively. Correlation between TBN and TBI during the maintenance phase was higher than correlation between TBN and TE (PCC = 0.74, p < 0.001) or TP (PCC = 0.81, p < 0.001). The 95% LoAs were narrowest between TBN and TP in the induction phase (-0.58 to 0.11), between TBN and TBI in the maintenance phase (-0.54 to 0.18), and between TBN and TR in the rewarming phase (-0.96 to 0.84). Noninvasive brain temperature showed good correlation with invasive brain temperature during TTM in a swine cardiac arrest model. Correlation was highest during the rewarming phase and lowest during the maintenance phase. Agreement between the two measurements was not clinically acceptable.

Carbon monoxide-releasing molecule-2 protects intestinal mucosal barrier function by reducing epithelial tight-junction damage in rats undergoing cardiopulmonary resuscitation

BackgroundIschemia-reperfusion injury (IRI) to the small intestine is associated with the development of systemic inflammation and multiple organ failure after cardiopulmonary resuscitation (CPR). It has been reported that exogenous carbon monoxide (CO) reduces IRI. This study aimed to assess the effects of carbon monoxide-releasing molecule-2 (CORM-2) on intestinal mucosal barrier function in rats undergoing CPR. MethodsWe established a rat model of asphyxiation-induced cardiac arrest (CA) and resuscitation to study intestinal IRI, and measured the serum levels of intestinal fatty acid-binding protein. Morphological changes were investigated using light and electron microscopes. The expression levels of claudin 3 (CLDN3), occludin (OCLN), zonula occludens 1 (ZO-1), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and nuclear factor kappa B (NF-κB) p65 were detected by western blotting. ResultsCompared with the sham-operated group, histological changes and transmission electron microscopy revealed severe intestinal mucosal injury in the CPR and inactive CORM-2 (iCORM-2) groups. In contrast, CORM-2 alleviated intestinal IRI. CORM-2, unlike iCORM-2, markedly decreased the Chiu's scores (2.38 ± 0.38 vs. 4.59 ± 0.34; P < 0.05) and serum intestinal fatty acid-binding protein level (306.10 ± 19.22 vs. 585.64 ± 119.84 pg/mL; P < 0.05) compared with the CPR group. In addition, CORM-2 upregulated the expression levels of tight junction proteins (CLDN3, OCLN, and ZO-1) (P < 0.05) and downregulated those of IL-10, TNF-α, and NF-кB p65 (P < 0.05) in the ileum tissue of rats that received CPR. ConclusionsCORM-2 prevented intestinal mucosal damage as a result of IRI during CPR. The underlying protective mechanism was associated with inhibition of ischemia-reperfusion-induced changes in intestinal epithelial permeability and inflammation in intestinal tissue.

Alda-1, an Activator of ALDH2, Improves Postresuscitation Cardiac and Neurological Outcomes by Inhibiting Pyroptosis in Swine

Aldehyde dehydrogenase 2 (ALDH2) has been proven to protect the heart and brain against regional ischemia/reperfusion injury, in which the protective role is related to the inhibition of pyroptosis. In the present study, we investigated whether an ALDH2 activator N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichloro-benzamide (Alda-1) would improve postresuscitation cardiac and neurological outcomes in a clinically relevant swine model of cardiac arrest (CA) and resuscitation. The animal model was established by 8min of untreated ventricular fibrillation and then 8min of cardiopulmonary resuscitation (CPR). After restoring spontaneous circulation, the animals were randomly divided to receive either Alda-1 (0.88mg/kg, n = 6) or saline (n = 5). Postresuscitation hemodynamic parameters, cardiac function, and cardiac and cerebral injuries were periodically measured for a total of 24h. At 24h postresuscitation, neurological function was evaluated, and then the animals were sacrificed, and cardiac and cerebral tissue samples were obtained for the measurements of oxidative stress, inflammation and pyroptosis. Consequently, postresuscitation cardiac and neurological dysfunction were significantly improved accompanied with significantly milder cardiac and cerebral injuries in the Alda-1 group compared with the CPR group. In addition, the increase in NLR family pyrin domain-containing 3 inflammasome expression and proinflammatory cytokine production, which indicated the occurrence of inflammatory response, were significantly less in the Alda1 group than in the CPR group. The expression level of gasdermin D used as a protein marker of pyroptosis was also significantly reduced in all resuscitated animals receiving Alda1 treatment. Moreover, the severity of oxidative stress indicated by the changes of 4-hydroxy-2-nonenal and malondialdehyde was significantly decreased in the heart and brain in all animals treated with Alda-1 compared to the CPR group. Thus, Alda-1 mitigated postresuscitation cardiac and neurological dysfunction and injuries possibly by inhibiting oxidative stress-mediated NLRP3 inflammasome activation and pyroptosis in a swine model of CA and resuscitation.

A comprehensive neuromonitoring approach in a large animal model of cardiac arrest.

BackgroundAnoxic brain injuries represent the main determinant of poor outcome after cardiac arrest (CA). Large animal models have been described to investigate new treatments during CA and post‐resuscitation phase, but a detailed model that includes extensive neuromonitoring is lacking.MethodBefore an electrically‐induced 10‐minute CA and resuscitation, 46 adult pigs underwent neurosurgery for placement of a multifunctional probe (intracranial pressure or ICP, tissue oxygen tension or PbtO2 and cerebral temperature) and a bolt‐based technique for the placement and securing of a regional blood flow probe and two sEEG electrodes; two modified cerebral microdialysis (CMD) probes were also inserted in the frontal lobes and accidental misplacement was prevented using a perforated head support.Result42 animals underwent the CA procedure and 41 achieved the return of spontaneous circulation (ROSC). In 4 cases (8.6%) an adverse event took place during preparation, but only in two cases (4.3%) this was related to the neurosurgery. In 6 animals (13.3%) the minor complications that occurred resolved after probe repositioning.ConclusionHerein we provide a detailed comprehensive neuromonitoring approach in a large animal model of CA that might help future research.

Early Thalamocortical Reperfusion Leads to Neurologic Recovery in a Rodent Cardiac Arrest Model.

Cerebral blood flow (CBF) plays an important role in neurological recovery after cardiac arrest (CA) resuscitation. However, the variations of CBF recovery in distinct brain regions and its correlation with neurologic recovery after return of spontaneous circulation (ROSC) have not been characterized. This study aimed to investigate the characteristics of regional cerebral reperfusion following resuscitation in predicting neurological recovery. Twelve adult male Wistar rats were studied, ten resuscitated from 7-min asphyxial CA and two uninjured rats, which were designated as healthy controls (HCs). Dynamic changes in CBF in the cerebral cortex, hippocampus, thalamus, brainstem, and cerebellum were assessed by pseudocontinuous arterial spin labeling magnetic resonance imaging, starting at 60min after ROSC to 156min (or time to spontaneous arousal). Neurologic outcomes were evaluated by the neurologic deficit scale at 24h post-ROSC in a blinded manner. Correlations between regional CBF (rCBF) and neurological recovery were undertaken. All post-CA animals were found to be nonresponsive during the 60-156min post ROSC, with reductions in rCBF by 24-42% compared with HC. Analyses of rCBF during the post-ROSC time window from 60 to 156min showed the rCBF recovery of hippocampus and thalamus were positively associated with better neurological outcomes (rs = 0.82, p = 0.004 and rs = 0.73, p < 0.001, respectively). During 96min before arousal, thalamic and cortical rCBF exhibited positive correlations with neurological recovery (rs = 0.80, p < 0.001 and rs = 0.65, p < 0.001, respectively); for predicting a favorable neurological outcome, the thalamic rCBF threshold was above 50.84ml/100g/min (34% of HC) (area under the curve of 0.96), whereas the cortical rCBF threshold was above 60.43ml/100g/min (38% of HC) (area under the curve of 0.88). Early magnetic resonance imaging analyses showed early rCBF recovery in thalamus, hippocampus, and cortex post ROSC was positively correlated with neurological outcomes at 24h. Our findings suggest new translational insights into the regional reperfusion and the time window that may be critical in neurological recovery and warrant further validation.

Rapid Treatment with Intramuscular Magnesium Sulfate During Cardiopulmonary Resuscitation Does Not Provide Neuroprotection Following Cardiac Arrest.

Brain injury is the most common cause of death for patients resuscitated from cardiac arrest. Magnesium is an attractive neuroprotective compound which protects neurons from ischemic injury by reducing neuronal calcium overload via NMDA receptor modulation and preventing calcium-induced mitochondrial permeability transition. Intramuscular (IM) delivery of MgSO4 during CPR has the potential to target these mechanisms within an early therapeutic window. We hypothesize that IM MgSO4 administrated during CPR could achieve therapeutic serum magnesium levels within 15min after ROSC and improve neurologic outcomes in a rat model of asphyxial cardiac arrest. Male Long Evans rats were subjected to 8-min asphyxial cardiac arrest and block randomized to receive placebo, 107mg/kg, 215mg/kg, or 430mg/kg MgSO4 IM at the onset of CPR. Serum magnesium concentrations increased rapidly with IM delivery during CPR, achieving twofold to fourfold increase by 15min after ROSC in all magnesium dose groups. Rats subjected to cardiac arrest or sham surgery were block randomized to treatment groups for assessment of neurological outcomes. We found that IM MgSO4 during CPR had no effect on ROSC rate (p > 0.05). IM MgSO4 treatment had no statistically significant effect on 10-day survival with good neurologic function or hippocampal CA1 pyramidal neuron survival compared to placebo treatment. In conclusion, a single dose IM MgSO4 during CPR achieves up to fourfold baseline serum magnesium levels within 15min after ROSC; however, this treatment strategy did not improve survival, recovery of neurologic function, or neuron survival. Future studies with repeated dosing or in combination with hypothermic targeted temperature management may be indicated.

Ketamine Mitigates Neurobehavioral Deficits in a Canine Model of Hypothermic Circulatory Arrest

Hypothermic circulatory arrest is a protective technique used when complete cessation of circulation is required during cardiac surgery. Prior efforts to decrease neurologic injury with the NMDA receptor antagonist MK801 were limited by unacceptable side effects. We hypothesized that ketamine would provide neuroprotection without dose-limiting side effects. Canines were peripherally cannulated for cardiopulmonary bypass, cooled to 18°C, and underwent 90 minutes of circulatory arrest. Ketamine-treated canines (n=5; total dose 2.85 mg/kg) were compared to untreated controls (n=10). A validated neurobehavioral deficit score was obtained at 24, 48, and 72 hours (0=no deficits/normal exam; higher score represents increasing deficits). Biomarkers of neuronal injury in the cerebrospinal fluid were examined at baseline and at 8, 24, 48, and 72 hours. Brain histopathologic injury was scored at 72 hours (higher score indicates more necrosis and apoptosis). Ketamine-treated canines had significantly improved, lower neurobehavioral deficit scores compared to controls (overall P=0.003; 24 hours: median 72 vs 112, P=0.030; 48 hours: 47 vs 90, P=0.021; 72 hours: 30 vs 89, P=0.069). Although the histopathologic injury scores of ketamine-treated canines (median 12) were lower than controls (16), there was no statistical difference (P=0.10). Levels of phosphorylated neurofilament-H and neuron specific enolase, markers of neuronal injury, were significantly lower in ketamine-treated animals (P=0.010 and=0.039, respectively). Ketamine significantly reduced neurologic deficits and biomarkers of injury in canines after hypothermic circulatory arrest. Ketamine represents a safe and approved medication that may be useful as a pharmacologic neuroprotectant during cardiac surgery with circulatory arrest.

Hemodynamic efficacy of a motor-driven automatic device performing simultaneous sternothoracic cardiopulmonary resuscitation compared to standard cardiopulmonary resuscitation in an animal model of cardiac arrest

The aim of this study was to investigate hemodynamic effects and resuscitation outcomes of simultaneous sternothoracic cardiopulmonary resuscitation (SST-CPR) with a prototype of a motor-driven automatic device, comparing to manual standard CPR (S-CPR), in an animal model of ventricular fibrillation (VF). 20 male pigs were randomized to receive standard CPR (S-CPR group) or CPR with an automatic SST-CPR device (A-CPR group) after 5 minutes of VF. Five minutes of basic life support CPR was performed, followed by 10 minutes of advanced life support CPR. Hemodynamic variables including systolic blood pressure (SBP), diastolic blood pressure (DBP), coronary perfusion pressure (CPP), and end-tidal carbon dioxide tension (ETCO2), and resuscitation outcomes including rate of restoration of spontaneous circulation (ROSC) and 2-hour survival were compared between two groups. Ten animals among the A-CPR group and 8 animals among the S-CPR group were included in the final analysis. SBP was higher in the A-CPR group than in the S-CPR group during CPR (p = 0.046). The DBP, CPP and ETCO2 were not different between two groups (p = 0.412, 0.585, and 0.243, respectively). ROSC rate was 38% in the S-CPR group and 10% in the A-CPR group (p = 0.275). The 2-hour survival rate was 25% in the S-CPR group and 0% in the A-CPR group (p = 0.183). In a swine model of cardiac arrest, CPR with a prototype of a motor-driven automatic SST-CPR device, compared with standard CPR, produced higher systolic blood pressure, but there was no difference in diastolic pressure, coronary perfusion pressure, ROSC rate and 2-hour survival rate.

The Selective NLRP3-inflammasome inhibitor MCC950 Mitigates Post-resuscitation Myocardial Dysfunction and Improves Survival in a Rat Model of Cardiac Arrest and Resuscitation

PurposeTo investigate the effects of the selective NLRP3 inflammasome inhibitor MCC950 on post-resuscitation myocardial function and survival in a rat model of cardiopulmonary resuscitation (CPR).MethodsThirty-six Sprague Dawley rats were randomized into three groups: (1) MCC950, (2) control, and (3) sham. Each group consisted of a 6 h non-survival subgroup (n = 6) and a 48 h survival subgroup (n = 6). Ventricular fibrillation (VF) was induced and untreated for 6 min. CPR was initiated and continued for 8 min. Resuscitation was attempted with a 4 J defibrillation. MCC950 (10 mg/kg) or vehicle was administered via intraperitoneal injection immediately after the return of spontaneous circulation (ROSC). Myocardial function and sublingual microcirculation were measured after ROSC in the non-survival subgroups. Plasma levels of interleukin Iβ (IL-1β) and cardiac troponin I (cTnI) were measured at baseline and 6 h in the non-survival subgroups. Heart tissue was harvested to measure the NLRP3 inflammasome constituents, including NLRP3, apoptosis-associated speck-like protein (ASC), Caspase-1, and IL-1β. Survival duration and neurologic deficit score (NDS) were recorded and evaluated among survival groups.ResultsPost-resuscitation myocardial function and sublingual microcirculation were improved in MCC950 compared with control (p < 0.05). IL-1β and cTnI were decreased in MCC950 compared to control (p < 0.01). The MCC950 treated groups showed significantly reduced ASC, caspase-1, and IL-1β compared with the control group (p < 0.05). Survival at 48 h after ROSC was greater in MCC950 (p < 0.05) with improved NDS (p < 0.05).ConclusionAdministration of MCC950 following ROSC mitigates post-resuscitation myocardial dysfunction and improves survival.