Min Of Ventricular Fibrillation Research Articles

Abstract 15552: Augmentation of Right Ventricular Strain Dynamics During Direct Mechanical Ventricular Actuation

Introduction: Available forms of mechanical circulatory support are associated with significant complications related to blood contact. Direct cardiac compression (DCC) devices avoid blood contact but may impair diastolic function. This derogatory effect of DCC devices may be related to a negative impact on RV function. Direct mechanical ventricular actuation (DMVA) uniquely augments LV diastolic function. The purpose of this study was to evaluate DMVA’s effect on RV function. Methods: Ischemic heart failure (HF) was induced using 5 mins of ventricular fibrillation (VF) circulatory arrest in large mature canines (n=9). Hearts were defibrillated and DMVA applied for 15 mins. VF circulatory arrest was subsequently re-induced for 5 mins to generate progressive HF. The experimental protocol was continued for 3 hrs. Intracardiac echocardiography was used to quantify longitudinal strain and peak strain rates in the RV and LV using speckle-tracking algorithms. Two-way ANOVA with Tukey HSD tests were used to evaluate statistical differences in strain metrics (baseline vs. HF vs. DMVA support and LV vs. RV). Results: DMVA increased RV fractional area change (DMVA: 0.282 ± 0.011, Mean ± SEM) relative to either baseline (0.221 ± 0.15, p=0.004) or HF (0.170 ± 0.006, p<0.001). DMVA statistically significantly augmented all RV strain metrics relative to either baseline or HF (Table). Additionally, all DMVA strain metrics were statistically significantly greater in the RV than the LV (LV strain: 18.8 ± 0.5 %, p<0.001, LV strain rate: systolic, -1.46 ± 0.04 1/s, p<0.001, diastolic, 1.51 ± 0.04 1/s, p<0.001). Conclusions: DMVA substantially improved RV strain dynamics compared to baseline or HF in this model. During DMVA support, strain dynamics in the RV were amplified more than the LV. This RV augmentation is important to achieving balanced biventricular DMVA support. Enhanced diastolic RV and LV augmentation during DMVA remains highly unique when compared to any other devices.

C2 DIFFERENT CLINICAL PREDICTORS OF EARLY AND LATE PRIMARY VENTRICULAR FIBRILLATION: RESULTS OF THE PREDESTINATION STUDY

Abstract Introduction Few studies evaluated risk factors for primary ventricular fibrillation (VF) before reperfusion during a first acute myocardial infarction (AMI). Important parameters such as kalemia, blood pressure (BP) and heart rate (HR) at presentation were rarely considered. Furthermore, potential differences according to the time elapsed between symptoms onset and VF onset have never been investigated. Objectives to evaluate predictors of primary VF in the PREDESTINATION (PRImary vEntricular fibrillation and suDden dEath during a firST myocardIal iNfArcTION) study cohort also differentiating between early (<60 min from symptoms onset) and late (>60 min) VF. Early VF is more likely to cause sudden death (SD) before medical services arrival. Patients and Methods PREDESTINATION is a prospective, multicenter, case–control (1:2 age– and sex–matched) study enrolling patients aged 18–80 years with a first AMI, either complicated (cases) or not (controls) by primary VF before reperfusion. Results 1478 patients were analysed: mean age was 59 years, 83% were male, 36% cases. The multivariate analysis (logistic regression) on the whole population (c–statistic= 0.74) identified 8 independent predictors of primary VF: atrial fibrillation as presenting rhythm (OR 4.61), kalemia ≤3.5 mEq/L (OR 2.8), HR at presentation ≥90 bpm (OR 2.25), first–degree family history of SD (OR 2.08), anterior infarct site (OR 1.54), physical inactivity (OR 1.59), systolic BP at presentation (OR 0.98 for each mmHg), and first–degree family history of coronary artery disease/myocardial infarction (OR 0.71). The time elapsed between symptoms onset and VF was known for 405 cases (184 early and 221 late VF). There were 6 predictors of early VF, with loss of significance of physical inactivity and of family history of coronary artery disease/infarction, and an increase in the OR of family history of SD to 2.85 (95% CI: 1.6–5.08), and in the c–statistic of the model to 0.80. Among the 6 predictors of late VF, on the other hand, anterior site of AMI and family history of SD were not confirmed (c–statistic of the model 0.7). Conclusions The present study identified 8 independent predictors of primary VF. First–degree family history of SD is a powerful independent predictor of early VF, but not of late VF, suggesting that genetic predisposition plays a determining role only in early–onset VF cases and therefore the advisability of a specific genetic investigation in these patients.

The monoacylglycerol lipase inhibitor, JZL184, has comparable effects to therapeutic hypothermia, attenuating global cerebral injury in a rat model of cardiac arrest

Post-resuscitation cerebral ischemia-reperfusion injury (IRI) is a vital contributor to poor neurological prognosis. Exploring novel therapeutics that attenuate cerebral IRI is of great significance. Inflammation plays a role in the development of cerebral IRI after successful cardiopulmonary resuscitation (CPR). Monoacylglycerol lipase (MAGL) is an enzyme that is predominantly responsible for the metabolism of endocannabinoid 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) metabolites, which are associated with inflammation. Therefore, we investigated the efficacy of the MAGL inhibitor, JZL184, on cerebral IRI and further compared the effects to therapeutic hypothermia (TH). Thirty-six rats were randomized into three groups: 1) JZL184; 2) Control; 3) TH (N = 12 for each group). Animals underwent 6 min of ventricular fibrillation (VF) followed with 8 min of CPR. After return of spontaneous circulation (ROSC), rats received an intraperitoneal injection of JZL184 (16 mg/kg) or DMSO (20 mg/ml) or body cooling was initiated. Cerebral microcirculation, brain edema, blood brain barrier (BBB) permeability, serum neuron-specific enolase (NSE), S-100β, interleukin-6 (IL-6) and interleukin-10 (IL-10) were quantified at 6 h post ROSC. Compared to control, treatment with JZL184 or TH was associated with significantly ameliorated cerebral microcirculation, mitigated brain edema, attenuated BBB permeability, decreased serum levels of NSE, S-100β and IL-6, and increased serum IL-10 levels (p < 0.05). There was no significant difference in the above measurements between JZL184 and TH. JZL184 has comparable neuroprotective effects to therapeutic hypothermia on global cerebral IRI in a rat model of cardiac arrest (CA).

Abstract 10941: Cerebral Consumption of Lactate Increases Neurological Injury After Experimental Cardiac Arrest in Rabbits

Introduction: Neuronal consumption of lactate is known to be protective after long duration of brain ischaemia. However, its consequences on neurological function after shorter duration of ischemia like after cardiac arrest are unknown. Hypothesis: We hypothesized that cerebral lactate consumption is deleterious for neurological outcome, whereas lactate dehydrogenase inhibition by oxamate could improve recovery. Methods: Male New-Zealand rabbits were anesthetized and surgically instrumented to assess lactate, glucose and O 2 cerebral consumption by measurement of the arterio-jugular differences. After 10 min of ventricular fibrillation, animals were resuscitated and randomly received a 30-min infusion of either saline (Control, n=6), lactate (Lact, 5 mg/kg/min, n=6) or oxamate (Oxa, 37.5 mg/kg/min, n=6). They were followed during 4 h. Additional animals were submitted to the same procedure without surgical instrumentation to allow recovery and assessment of neurological function during 48 h after cardiac arrest. In both experiments, neuronal death was assessed histologically by fluorojade C staining. Results: In Control group, a strong increase of the cerebral consumption of O 2 , glucose and lactate was observed during the 4 hours following resuscitation. In Lact group, lactate consumption was increased as compared to Control, whereas it was almost abolished in Oxa group (17.13±3.59, 32.60±6.24 and 4.04±1.58 mmol/L/min in Control, Lact and Oxa, respectively). Additionally, Oxa group presented a reduced consumption of glucose and O 2 after cardiac arrest as compared to other groups. Interestingly, administration of oxamate was highly neuroprotective whereas lactate administration worsened the neurological outcome after cardiac arrest (38±4, 64±10 and 15±6 % of neurological dysfunction score at 48h in Control, Lact and Oxa, respectively). Oxamate infusion was also associated with a significant reduction in the number of degenerative neurons at 4 h and 48 h of follow-up. Conclusions: The cerebral consumption of lactate appeared to be detrimental in rabbits after cardiac arrest. Its inhibition by oxamate is potently neuroprotective.

Compression depth of 30 mm has similar efficacy and fewer complications versus 50 mm during mechanical chest compression with miniaturized chest compressor in a porcine model of cardiac arrest.

BackgroundCurrent guidelines recommend a 50 mm or greater compression depth for manual chest compression in adults. However, whether this uniform compression depth is a suitable requirement for mechanical CPR remains to be determined. We hypothesized that a relatively shallow compression depth (30 mm) would have similar hemodynamic efficacy but fewer complications versus the standard compression depth (50 mm) during mechanical cardiopulmonary resuscitation (CPR) with the miniaturized chest compressor (MCC) in a porcine model.MethodsIn the current study, we used a total of 16 domestic male pigs (38±2 kg). All pigs were exposed to 7 min of ventricular fibrillation (VF) followed by 5 min of CPR. Then the animals were randomly assigned to the shallow (30 mm) group and the standard (50 mm) group. At the second min of CPR, every pig was given epinephrine (20 µg/kg) through the femoral vein and repeated every 3 min. First defibrillation was delivered with a single 120 J shock at 5 min of CPR. Hemodynamics, carotid blood flow (CBF), end-tidal carbon dioxide (ETCO2), coronary perfusion pressure (CPP), intrathoracic pressure (ITP) and arterial blood gas were measured. Rib fractures and lung injuries, as indicated by ground-glass opacification (GGO), as well as intense parenchymal opacification (IPO), were assessed and calculated by quantitative computed tomography (QCT) scan.ResultsWe found no significant differences in CPP, CBF, or ETCO2 between the both groups throughout the CPR period. After administration of epinephrine, the CPP of all animals increased while ETCO2 and CBF decreased during CPR. A significantly lower intrathoracic positive pressure (ITPP) and systolic artery pressure (SAP) were measured in the shallow group at the first min of CPR. However, we didn’t find remarkable differences in these values between the both groups for the next 4 min of CPR. All animals were successfully resuscitated. The shallow group had significantly lower IPO QCT scores compared with the standard group. We found no significant differences in GGO QCT scores after resuscitation between both groups.ConclusionsRelatively shallow compression depth has similar hemodynamic efficacy but fewer complications versus the standard compression depth.

Effect of Epinephrine Administered during Cardiopulmonary Resuscitation on Cerebral Oxygenation after Restoration of Spontaneous Circulation in a Swine Model with a Clinically Relevant Duration of Untreated Cardiac Arrest.

Severe neurological impairment was more prevalent in cardiac arrest survivors who were administered epinephrine than in those administered placebo in a randomized clinical trial; short-term reduction of brain tissue O2 tension (PbtO2) after epinephrine administration in swine following a short duration of untreated cardiac arrest has also been reported. We investigated the effects of epinephrine administered during cardiopulmonary resuscitation (CPR) on cerebral oxygenation after restoration of spontaneous circulation (ROSC) in a swine model with a clinically relevant duration of untreated cardiac arrest. After 7 min of ventricular fibrillation, 24 pigs randomly received either epinephrine or saline placebo during CPR. Parietal cortex measurements during 60-min post-resuscitation period showed that the area under the curve (AUC) for PbtO2 was smaller in the epinephrine group than in the placebo group during the initial 10-min period and subsequent 50-min period (both p < 0.05). The AUC for number of perfused cerebral capillaries was smaller in the epinephrine group during the initial 10-min period (p = 0.005), but not during the subsequent 50-min period. In conclusion, epinephrine administered during CPR reduced PbtO2 for longer than 10 min following ROSC in a swine model with a clinically relevant duration of untreated cardiac arrest.

Inhibiting Cardiac Mitochondrial Fatty Acid Oxidation Attenuates Myocardial Injury in a Rat Model of Cardiac Arrest.

Mitochondrial fatty acid oxidation (FAO) is involved in myocardial damage after cardiopulmonary resuscitation (CPR). This study is aimed at investigating the effect of inhibiting mitochondrial FAO on myocardial injury and the underlying mechanisms of postresuscitation myocardial dysfunction. Rats were induced, subjected to 8 min of ventricular fibrillation, and underwent 6 min of CPR. Rats with return of spontaneous circulation (ROSC) were randomly divided into the Sham group, CPR group, and CPR + Trimetazidine (TMZ) group. Rats in the CPR + TMZ group were administered TMZ (10 mg/kg) at the onset of ROSC via the right external jugular vein, while rats in the CPR group were injected with equivalent volumes of vehicle. The sham rats were only administered equivalent volumes of vehicle. We found that the activities of enzymes related to cardiac mitochondrial FAO were partly improved after ROSC. TMZ, as a reversible inhibitor of 3-ketoacyl CoA thiolase, inhibited myocardial mitochondrial FAO after ROSC. In the CPR + TMZ group, the levels of mitochondrial injury in cardiac tissue were alleviated following attenuated myocardial damage and oxidative stress after ROSC. In addition, the disorder of cardiac mitochondrial metabolism was ameliorated, and specifically, the superfluous succinate related to mitochondrial reactive oxygen species (ROS) generation was decreased by inhibiting myocardial mitochondrial FAO with TMZ administration after ROSC. In conclusion, in the early period after ROSC, inhibiting cardiac mitochondrial FAO attenuated excessive cardiac ROS generation and preserved myocardial function, probably by alleviating the dysfunction of cardiac mitochondrial metabolism in a rat model of cardiac arrest.

Effects of Shenfu Injection () on Inflammatory Response during Post-Resuscitation Myocardial Dysfunction after Cardiac Arrest in Swine.

ObjectiveTo investigate whether Shenfu Injection (SFI, 参附注射液) can alleviate post-resuscitation myocardial dysfunction by inhibiting the inflammatory response.MethodsAfter 8 min of ventricular fibrillation and 2 min of basic life support, 24 pigs were randomly divided into 3 groups (n=8), which were given intravenous bolus injections of SFI (1.0 mL/kg), epinephrine (EP, 0.02 mg/kg) and normal saline (SA), respectively. The animals were sacrificed at 24 h after restoration of spontaneous circulation (ROSC), and serum interleuking-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assay (ELISA); expressions of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) mRNAs and proteins were determined by RT-PCR and Western blot, respectively.ResultsCompared with the EP and the SA groups, the ultrastructure of myocardial cells were slightly damaged and the systolic function of the left ventricle was markedly improved in the SFI group at 24 h after ROSC (P<0.05). In addition, compared with the EP and SA groups, the SFI group also showed significantly reduced levels of serum IL-6 and TNF-α, protein and mRNA levels of myocardial NF- κB and TLR4 (P<0.05).ConclusionsActivation of TLR4/NF-κB signaling pathway may be involved in the pathological mechanisms of post-resuscitation myocardial dysfunction. SFI may block NF-κB-mediated inflammatory response by reducing the activity of NF- κB and the level of TNF-α, thus playing a protective role in post-resuscitation myocardial dysfunction.

Aerosol generation during chest compression and defibrillation in a swine cardiac arrest model

AimIt remains unclear whether cardiac arrest (CA) resuscitation generates aerosols that can transmit respiratory pathogens. We hypothesize that chest compression and defibrillation generate aerosols that could contain the SARS-CoV-2 virus in a swine CA model. MethodsTo simulate witnessed CA with bystander-initiated cardiopulmonary resuscitation, 3 female non-intubated swine underwent 4 min of ventricular fibrillation without chest compression or defibrillation (no-flow) followed by ten 2-min cycles of mechanical chest compression and defibrillation without ventilation. The diameter (0.3–10 μm) and quantity of aerosols generated during 45-s intervals of no-flow and chest compression before and after defibrillation were analyzed by a particle analyzer. Aerosols generated from the coughs of 4 healthy human subjects were also compared to aerosols generated by swine. ResultsThere was no significant difference between the total aerosols generated during chest compression before defibrillation compared to no-flow. In contrast, chest compression after defibrillation generated significantly more aerosols than chest compression before defibrillation or no-flow (72.4 ± 41.6 × 104 vs 12.3 ± 8.3 × 104 vs 10.5 ± 11.2 × 104; p < 0.05), with a shift in particle size toward larger aerosols. Two consecutive human coughs generated 54.7 ± 33.9 × 104 aerosols with a size distribution smaller than post-defibrillation chest compression. ConclusionsChest compressions alone did not cause significant aerosol generation in this swine model. However, increased aerosol generation was detected during chest compression immediately following defibrillation. Additional research is needed to elucidate the clinical significance and mechanisms by which aerosol generation during chest compression is modified by defibrillation.

Abstract 246: Therapeutic Hypothermia Mimicking Peptide Administration During Cardiopulmonary Resuscitation Improved Cardiac Arrest Survival in Swine

Background: Out-of-hospital sudden cardiac arrest is a leading cause of death in the United States, affecting over 350,000 people per year with an overall survival rate around 10%. CPR, defibrillation, and therapeutic hypothermia are common resuscitation strategies, but hypothermia is difficult to implement timely to achieve survival benefit. A cell-permeable peptide TAT-PHLPP9c has been shown to alter metabolic pathways similar to hypothermia, and decreases the release of two biomarkers, taurine and glutamate, during the high osmotic stress of heart stunning and brain injury in a mouse arrest model. Hypothesis: TAT-PHLPP9c, given during CPR, enhances 24-hour survival in a swine ventricular fibrillation (VF) model. Methods: In 14 (8 controls and 6 treated) sedated, intubated, and mechanically ventilated swine, after 5 min of VF, ACLS with vest CPR and periodic defibrillations was performed. Venous blood samples were collected at baseline, after 2 min of CPR, and at 2 and 30 min after return of spontaneous circulation (ROSC). The animals were survived up to 24 hrs and plasma samples were analyzed for glutamate and taurine in 2 controls and 1 animal given peptide. Results: Three of the control animals had ROSC, but none survived for 24 hrs, while 4 of 6 treated animals achieved neurologically intact survival at 24 hrs (p &lt; 0.02). Compared to baseline, both taurine and glutamate plasma concentrations increased in the control group, but the increase was reduced substantially by the peptide treatment at 30 min after ROSC (Figure). Conclusion: The use of the cooling mimicking peptide TAT-PHLPP9c administered during CPR significantly improved 24-hour survival in this swine model of cardiac arrest. It reduced the increase of cerebral and myocardial metabolic biomarkers, which encourages utilizing a strategy of cell-permeable peptides for intravenous administration for more rapid onset of hypothermia-like salutary effects than are possible with current CPR cooling devices.

Abstract 145: High Mobility Group Box 1 (HMGB1) is a Major Mediator of the Post-cardiac Arrest Syndrome

Introduction: Profound immune disorders are triggered by cell death and subsequent release of danger signals after cardiac arrest (CA). Hypothesis: High mobility group box-1 (HMGB1) is one of the main endogenous mediators released by ischemic cell death. Our goal was to determine whether its inhibition could provide neuroprotection and improve the outcome after experimental CA. Methods: After 10 min of ventricular fibrillation and resuscitation, rabbits either received an administration of saline (CT group, n=10) or glycyrrhizin (GL group, n=10), a direct inhibitor of HMGB1 (4 mg/kg, i.v.). Animals were followed during 3 days after CA to evaluate the neurological dysfunction. Additional animals were submitted to the same protocol with brain withdrawal 2 or 6 h after CA for immune cell count by cytometry. Results: After CA, HMGB1 blood levels was significantly reduced in CT vs GL group (30±7 vs 17±2 ng/ml at t=30 min after CA). The systemic inflammatory response was subsequently attenuated in GL vs CT, as shown by reduced interleukin-6 concentration (231±34 vs 993±331 pg/ml at 180 min, respectively). In the CT group, a rapid accumulation of neutrophils (CD11b+) and T cells (CD3+, CD4+ and CD8+) was also evidenced in the brain after cardiac arrest. GL specifically reduced the influx of T cells (e.g., 2.7±0.3 vs 7.3±2.6% of CD3+ cells in the brain at 6 h after CA in GL vs CT, respectively) without modifying neutrophils counts. This effect was neither related to differences in blood cells counts nor a modification of blood-brain-barrier permeability between groups, which then suggests a specific inhibition of cerebral chemo-attraction of T cells by glycyrrhizin. Those modifications were ultimately associated with a reduction in neuronal cell death (fluorojade C staining), as well as improved neurological recovery in GL vs CT groups (mean neurological dysfunction scores at day 3 = 58±13 vs 100±0 %, respectively). Conclusion: HMGB1 is a major mediator of the cerebral early infiltration by T cells following CA. Its inhibition by glycyrrhizin could be a relevant therapeutic target to prevent the propagation of neurological damages.

Pralidoxime-Induced Potentiation of the Pressor Effect of Adrenaline and Hastened Successful Resuscitation by Pralidoxime in a Porcine Cardiac Arrest Model.

Pralidoxime potentiated the pressor effect of adrenaline and facilitated restoration of spontaneous circulation (ROSC) after prolonged cardiac arrest. In this study, we hypothesised that pralidoxime would hasten ROSC in a model with a short duration of untreated ventricular fibrillation (VF). We also hypothesised that potentiation of the pressor effect of adrenaline by pralidoxime would not be accompanied by worsening of the adverse effects of adrenaline. After 5min of VF, 20 pigs randomly received either pralidoxime (40mg/kg) or saline, in combination with adrenaline, during cardiopulmonary resuscitation (CPR). Coronary perfusion pressure (CPP) during CPR, and ease of resuscitation were compared between the groups. Additionally, haemodynamic data, severity of ventricular arrhythmias, and cerebral microcirculation were measured during the 1-h post-resuscitation period. Cerebral microcirculatory blood flow and brain tissue oxygen tension (PbtO2) were measured on parietal cortices exposed through burr holes. All animals achieved ROSC. The pralidoxime group had higher CPP during CPR (P = 0.014) and required a shorter duration of CPR (P = 0.024) and smaller number of adrenaline doses (P = 0.024). During the post-resuscitation period, heart rate increased over time in the control group, and decreased steadily in the pralidoxime group. No inter-group differences were observed in the incidences of ventricular arrhythmias, cerebral microcirculatory blood flow, and PbtO2. Pralidoxime improved CPP and hastened ROSC in a model with a short duration of untreated VF. The potentiation of the pressor effect of adrenaline was not accompanied by the worsening of the adverse effects of adrenaline.

Establishment of a swine model of traumatic cardiac arrest induced by haemorrhage and ventricular fibrillation

ObjectiveTo establish and evaluate a swine model of traumatic cardiac arrest (TCA) induced by haemorrhage and ventricular fibrillation.MethodsThirteen male pigs were divided into a sham group (n = 5) and TCA group (n = 8). Animals in the sham-operated group underwent intubation and monitoring but not haemorrhage and resuscitation, while animals in the TCA group underwent 40% blood volume haemorrhage over 20 min followed by 5 min of ventricular fibrillation and 5 min of cardiopulmonary resuscitation with fluid resuscitation.ResultsRestoration of spontaneous circulation was achieved in seven of eight animals in the TCA group. After resuscitation, the heart rate was significantly increased while the mean arterial pressure and ejection fraction were significantly decreased in the TCA group. The TCA group had significant cardiac and neurological injuries post-resuscitation and had higher serum creatinine and blood lactic acid levels and lower PaO2 than the sham group. Animals in the TCA group also exhibited significantly higher apoptotic indices and caspase-3 protein levels in the heart, brain and kidney than the sham group.ConclusionAnimals in this swine model of TCA exhibited high rates of successful resuscitation, significant vital organ injury and prolonged survival. The model is suitable for use in further TCA research.

Effects of therapeutic hypothermia on cerebral tissue oxygen saturation in a swine model of post-cardiac arrest.

Since the introduction of therapeutic hypothermia (TH), trends have changed in the monitoring indicators used during and after cardiac arrest. During hypothermia, the cerebral metabolic rate of oxygen is reduced, which leads to uncertainty in regional cerebral tissue oxygen saturation (SctO2). The aim of the present study was to evaluate the effect of TH on changes in SctO2 using near-infrared spectroscopy. A total of 23 male domestic pigs were randomized into three groups: TH (n=9), normothermia (NT; n=9) and control (n=5). Animals in the control group underwent surgical preparation only. The animal models were established using 8 min of ventricular fibrillation and 5 min of cardiopulmonary resuscitation. In the TH group, at 5 min after resuscitation, the animals were cooled with a cooling blanket and ice packs for 24 h. SctO2 was recorded throughout the experiment. In all groups, The mean arterial pressure, arterial carbon dioxide partial pressure, arterial oxygen partial pressure, lactate, neuron-specific enolase (NSE) and S100B were measured at baseline and at 1, 3, 6, 12, 24 and 30 h after resuscitation. SctO2 significantly decreased after ventricular fibrillation, compared with the baseline. Following resuscitation, the SctO2 values gradually increased to 55.6±3.8% of baseline in the TH group and 51.2±3.5% in the NT group (P=0.039). Significant differences between the two groups were observed, starting at 6 h after cardiac arrest. Throughout the hypothermic period, NSE and S100B showed an increasing trend, then decreased during rewarming in the TH and NT groups. NSE and S100B showed greater improvement in the TH group compared with the NT group at 6 and 24 h after resuscitation. Following cardiac arrest, therapeutic hypothermia could increase SctO2 after resuscitation and could improve neurological outcome. In conclusion, SctO2 may be a feasible marker for use in the early assessment of brain damage during and after cardiac arrest.

Abstract 19: Ultra-Fast Cooling Induced by Total Liquid Ventilation Provides Neuroprotection Through a Delay in the Acute Systemic Inflammatory Response After Cardiac Arrest in Rabbits

Introduction: Ultra-fast cooling with total liquid ventilation (TLV) is potently protective in animal models of cardiac arrest. Hypothesis: Here, we hypothesized that this protection involves a mitigation of the acute phase of the inflammatory syndrome after cardiac arrest. Methods: Rabbits were anesthetized and submitted to 10 min of ventricular fibrillation. After resuscitation, animals underwent normothermic follow-up (Control, n=6) or ultra-fast cooling by TLV started after resuscitation (TLV, n=6). TLV was used for induction of cooling during 20 min and hypothermia was further maintained during 3 h using external techniques before rewarming. A third group was submitted to a Sham procedure (n=5). Survival and neurological dysfunction were assessed during 3 days. Results: TLV improved the clinical neurological recovery as compared to Control group after cardiac arrest. It was corroborated by histological examination showing an attenuation of neuronal degeneration in parasagittal cortex and hippocampus in TLV vs Control groups. After resuscitation, TLV delayed the elevation of interleukin-6 blood levels as compared to Control after cardiac arrest (e.g., 298±63 vs 991±471 pg/ml at 180 min after cardiac arrest in TLV vs Control, respectively). Blood cytometry analyses showed a massive recruitment of neutrophils and leukocytes (including T4, T8 and B-lymphocytes) in both groups. The early lymphocytosis was attenuated in TLV vs Control groups, despite not achieving statistical significance. Blood levels of high-mobility group box 1 increased rapidly and similarly in both groups after cardiac arrest. This suggests that TLV does not mitigate the early release of danger-associated molecular patterns after resuscitation, which is closely related to the immediate cell death after resuscitation. Altogether, these results show an attenuation of the early inflammatory response during hypothermia, suggesting a role of early but not delayed inflammation in the mechanism of ultra-fast cooling after cardiac arrest. Conclusion: Beneficial effect of hypothermic TLV could be explained by a delay in immune peripheral cells activation and cytokine release, rather than sustained inhibition of inflammation after cardiac arrest.

Minocycline fails to improve neurologic and histologic outcome after ventricular fibrillation cardiac arrest in rats.

BACKGROUNDProlonged cardiac arrest (CA) produces extensive neuronal death and microglial proliferation and activation resulting in neuro-cognitive disabilities. Among other potential mechanisms, microglia have been implicated as triggers of neuronal death after hypoxic-ischemic insults. Minocycline is neuroprotective in some brain ischemia models, either by blunting the microglial response or by a direct effect on neurons.AIMTo improve survival, attenuate neurologic deficits, neuroinflammation, and histological damage after ventricular fibrillation (VF) CA in rats.METHODSAdult male isoflurane-anesthetized rats were subjected to 6 min VF CA followed by 2 min resuscitation including chest compression, epinephrine, bicarbonate, and defibrillation. After return of spontaneous circulation (ROSC), rats were randomized to two groups: (1) Minocycline 90 mg/kg intraperitoneally (i.p.) at 15 min ROSC, followed by 22.5 mg/kg i.p. every 12 h for 72 h; and (2) Controls, receiving the same volume of vehicle (phosphate-buffered saline). The rats were kept normothermic during the postoperative course. Neurologic injury was assessed daily using Overall Performance Category (OPC; 1 = normal, 5 = dead) and Neurologic Deficit Score (NDS; 0% = normal, 100% = dead). Rats were sacrificed at 72 h. Neuronal degeneration (Fluoro-Jade C staining) and microglia proliferation (anti-Iba-1 staining) were quantified in four selectively vulnerable brain regions (hippocampus, striatum, cerebellum, cortex) by three independent reviewers masked to the group assignment.RESULTSIn the minocycline group, 8 out of 14 rats survived to 72 h compared to 8 out of 19 rats in the control group (P = 0.46). The degree of neurologic deficit at 72 h [median, (interquartile range)] was not different between survivors in minocycline vs controls: OPC 1.5 (1-2.75) vs 2 (1.25-3), P = 0.442; NDS 12 (2-20) vs 17 (7-51), P = 0.328) or between all studied rats. The number of degenerating neurons (minocycline vs controls, mean ± SEM: Hippocampus 58 ± 8 vs 76 ± 8; striatum 121 ± 43 vs 153 ± 32; cerebellum 20 ± 7 vs 22 ± 8; cortex 0 ± 0 vs 0 ± 0) or proliferating microglia (hippocampus 157 ± 15 vs 193 cortex 0 ± 0 vs 0 ± 0; 16; striatum 150 ± 22 vs 161 ± 23; cerebellum 20 ± 7 vs 22 ± 8; cortex 26 ± 6 vs 31 ± 7) was not different between groups in any region (all P > 0.05). Numerically, there were approximately 20% less degenerating neurons and proliferating microglia in the hippocampus and striatum in the minocycline group, with a consistent pattern of histological damage across the individual regions of interest.CONCLUSIONMinocycline did not improve survival and failed to confer substantial benefits on neurologic function, neuronal loss or microglial proliferation across multiple brain regions in our model of rat VF CA.

Abstract 199: TNF-Alpha Response After Experimental Cardiac Arrest in Rats is Not Attenuated by Thalidomide

Background: Resuscitation from cardiac arrest (CA) results in systemic cytokines response, and neuroinflammation. Thalidomide has been reported to selectively decrease tumor necrosis factor alpha (TNFa) and shown to be neuroprotective. Hypothesis: Thalidomide would decrease systemic and organ-specific cytokine response and biomarkers of injury after CA in rats. Methods: Adult male rats were subjected to 10 min ventricular fibrillation CA. Three groups were studied (n=4-6 per group): naives, CA treated with vehicle and CA treated with thalidomide (CA+T, 50 mg/kg i.p.). TNFa was assessed at 3 h in the cortex, hippocampus, striatum, cerebellum, plasma, heart and lung (Luminex). NSE and S100b were used to assess neuronal and glial injury, cardiac troponin I (cTnI) cardiac ichemia and IFABP to assess intestinal damage (ELISA). Results: CA resulted in a robust increase of TNFa in plasma (Figure 1) and tissues (Figure 2) with no differences between CA and CA+T groups in any region. NSE, S100b, cTnI and IFABP were increased after CA or CA+T vs. naives (all p&lt;0.05) without differences between CA vs. CA+T. Conclusions: CA resulted in an early massive TNFa response systemically and in target organs, with increased biomarkers of organ injury. Thalidomide in a dose reported previously to improve outcome of in vivo models of brain ischemia did not decrease TNFa levels in plasma, brain or extracerebral organs, or biomarkers of injury in our model of experimental CA. Cytokine response to CA was identified as a therapeutic target for future interventions on systemic and end-organ levels. Other promising anti-TNFa strategies incl. anti-TNFa antibodies are currently being evaluated in CA models.

Protective effect of ulinastatin on myocardial injury after cardiopulmonary resuscitation in pigs

Objective To evaluate the protective effect of ulinastatin (UTI) on myocardial injury after post-cardiac arrest syndrome (PCAS) of cardiopulmonary resuscitation in pigs. Methods Twelve male 3-4 months pigs were randomly divided into two groups, UTI group and control group. The ventricular fibrillation (VF) animal model was replicated by programmed stimulation method. Among the 12 pigs, 11 pigs were successfully resuscitated by CPR after 5 min VF, of which, 6 pigs were in the UTI group and 5 pigs in the control group. Immediately after resuscitation, pigs in the UTI group was given 100 kU dissolved in 5 mL normal saline with slowly injection every 3 h until 24 h after recovery (no drug was given at 24 h). In the control group, 5 mL normal saline was given with same delivery time and frequency as that in the UTI group. The venous blood of the pigs was collected at VF, 2, 4, 6, 12, and 24 h after ROCS, and tumor necrosis factor -α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), malondialdehyde (MDA), and ischemia modified albumin (IMA) were measured by enzyme-linked immunosorbent assay (ELISA) method. Because IMA was sensitive and increased rapidly, venous blood was detected at 1 h after ROSC, and the rest test time were same with the rest of the blood factors. Statistical analysis was performed using LSD-t test and variance analysis. The pigs were sacrificed 24 h after ROSC, and specimens from heart tissue were taken for HE staining. Results Before ventricular fibrillation in three groups, there was no significant difference in serum levels of inflammatory cytokines, oxidative stress indexes, and myocardial ischemia markers between the two groups (P>0.05). At 2 h after ventricular fibrillation, the levels of TNF-α and IL-6 level in the UTI group was significantly lower than those in the control group. At 4 h, MDA level in the UTI group was significantly lower than that in the control group (P 0.05). HE staining results showed that the damage degree of myocardial tissue in the UTI group was significantly lower than that in the control group at 24 h after ROSC. Conclusions UTI can significantly antagonize inflammatory response, reduce oxidative stress, and improve the myocardial tissue injury after resuscitation. It can protect myocardial injury after cardiopulmonary resuscitation. Key words: Ulinastatin; Cardiopulmonary resuscitation; Post-cardiac arrest syndrome; Tumor necrosis factor -αInterleukin-6; Superoxide dismutase; Ischemia modified albumin

Cardioplegia defibrillation of circulatory and metabolic phase ventricular fibrillation in a swine model

IntroductionWe previously found potassium cardioplegia followed by rapid calcium reversal (Kplegia) can achieve defibrillation in a swine model of electrical phase of ventricular fibrillation (VF) comparable to standard care. HypothesisExploring 3 possible potassium dose and timing protocols, we hypothesize Kplegia may benefit resuscitation of longer duration untreated VF. MethodsThree separate blinded randomized placebo-controlled trials were performed with electrically-induced VF untreated for durations of 6, 9, and 12min in a swine model. Experimental groups received infusion of 1 or 2 boluses of intravenous (IV) potassium followed by a single calcium reversal bolus. Potassium was replaced by saline in the control groups. Outcomes included: amplitude spectrum area (AMSA) during VF, resulting rhythms, number of defibrillations, return of spontaneous circulation (ROSC), and hemodynamics for 1h post ROSC. Binomial and interval data outcomes were compared with exact statistics. Serial interval data were assessed with mixed regression models. ResultsTwelve, 12, and 8 animals were included at 6, 9, and 12min VF durations for a total of 32. ROSC was achieved in: 4/6 Kplegia and 3/6 control animals in the 6min protocol, (p=1.00), 4/6 Kplegia and 2/6 control animals in the 9min protocol,(p=0.57), and 0/5 Kplegia and 1/3 control animals in the 12min protocol,(p=0.38). Two of 8 Kplegia animals achieved ROSC with chemical defibrillation alone. ConclusionsThe majority of animals achieved ROSC after up to 9min of untreated VF arrest using K plegia protocols. K plegia requires further optimization for both peripheral IV and intraosseous infusion, and to assess for superiority over standard care.Institutional Animal Care and Use Committee protocol #15127224.

Nitrite pharmacokinetics, safety and efficacy after experimental ventricular fibrillation cardiac arrest

IntroductionBesides therapeutic hypothermia or targeted temperature management no novel therapies have been developed to improve outcomes of patients after cardiac arrest (CA). Recent studies suggest that nitrite reduces neurological damage after asphyxial CA. Nitrite is also implicated as a new mediator of remote post conditioning produced by tourniquet inflation-deflation, which is under active investigation in CA. However, little is known about brain penetration or pharmacokinetics (PK). Therefore, to define the optimal use of this agent, studies on the PK of nitrite in experimental ventricular fibrillation (VF) are needed. We tested the hypothesis that nitrite administered after resuscitation from VF is detectable in cerebrospinal fluid (CSF), brain and other organ tissues, produces no adverse hemodynamic effects, and improves neurologic outcome in rats. MethodsAfter return of spontaneous circulation (ROSC) of 5 min untreated VF, adult male Sprague-Dawley rats were given intravenous nitrite (8 μM, 0.13 mg/kg) or placebo as a 5 min infusion beginning at 5 min after CA. Additionally, sham groups with and without nitrite treatment were also studied. Whole blood nitrite levels were serially measured.After 15 min, CSF, brain, heart and liver tissue were collected. In a second series, using a randomized and blinded treatment protocol, rats were treated with nitrite or placebo after arrest. Neurological deficit scoring (NDS) was performed daily and eight days after resuscitation, fear conditioning testing (FCT) and brain histology were assessed. ResultsIn an initial series of experiments, rats (n = 21) were randomized to 4 groups: VF-CPR and nitrite therapy (n = 6), VF-CPR and placebo therapy (n = 5), sham (n = 5), or sham plus nitrite therapy (n = 5). Whole blood nitrite levels increased during drug infusion to 57.14 ± 10.82 μM at 11 min post-resuscitation time (1 min after dose completion) in the VF nitrite group vs. 0.94 ± 0.58 μM in the VF placebo group (p < 0.001). There was a significant difference between the treatment and placebo groups in nitrite levels in blood between 7.5 and 15 min after CPR start and between groups with respect to nitrite levels in CSF, brain, heart and liver. In a second series (n = 25 including 5 shams), 19 out of 20 animals survived until day 8. However, NDS, FCT and brain histology did not show any statistically significant difference between groups. ConclusionsNitrite, administered early after ROSC from VF, was shown to cross the blood brain barrier after a 5 min VF cardiac arrest. We characterized the PK of intravenous nitrite administration after VF and were able to demonstrate nitrite safety in this feasibility study.