Cardiac Arrest Model Research Articles

Insight into the mechanisms of therapeutic hypothermia for asphyxia cardiac arrest using a comprehensive approach of GC-MS/MS and UPLC-Q-TOF-MS/MS based on serum metabolomics

Cardiac arrest (CA) is a severe worldwide health problem. Therapeutic hypothermia is widely used to reduce the cardiac injury and improve the neurological outcomes after CA. However, a few studies have reported the changes of serum metabolic characteristics after CA. The healthy male New Zealand Rabbits successfully resuscitated from 10-min asphyxia-induced CA were divided randomly into the normothermia (NT) group and mild therapeutic hypothermia (HT) group. The sham group underwent sham-operation. Survival was recorded and neurological deficit score (NDS) was assessed. The serum non-targeted metabolomics were detected using ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS) and gas chromatography tandem mass spectrometry (GC-MS/MS) at 15 min, 3 h, 6 h and 24 h after return of spontaneous circulation (ROSC). Our study showed that the heart rate (HR) significantly slowed down during 0.5–6 h post ROSC, consistent with the decreasing trend of body temperature in the HT group. Compared with the NT group, the levels of Lac and PCO2 at 24 h post ROSC were lower, while a significant increase in PO2 level at 24 h post ROSC was observed in the HT group. The survival rate of the HT group was significantly higher than that of the NT group, and NDS scores were remarkably increased at 24 h post ROSC in the NT group. Significant differences in metabolic profiles at 15 min, 3 h, 6 h and 24 h post ROSC were observed among the Sham, NT and HT groups. The differential metabolites detected by UPLC-Q-TOF-MS/MS and GC-MS/MS were screened for further study between every two groups (NT vs sham, HT vs sham and HT vs NT) at 15 min, 3 h, 6 h and 24 h post ROSC. Phenylalanine metabolism, alanine, aspartate and glutamate metabolism and tricarboxylic acid (TCA) cycle were enriched in NT vs sham, HT vs sham and HT vs NT respectively. Our study demonstrated that therapeutic hypothermia improves the survival and neurological outcomes in rabbit model of cardiac arrest, and firstly represents the dynamic metabolic changes in the hypothermia therapy for CA by comprehensive UPLC-Q-TOF-MS/MS- and GC-MS/MS-based metabolomics.

Therapeutic Effect of Argatroban During Cardiopulmonary Resuscitation and Streptokinase During Extracorporeal Cardiopulmonary Resuscitation in a Porcine Model of Prolonged Cardiac Arrest.

Randomized interventional trial. University laboratory. Swine. In a blinded study, 48 swine were subjected to 8 minutes of ventricular fibrillation CA followed by 30 minutes of goal-directed CPR and 8 hours of ECPR. Animals were randomized into four groups (n = 12) and given either placebo (P) or argatroban (ARG; 350 mg/kg) at minute 12 of CA and either placebo (P) or streptokinase (STK, 1.5 MU) at the onset of ECPR. Primary outcomes included recovery of cardiac function measured by cardiac resuscitability score (CRS: range 0-6) and recovery of brain function measured by the recovery of somatosensory-evoked potential (SSEP) cortical response amplitude. There were no significant differences in recovery of cardiac function as measured by CRS between groups (p = 0.16): P + P 2.3 (1.0); ARG + P = 3.4 (2.1); P + STK = 1.6 (2.0); ARG + STK = 2.9 (2.1). There were no significant differences in the maximum recovery of SSEP cortical response relative to baseline between groups (p = 0.73): P + P = 23% (13%); ARG + P = 20% (13%); P + STK = 25% (14%); ARG + STK = 26% (13%). Histologic analysis demonstrated reduced myocardial necrosis and neurodegeneration in the ARG + STK group relative to the P + P group. In this swine model of prolonged CA treated with ECPR, early intra-arrest anticoagulation during goal-directed CPR and thrombolytic therapy during ECPR did not improve initial recovery of heart and brain function but did reduce histologic evidence of ischemic injury. The impact of this therapeutic strategy on the long-term recovery of cardiovascular and neurological function requires further investigation.

Surge of neurophysiological coupling and connectivity of gamma oscillations in the dying human brain

The brain is assumed to be hypoactive during cardiac arrest. However, animal models of cardiac and respiratory arrest demonstrate a surge of gamma oscillations and functional connectivity. To investigate whether these preclinical findings translate to humans, we analyzed electroencephalogram and electrocardiogram signals in four comatose dying patients before and after the withdrawal of ventilatory support. Two of the four patients exhibited a rapid and marked surge of gamma power, surge of cross-frequency coupling of gamma waves with slower oscillations, and increased interhemispheric functional and directed connectivity in gamma bands. High-frequency oscillations paralleled the activation of beta/gamma cross-frequency coupling within the somatosensory cortices. Importantly, both patients displayed surges of functional and directed connectivity at multiple frequency bands within the posterior cortical "hot zone," a region postulated to be critical for conscious processing. This gamma activity was stimulated by global hypoxia and surged further as cardiac conditions deteriorated in the dying patients. These data demonstrate that the surge of gamma power and connectivity observed in animal models of cardiac arrest can be observed in select patients during the process of dying.

Optimal oxygen use in neonatal advanced cardiopulmonary resuscitation-a literature review.

Oxygen (O2) use during neonatal cardiopulmonary resuscitation (CPR) remains a subject of controversy. The inspired O2 concentration during neonatal CPR, that hastens return of spontaneous circulation (ROSC), allows adequate cerebral and myocardial O2 delivery, and enhances survival to discharge, is not known. The optimal FiO2 during CPR should decrease incidence of hypoxia but also avoid hyperoxia, and ultimately lead to improved neurodevelopmental outcomes. Due to infrequent need for extensive resuscitation, and emergent circumstances surrounding neonatal CPR, conducting randomized clinical trials continues to be a challenge. The goal of this study was to review the evolution of oxygen use during neonatal CPR, the evidence from animal and clinical studies on oxygen use during neonatal CPR and after ROSC, the pertinent physiology including myocardial oxygen consumption and cerebral oxygen delivery during CPR, and outcomes following CPR in the DR and in the neonatal intensive care unit. This narrative review is based on recent and historic English literature in PubMed and Google scholar over the past 35 years (January 1, 1985 - May 1, 2021). Several studies in animal models have compared ventilation with different inspired O2 concentrations (mostly 21% and 100%) during chest compressions and after ROSC. These studies reported no difference in short-term outcomes, even with as low as 18% O2. However, in lamb models of cardiac arrest and CPR, 100% O2 during chest compressions is associated with better oxygen delivery to the brain compared to 21% O2. Abrupt weaning to 21% O2 following ROSC followed by titration to achieve preductal SpO2 of 85-95% minimizes systemic hyperoxia and oxidative stress compared to slow weaning from 100% O2 following ROSC. Clinical research is needed to arrive at the best strategy for assessment of oxygenation and choice of FiO2 during neonatal CPR that lead to improved survival and outcomes. In this article, we have reviewed the literature on evidence behind O2 use during neonatal advanced CPR and after ROSC.

CPR: cardiac phosphatase in resuscitation.

Out-of-hospital cardiac arrest is associated with a dismal mortality rate and low long-term survival. A large pharmacological knowledge gap exists in identifying drugs that preserve neurological function and increase long-term survival after cardiac arrest. In this issue of the JCI, Li, Zhu, and colleagues report on their engineering of a 20-amino acid cell-permeable peptide (TAT-PHLPP9c) that antagonized the phosphatase PHLPP1 and prevented PHLPP1-mediated dephosphorylation and AKT inactivation. TAT-PHLPP9c administration maintained activated AKT after arrest and led to AKT-mediated beneficial effects on the heart, brain, and metabolism, resulting in increased cardiac output and cerebral blood flow and rescue of ATP levels in affected tissues. TAT-PHLPP9c improved neurological outcomes and increased survival after cardiac arrest in murine and porcine models of cardiac arrest. These findings provide proof of concept that pharmacological targeting of PHLPP1 may be a promising approach to augmenting long-term survival after cardiac arrest.

A cell-penetrating PHLPP peptide improves cardiac arrest survival in murine and swine models.

Out-of-hospital cardiac arrest is a leading cause of death in the US, with a mortality rate over 90%. Preclinical studies demonstrate that cooling during cardiopulmonary resuscitation (CPR) is highly beneficial, but can be challenging to implement clinically. No medications exist for improving long-term cardiac arrest survival. We have developed a 20-amino acid peptide, TAT-PHLPP9c, that mimics cooling protection by enhancing AKT activation via PH domain leucine-rich repeat phosphatase 1 (PHLPP1) inhibition. Complementary studies were conducted in mouse and swine. C57BL/6 mice were randomized into blinded saline control and peptide-treatment groups. Following a 12-minute asystolic arrest, TAT-PHLPP9c was administered intravenously during CPR and significantly improved the return of spontaneous circulation, mean arterial blood pressure and cerebral blood flow, cardiac and neurological function, and survival (4 hour and 5 day). It inhibited PHLPP-NHERF1 binding, enhanced AKT but not PKC phosphorylation, decreased pyruvate dehydrogenase phosphorylation and sorbitol production, and increased ATP generation in heart and brain. TAT-PHLPP9c treatment also reduced plasma taurine and glutamate concentrations after resuscitation. The protective benefit of TAT-PHLPP9c was validated in a swine cardiac arrest model of ventricular fibrillation. In conclusion, TAT-PHLPP9c may improve neurologically intact cardiac arrest survival without the need for physical cooling.

Hypertonic sodium lactate infusion reduces vasopressor requirements and biomarkers of brain and cardiac injury after experimental cardiac arrest

IntroductionPrognosis after resuscitation from cardiac arrest (CA) remains poor, with high morbidity and mortality as a result of extensive cardiac and brain injury and lack of effective treatments. Hypertonic sodium lactate (HSL) may be beneficial after CA by buffering severe metabolic acidosis, increasing brain perfusion and cardiac performance, reducing cerebral swelling, and serving as an alternative energetic cellular substrate. The aim of this study was to test the effects of HSL infusion on brain and cardiac injury in an experimental model of CA.MethodsAfter a 10-min electrically induced CA followed by 5 min of cardiopulmonary resuscitation maneuvers, adult swine (n = 35) were randomly assigned to receive either balanced crystalloid (controls, n = 11) or HSL infusion started during cardiopulmonary resuscitation (CPR, Intra-arrest, n = 12) or after return of spontaneous circulation (Post-ROSC, n = 11) for the subsequent 12 h. In all animals, extensive multimodal neurological and cardiovascular monitoring was implemented. All animals were treated with targeted temperature management at 34 °C.ResultsThirty-four of the 35 (97.1%) animals achieved ROSC; one animal in the Intra-arrest group died before completing the observation period. Arterial pH, lactate and sodium concentrations, and plasma osmolarity were higher in HSL-treated animals than in controls (p < 0.001), whereas potassium concentrations were lower (p = 0.004). Intra-arrest and Post-ROSC HSL infusion improved hemodynamic status compared to controls, as shown by reduced vasopressor requirements to maintain a mean arterial pressure target > 65 mmHg (p = 0.005 for interaction; p = 0.01 for groups). Moreover, plasma troponin I and glial fibrillary acid protein (GFAP) concentrations were lower in HSL-treated groups at several time-points than in controls.ConclusionsIn this experimental CA model, HSL infusion was associated with reduced vasopressor requirements and decreased plasma concentrations of measured biomarkers of cardiac and cerebral injury.

Differences in Cerebral Oxygenation in Cardiogenic and Respiratory Cardiac Arrest Before, During, and After Cardiopulmonary Resuscitation.

We compared the changes in cerebral oxygen saturation (ScO2) levels during cardiac arrest (CA) events using porcine models of ventricular fibrillation CA (VF-CA) and asphyxial CA (A-CA). Twenty female pigs were randomly divided into VF-CA and A-CA groups. We initiated cardiopulmonary resuscitation (CPR) 4 min after CA and measured the cerebral tissue oxygenation index (TOI) using near-infrared spectroscopy (NIRS) before, during, and after CPR. In both groups, the TOI was the lowest at 3-4 min after pre-CPR phase initiation (VF-CA group: 3.4 min [2.8-3.9]; A-CA group: 3.2 min [2.9-4.6]; p = 0.386). The increase in TOI differed between the groups in the CPR phase (p < 0.001); it increased more rapidly in the VF-CA group (16.6 [5.5-32.6] vs. 1.1 [0.6-3.3] %/min; p < 0.001). Seven pigs surviving for 60 min after the return of spontaneous circulation in the VF-CA group recovered limb movement, whereas only one in the A-CA group (p = 0.023) achieved movement recovery. The increase in the TOI did not differ significantly between the groups in the post-CPR phase (p = 0.341). Therefore, it is better to monitor ScO2 concomitantly with CPR initiation using NIRS to assess the responsiveness to CPR in clinical settings.

Mouse Cardiac Arrest Model for Brain Imaging and Brain Physiology Monitoring During Ischemia and Resuscitation.

Most cardiac arrest (CA) survivors experience varying degrees of neurologic deficits. To understand the mechanisms that underpin CA-induced brain injury and, subsequently, develop effective treatments, experimental CA research is essential. To this end, a few mouse CA models have been established. In most of these models, the mice are placed in the supine position in order to perform chest compression for cardiopulmonary resuscitation (CPR). However, this resuscitation procedure makes the real-time imaging/monitoring of brain physiology during CA and resuscitation challenging. To obtain such critical knowledge, the present protocol presents a mouse asphyxia CA model that does not require the chest compression CPR step. This model allows for the study of dynamic changes in blood flow, vascular structure, electrical potentials, and brain tissue oxygen from the pre-CA baseline to early post-CA reperfusion. Importantly, this model applies to aged mice. Thus, this mouse CA model is expected to be a critical tool for deciphering the impact of CA on brain physiology.

THE PROTECTIVE EFFECT OF C23 IN A RAT MODEL OF CARDIAC ARREST AND RESUSCITATION.

Background : Systemic inflammation acts as a contributor to neurologic deficits after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Extracellular cold-inducible RNA-binding, protein (CIRP) has been demonstrated to be responsible in part for the inflammation through binding to toll-like receptor 4 (TLR4) after cerebral ischemia. The short peptide C23 derived from CIRP has a high affinity for TLR4, we hypothesize that C23 reduces systemic inflammation after CA/CPR by blocking the binding of CIRP to TLR4. Methods : Adult male SD rats in experimental groups were subjected to 5 min of CA followed by resuscitation. C23 peptide (8 mg/kg) or normal saline was injected intraperitoneally at the beginning of the return of spontaneous circulation (ROSC). Results : The expressions of CIRP, TNF-α, IL-6, and IL-1β in serum and brain tissues were significantly increased at 24 h after ROSC ( P < 0.05). C23 treatment could markedly decrease the expressions of TNF-α, IL-6, and IL-1β in serum ( P < 0.05). Besides, it can decrease the expressions of TLR4, TNF-α, IL-6, and IL-1β in the cortex and hippocampus and inhibit the colocalization of CIRP and TLR4 ( P < 0.05). In addition, C23 treatment can reduce the apoptosis of hippocampus neurons ( P < 0.05). Finally, the rats in the C23 group have improved survival rate and neurological prognosis ( P < 0.05). Conclusions: These findings suggest that C23 can reduce systemic inflammation and it has the potential to be developed into a possible therapy for post-CA syndrome.

Efficacy of inhaled hydrogen on neurological outcome following brain ischaemia during post-cardiac arrest care (HYBRID II): a multi-centre, randomised, double-blind, placebo-controlled trial

Inhaled molecular hydrogen gas (H2) has been shown to improve outcomes in animal models of cardiac arrest (CA). H2 inhalation is safe and feasible in patients after CA. We investigated whether inhaled H2 would improve outcomes after out-of-hospital CA (OHCA). HYBRID II is a prospective, multicentre, randomised, double-blind, placebo-controlled trial performed at 15 hospitals in Japan, between February 1, 2017, and September 30, 2021. Patients aged 20-80 years with coma following cardiogenic OHCA were randomly assigned (1:1) using blinded gas cylinders to receive supplementary oxygen with 2% H2 or oxygen (control) for 18h. The primary outcome was the proportion of patients with a 90-day Cerebral Performance Category (CPC) of 1 or 2 assessed in a full-analysis set. Secondary outcomes included the 90-day score on a modified Rankin scale (mRS) and survival. HYBRID II was registered with the University Hospital Medical Information Network (registration number: UMIN000019820) and re-registered with the Japan Registry for Clinical Trials (registration number: jRCTs031180352). The trial was terminated prematurely because of the restrictions imposed on enrolment during the COVID-19 pandemic. Between February 1, 2017, and September 30, 2021, 429 patients were screened for eligibility, of whom 73 were randomly assigned to H2 (n=39) or control (n=34) groups. The primary outcome, i.e., a CPC of 1 or 2at 90 days, was achieved in 22 (56%) and 13 (39%) patients in the H2 and control groups (relative risk compared with the control group, 0.72; 95% CI, 0.46-1.13; P=0.15), respectively. Regarding the secondary outcomes, median mRS was 1 (IQR: 0-5) and 5 (1-6) in the H2 and control groups, respectively (P=0.01). An mRS score of 0 was achieved in 18 (46%) and 7 (21%) patients in the H2 and control groups, respectively (P=0.03). The 90-day survival rate was 85% (33/39) and 61% (20/33) in the H2 and control groups, respectively (P=0.02). The increase in participants with good neurological outcomes following post-OHCA H2 inhalation in a selected population of patients was not statistically significant. However, the secondary outcomes suggest that H2 inhalation may increase 90-day survival without neurological deficits. Taiyo Nippon Sanso Corporation. For the Japanese translation of the abstract see Supplementary Materials section.

Calpain inhibitor MDL28170 alleviates cerebral ischemia‑reperfusion injury by suppressing inflammation and autophagy in a rat model of cardiac arrest.

Cerebral ischemia-reperfusion injury (CIRI) is associated with a poor neurological prognosis in patients who have experienced cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). The aim of the current study was to investigate the potential role of a calpain inhibitor in CIRI using a rat model of CA. CA was induced in adult male Sprague-Dawley rats, and MDL28170 (a calpain inhibitor) was administered to the rats within 30 min after the return of spontaneous circulation. Differences between groups were evaluated by measuring survival rate, CPR duration and neurological deficit score. Hematoxylin-eosin staining and Nissl staining were performed to assess cerebral injury, and microstructure and autophagy were assessed by transmission electron microscopy. The levels of calpain-1, calpain-2, calpastatin, interleukin (IL)-1β, tumor necrosis factor (TNF)-α, P62, beclin-1 and LC3 in the brain tissues were determined using western blotting and double immunofluorescence staining. There was no significant difference in CPR duration or survival rate among the groups. At 24 h after CPR, the CA group demonstrated damaged tissue morphology; decreased neurological deficit scores, and P62 expression; and upregulated calpain-2, IL-1βp17, TNF-α, beclin-1 and LC3 levels in the cortex. However, MDL28170 improved neuronal function and suppressed inflammation and autophagy by inhibiting calpain-2 level, but there were no differences in the calpain-1 and calpastatin levels. These results suggest that calpain-2, inflammation and autophagy are involved in CA-induced CIRI. MDL28170 inhibited calpain-2 expression, inflammation and autophagy, which suggests its potential efficacy in treating post-CA nerve damage.

Exogenous mitochondrial transplantation improves survival and neurological outcomes after resuscitation from cardiac arrest

BackgroundMitochondrial transplantation (MTx) is an emerging but poorly understood technology with the potential to mitigate severe ischemia–reperfusion injuries after cardiac arrest (CA). To address critical gaps in the current knowledge, we test the hypothesis that MTx can improve outcomes after CA resuscitation.MethodsThis study consists of both in vitro and in vivo studies. We initially examined the migration of exogenous mitochondria into primary neural cell culture in vitro. Exogenous mitochondria extracted from the brain and muscle tissues of donor rats and endogenous mitochondria in the neural cells were separately labeled before co-culture. After a period of 24 h following co-culture, mitochondrial transfer was observed using microscopy. In vitro adenosine triphosphate (ATP) contents were assessed between freshly isolated and frozen-thawed mitochondria to compare their effects on survival. Our main study was an in vivo rat model of CA in which rats were subjected to 10 min of asphyxial CA followed by resuscitation. At the time of achieving successful resuscitation, rats were randomly assigned into one of three groups of intravenous injections: vehicle, frozen-thawed, or fresh viable mitochondria. During 72 h post-CA, the therapeutic efficacy of MTx was assessed by comparison of survival rates. The persistence of labeled donor mitochondria within critical organs of recipient animals 24 h post-CA was visualized via microscopy.ResultsThe donated mitochondria were successfully taken up into cultured neural cells. Transferred exogenous mitochondria co-localized with endogenous mitochondria inside neural cells. ATP content in fresh mitochondria was approximately four times higher than in frozen-thawed mitochondria. In the in vivo survival study, freshly isolated functional mitochondria, but not frozen-thawed mitochondria, significantly increased 72-h survival from 55 to 91% (P = 0.048 vs. vehicle). The beneficial effects on survival were associated with improvements in rapid recovery of arterial lactate and glucose levels, cerebral microcirculation, lung edema, and neurological function. Labeled mitochondria were observed inside the vital organs of the surviving rats 24 h post-CA.ConclusionsMTx performed immediately after resuscitation improved survival and neurological recovery in post-CA rats. These results provide a foundation for future studies to promote the development of MTx as a novel therapeutic strategy to save lives currently lost after CA.

The Effect of Early Application of Synthetic Peptides 19-2.5 and 19-4LF to Improve Survival and Neurological Outcome in a Mouse Model of Cardiac Arrest and Resuscitation

The synthetic antimicrobial peptides (sAMPs) Pep19-2.5 and Pep19-4LF have been shown in vitro and in vivo to reduce the release of pro-inflammatory cytokines, leading to the suppression of inflammation and immunomodulation. We hypothesized that intervention with Pep19-2.5 and Pep19-4LF immediately after cardiac arrest and resuscitation (CA-CPR) might attenuate immediate systemic inflammation, survival, and long-term outcomes in a standardized mouse model of CA-CPR. Long-term outcomes up to 28 days were assessed between a control group (saline) and two peptide intervention groups. Primarily, survival as well as neurological and cognitive parameters were assessed. In addition, systemic inflammatory molecules and specific biomarkers were analyzed in plasma as well as in brain tissue. Treatment with sAMPs did not provide any short- or long-term benefits for either survival or neurological outcomes, and no significant benefit on inflammation in the CA-CPR animal model. While no difference was found in the plasma analysis of early cytokines between the intervention groups four hours after resuscitation, a significant increase in UCH-L1, a biomarker of neuronal damage and blood-brain barrier rupture, was measured in the Pep19-4LF-treated group. The theoretical benefit of both sAMPs tested here for the treatment of post-cardiac arrest syndrome could not be proven.

EFFECTS OF MESENCHYMAL STEM CELLS ON POSTRESUSCITATION RENAL AND INTESTINAL INJURIES IN A PORCINE CARDIAC ARREST MODEL.

Objectives: Systemic ischemia-reperfusion triggered by cardiac arrest (CA) and resuscitation often causes postresuscitation multiple organ injuries. Mesenchymal stem cells (MSCs) have been proven to be a promising treatment for regional renal and intestinal ischemia reperfusion injuries. This study aimed to investigate the effects of MSCs on renal and intestinal injuries after cardiopulmonary resuscitation (CPR) in a porcine CA model. Methods: Twenty-two male pigs were randomly assigned to the sham (n = 6), CA/CPR (n = 8), and CA/CPR + MSC (n = 8) groups. Mesenchymal stem cells were differentiated from human embryonic stem cells and then intravenously administered at a dose of 2.5 × 10 6 /kg at 1.5 and 3 d before the CA/CPR procedure. The experimental model was established by 8 min of untreated CA, followed by 8 min of CPR. Renal and intestinal injuries were evaluated based on the serum levels of creatinine, serum urea nitrogen, intestinal fatty acid-binding protein, and diamine oxidase at 1, 2, 4, and 24 h after resuscitation. At the end of the experiment, pathological damage was determined by cell apoptosis and ferroptosis in the renal and intestinal tissues. Results: During CPR, five pigs in the CA/CPR group and seven pigs in the CA/CPR + MSC group were successfully resuscitated. After resuscitation, the serum levels of creatinine, serum urea nitrogen, intestinal fatty acid-binding protein, and diamine oxidase were significantly increased in the CA/CPR and CA/CPR + MSC groups compared with those in the sham group. However, MSC administration significantly decreased the levels of renal and intestinal injury biomarkers compared with those in the CA/CPR group. Cell apoptosis and ferroptosis, which were indicated by the levels of apoptotic cells, iron deposition, lipid peroxidation, antioxidants, and ferroptosis-related proteins, were observed in renal and intestinal tissues after resuscitation in the CA/CPR and CA/CPR + MSC groups. Nevertheless, both were significantly milder in the CA/CPR + MSC group than in the CA/CPR group. Conclusions: MSC administration was effective in alleviating postresuscitation renal and intestinal injuries possibly through inhibition of cell apoptosis and ferroptosis in a porcine CA model.

Masked Randomized Trial of Epinephrine versus Vasopressin in an Ovine Model of Perinatal Cardiac Arrest.

Current neonatal resuscitation guidelines recommend the use of epinephrine for bradycardia/arrest not responding to ventilation and chest compressions. Vasopressin is a systemic vasoconstrictor and is more effective than epinephrine in postnatal piglets with cardiac arrest. There are no studies comparing vasopressin with epinephrine in newly born animal models with cardiac arrest induced by umbilical cord occlusion. Objective: To compare the effect of epinephrine and vasopressin on the incidence and time to return of spontaneous circulation (ROSC), hemodynamics, plasma drug levels, and vasoreactivity in perinatal cardiac arrest. Design/Methods: Twenty-seven term fetal lambs in cardiac arrest induced by cord occlusion were instrumented and resuscitated following randomization to epinephrine or vasopressin through a low umbilical venous catheter. Results: Eight lambs achieved ROSC prior to medication. Epinephrine achieved ROSC in 7/10 lambs by 8 ± 2 min. Vasopressin achieved ROSC in 3/9 lambs by 13 ± 6 min. Plasma vasopressin levels in nonresponders were much lower than responders after the first dose. Vasopressin caused in vivo increased pulmonary blood flow and in vitro coronary vasoconstriction. Conclusions: Vasopressin resulted in lower incidence and longer time to ROSC compared to epinephrine in a perinatal model of cardiac arrest supporting the current recommendations for exclusive use of epinephrine in neonatal resuscitation.

High central venous pressure amplitude predicts successful defibrillation in a porcine model of cardiac arrest

AimIncreasing venous return during cardiopulmonary resuscitation (CPR) has been shown to improve hemodynamics during CPR and outcomes following cardiac arrest (CA). We hypothesized that a high central venous pressure amplitude (CVP-A), the difference between the maximum and minimum central venous pressure during chest compressions, could serve as a robust predictor of return of spontaneous circulation (ROSC) in addition to traditional measurements of coronary perfusion pressure (CPP) and end-tidal CO2 (etCO2) in a porcine model of CA. MethodsAfter 10 min of ventricular fibrillation, 9 anesthetized and intubated female pigs received mechanical chest compressions with active compression/decompression (ACD) and an impedance threshold device (ITD). CPP, CVP-A and etCO2 were measured continuously. All groups received biphasic defibrillation (200 J) at minute 4 of CPR and were classified into two groups (ROSC, NO ROSC). Mean values were analyzed over 3 min before defibrillation by repeated-measures Analysis of Variance and receiver operating characteristic (ROC). ResultsFive animals out of 9 experienced ROSC. CVP-A showed a statistically significant difference (p = 0.003) between the two groups during 3 min of CPR before defibrillation compared to CPP (p = 0.056) and etCO2 (p = 0.064). Areas-under-the-curve in ROC analysis for CVP-A, CPP and etCO2 were 0.94 (95% Confidence Interval 0.86, 1.00), 0.74 (0.54, 0.95) and 0.78 (0.50, 1.00), respectively. ConclusionIn our study, CVP-A was a potentially useful predictor of successful defibrillation and return of spontaneous circulation. Overall, CVP-A could serve as a marker for prediction of ROSC with increased venous return and thereby monitoring the beneficial effects of ACD and ITD.

Abstract WP216: Intraperitoneal Delivery Of Capsinoids (Non-pungent TRPV1 Agonists) Promotes Mild Hypothermia And Improved Long-term Outcome Following Stroke

Intro: Mild hypothermia has been shown to improve outcomes in cardiac arrest and experimental stroke models. Unfortunately, hypothermia protocols in awake subjects are hampered by inconsistent temperature management due to incomplete suppression of cold defense mechanisms (e.g. shiver response). To address a need for better strategies for cooling conscious subjects, we sought to promote mild hypothermia by pharmacological activation of heat-sensing nerve fibers in the thermoregulatory system. We hypothesize that capsinoids - non-pungent agonists of the transient receptor potential vanilloid 1 (TRPV1) channel - activate vagal afferents, triggering thermoregulatory regions of the brain to induce mechanisms of whole-body cooling, protecting the brain and preventing injury progression after a stroke. Methods: C57BL6 male mice of 11wks underwent permanent distal middle cerebral artery occlusion (pdMCAO) or sham. Mice recovered for 2hrs in warming cages to maintain normal body temperatures during post-stroke recovery before being administered capsinoids or vehicle (4 IP injections, 90 min interval) to produce 6 hours of mild hypothermia (or normothermic control). After 1 month, mice underwent functional tests and brains were collected for histological analysis. Results: Capsinoids provided a significant and consistent hypothermia whereas vehicle maintained a baseline temperature (two-way ANOVA, n=7, p=0.0036). Capsinoid-treated mice showed ~50% infarct volume reduction 1 month after stroke, measured by cresyl-violet staining (0.7% ± 0.1% SEM vs 1.5% ± 0.2% SEM, n=7, two-tailed unpaired t-test: p=0.0046). Additionally, a stroke-induced breathing dysfunction (decrease in tidal volume by plethysmography) was significantly restored toward normal in the capsinoid-treated group (7.7e-3 ± 5.6e-4 SEM vs 5.8e-3 ± 2.4e-4 SEM, n=8, one-way ANOVA: p=0.033). Conclusion: Capsinoids delivered to TRPV1-containing visceral afferents promotes reversible mild hypothermia in freely moving conscious mice. Application of this form of cooling in the pdMCAO model provides significant reduction of stroke injury volume and long-term improvement in functional outcome.

Therapeutic Hypothermia after Cardiac Arrest Attenuates Hindlimb Paralysis and Damage of Spinal Motor Neurons and Astrocytes through Modulating Nrf2/HO-1 Signaling Pathway in Rats.

Cardiac arrest (CA) and return of spontaneous circulation (ROSC), a global ischemia and reperfusion event, lead to neuronal damage and/or death in the spinal cord as well as the brain. Hypothermic therapy is reported to protect neurons from damage and improve hindlimb paralysis after resuscitation in a rat model of CA induced by asphyxia. In this study, we investigated roles of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the lumbar spinal cord protected by therapeutic hypothermia in a rat model of asphyxial CA. Male Sprague-Dawley rats were subjected to seven minutes of asphyxial CA (induced by injection of 2 mg/kg vecuronium bromide) and hypothermia (four hours of cooling, 33 ± 0.5 °C). Survival rate, hindlimb motor function, histopathology, western blotting, and immunohistochemistry were examined at 12, 24, and 48 h after CA/ROSC. The rats of the CA/ROSC and hypothermia-treated groups had an increased survival rate and showed an attenuated hindlimb paralysis and a mild damage/death of motor neurons located in the anterior horn of the lumbar spinal cord compared with those of the CA/ROSC and normothermia-treated groups. In the CA/ROSC and hypothermia-treated groups, expressions of cytoplasmic and nuclear Nrf2 and HO-1 were significantly higher in the anterior horn compared with those of the CA/ROSC and normothermia-treated groups, showing that cytoplasmic and nuclear Nrf2 was expressed in both motor neurons and astrocytes. Moreover, in the CA/ROSC and hypothermia-treated group, interleukin-1β (IL-1β, a pro-inflammatory cytokine) expressed in the motor neurons was significantly reduced, and astrocyte damage was apparently attenuated compared with those found in the CA/ROSC and normothermia group. Taken together, our results indicate that hypothermic therapy after CA/ROSC attenuates CA-induced hindlimb paralysis by protecting motor neurons in the lumbar spinal cord via activating the Nrf2/HO-1 signaling pathway and attenuating pro-inflammation and astrocyte damage (reactive astrogliosis).

A Piglet Perinatal Asphyxia Model to Study Cardiac Injury and Hemodynamics after Cardiac Arrest, Resuscitation, and the Return of Spontaneous Circulation.

Neonatal piglets have been extensively used as translational models for perinatal asphyxia. In 2007, we adapted a well-established piglet asphyxia model by introducing cardiac arrest. This enabled us to study the impact of severe asphyxia on key outcomes, including the time taken for the return of spontaneous circulation (ROSC), as well as the effect of chest compressions according to alternative protocols for cardiopulmonary resuscitation. Due to the anatomical and physiological similarities between piglets and human neonates, piglets serve as good models in studies of cardiopulmonary resuscitation and hemodynamic monitoring. In fact, this cardiac arrest model has provided evidence for guideline development through research on resuscitation protocols, pathophysiology, biomarkers, and novel methods for hemodynamic monitoring. Notably, the incidental finding that a substantial fraction of piglets have pulseless electrical activity (PEA) during cardiac arrest may increase the applicability of the model (i.e., it may be used to study pathophysiology extending beyond the perinatal period). However, the model generation is technically challenging and requires various skill sets, dedicated personnel, and a fine balance of the measures, including the surgical protocols and the use of sedatives/analgesics, to ensure a reasonable rate of survival. In this paper, the protocol is described in detail, as well as experiences with adaptations to the protocol over the years.