post-CA Syndrome Research Articles

Differences in Pathophysiology and Treatment Efficacy Based on Heterogeneous Out-of-Hospital Cardiac Arrest.

Out-of-hospital cardiac arrest (OHCA) is heterogeneous in terms of etiology and severity. Owing to this heterogeneity, differences in outcome and treatment efficacy have been reported from case to case; however, few reviews have focused on the heterogeneity of OHCA. We conducted a literature review to identify differences in the prognosis and treatment efficacy in terms of CA-related waveforms (shockable or non-shockable), age (adult or pediatric), and post-CA syndrome severity and to determine the preferred treatment for patients with OHCA to improve outcomes.

Immune cell expression patterns of CD39/CD73 ectonucleotidases in rodent models of cardiac arrest and resuscitation.

Cardiac arrest (CA) is a significant public health concern. There is the high imminent mortality and survival in those who are resuscitated is substantively compromised by the post-CA syndrome (PCAS), characterized by multiorgan ischemia-reperfusion injury (IRI). The inflammatory response in PCAS is complex and involves various immune cell types, including lymphocytes and myeloid cells that have been shown to exacerbate organ IRI, such as myocardial infarction. Purinergic signaling, as regulated by CD39 and CD73, has emerged as centrally important in the context of organ-specific IRI. Hence, comprehensive understanding of such purinergic responses may be likewise imperative for improving outcomes in PCAS. We have investigated alterations of immune cell populations after CA by utilizing rodent models of PCAS. Blood and spleen were collected after CA and resuscitation and underwent flow cytometry analysis to evaluate shifts in CD3+CD4+ helper T cells, CD3+CD8a+ cytotoxic T cells, and CD4/CD8a ratios. We then examined the expression of CD39 and CD73 across diverse cell types, including myeloid cells, T lymphocytes, and B lymphocytes. In both rat and mouse models, there were significant increases in the frequency of CD3+CD4+ T lymphocytes in PCAS (rat, P < 0.01; mouse, P < 0.001), with consequently elevated CD4/CD8a ratios in whole blood (both, P < 0.001). Moreover, CD39 and CD73 expression on blood leukocytes were markedly increased (rat, P < 0.05; mouse, P < 0.01 at 24h). Further analysis in the experimental mouse model revealed that CD11b+ myeloid cells, with significant increase in their population (P < 0.01), had high level of CD39 (88.80 ± 2.05 %) and increased expression of CD73 (P < 0.05). CD19+ B lymphocytes showed slight increases of CD39 (P < 0.05 at 2h) and CD73 (P < 0.05 at 2h), while, CD3+ T lymphocytes had decreased levels of them. These findings suggested a distinct patterns of expression of CD39 and CD73 in these specific immune cell populations after CA. These data have provided comprehensive insights into the immune response after CA, highlighting high-level expressions of CD39 and CD73 in myeloid cells.

Insufficient oxygen inhalation during cardiopulmonary resuscitation induces early changes in hemodynamics followed by late and unfavorable systemic responses in post-cardiac arrest rats.

Cardiac arrest (CA) and concomitant post-CA syndrome lead to a lethal condition characterized by systemic ischemia-reperfusion injury. Oxygen (O2 ) supply during cardiopulmonary resuscitation (CPR) is the key to success in resuscitation, but sustained hyperoxia can produce toxic effects post CA. However, only few studies have investigated the optimal duration and dosage of O2 administration. Herein, we aimed to determine whether high concentrations of O2 at resuscitation are beneficial or harmful. After rats were resuscitated from the 10-min asphyxia, mechanical ventilation was restarted at an FIO2 of 1.0 or 0.3. From 10 min after initiating CPR, FIO2 of both groups were maintained at 0.3. Bio-physiological parameters including O2 consumption (VO2 ) and mRNA gene expression in multiple organs were evaluated. The FIO2 0.3 group decreased VO2 , delayed the time required to achieve peak MAP, lowered ejection fraction (75.1 ± 3.3% and 59.0 ± 5.7% with FIO2 1.0 and 0.3, respectively; p < .05), and increased blood lactate levels (4.9 ± 0.2 mmol/L and 5.6 ± 0.2 mmol/L, respectively; p < .05) at 10 min after CPR. FIO2 0.3 group had significant increases in hypoxia-inducible factor, inflammatory, and apoptosis-related mRNA gene expression in the brain. Likewise, significant upregulations of hypoxia-inducible factor and apoptosis-related gene expression were observed in the FIO2 0.3 group in the heart and lungs. Insufficient O2 supplementation in the first 10 min of resuscitation could prolong ischemia, and may result in unfavorable biological responses 2 h after CA. Faster recovery from the impairment of O2 metabolism might contribute to the improvement of hemodynamics during the early post-resuscitation phase; therefore, it may be reasonable to provide the maximum feasible O2 concentrations during CPR.

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.

Abstract 126: The Association Of Higher Or Lower Mean Arterial Pressure On Kidney Function After Cardiac Arrest: A Post-hoc Analysis Of The Comacare And Neuroprotect Trials

Introduction: Acute kidney injury (AKI) denotes a sudden reduction in kidney function manifested by a rise in S-creatine levels and reduced urine output. Studies have suggested an association between AKI severity and outcomes after OHCA. Various criteria have been used to define AKI, the Kidney Disease Improving Global Outcomes (KDIGO) published in 2012 being the currently used tool. AKI is a feature of post-cardiac arrest syndrome.During post-CA syndrome, possible causes of renal damage are direct renal ischaemic-reperfusion injury and indirect renal damage characterized by the activation of inflammatory and coagulation pathways. Although the overall mortality rate after CA mainly relates to hypoxic-ischaemic brain injury, damage to other organs also has prognostic implications. Methods: Pooled post-hoc analysis of the COMACARE (NCT02698917) and NEUROPROTECT (NCT02541591) trials that randomized patients to lower (MAP 65-70 mmHg) or higher (MAP 80-100 mmHg) targets for the first 36 hours of post-CA intensive care. Kidney function was categorised using the KDIGO classification during the first five days after OHCA. We used Cox regression analysis to identify factors associated with AKI after OHCA. Results: A total of 227 patients were included: 115 in the high MAP group and 112 in the low MAP group. Eighty-six (38%) patients developed AKI during the first five days; 40 (47%) patients had AKI in the high MAP group and 46 (54%) in the low MAP group (p = 0.51). The mean creatinine and mean daily diuresis were 104 (95% CI 94-115) μmol/l and 1989 (95% CI 1829-2150) mL/day in the high MAP group and 111 (95% CI 99-122) μmol/l and 1677 (95% CI 1530-1824) mL/day in the low MAP group. In a Cox regression model, independent AKI predictors were previous hypertension (HR 1.72; 95% CI 1.07-2.78; p = 0.03), bystander cardiopulmonary resuscitation (hazard ratio [HR] 0.46; 95% CI 0.29-0.73; p &lt; 0.01), shockable initial rhythm (HR 0.36; 95% CI 0.21-0.61; p ≤ 0.01), and time to ROSC (HR 1.04; 95% CI 1.02-1.06; p &lt; 0.01) whereas high/low MAP was not an independent predictor of AKI. Conclusions: KDIGO1-staged AKI is common after CA and is associated with previous hypertension and CA factors. Targeting higher MAP after CA does not appear to influence the development of AKI.

Abstract 104: Taurine As Biomarker And Therapeutic Target For Cardiac Arrest

Introduction: Out-of-hospital cardiac arrest (CA) is a leading cause of death with high mortality. Most patients die from post-CA syndrome due to ischemia/reperfusion injury-triggered responses. Taurine and glutamate, amino acids with cellular activities that are expressed primarily in heart and brain tissues, respectively, are released in response to CA. Hypothesis: Taurine and glutamate levels in blood reflect the extent of injury of CA. Taurine and glutamate could potentially regulate CA outcomes. Methods: Adult CA patients (n=51, 19 survivors, S and 32 nonsurvivors, NS; 35 received cooling treatment, C while 16 did not, NC) at an urban academic ED were enrolled from 2018-2019. Plasma taurine and glutamate collected at various time points including hospital arrival, 6, 24, 48 and 72 hours after arrival, and measured with commercially available assay kits. In a mouse model, 8-min asystolic cardiac arrest was induced with KCl, followed by initiation of CPR and randomized to blinded administration of taurine (50 mg/kg) or saline placebo at 90 second during CPR. Survival (4h) and mean arterial blood pressure (MAP) were evaluated. The Wilcoxon test and generalized estimating equation were used for comparison at each time point and longitudinal trend analysis for human data. Kaplan-Meier estimate and T-test were used for survival and mean comparison in mice. p &lt;0.05 was considered statistically significant. Results: Plasma taurine and glutamate levels were highest at R0 and decreased over time in both S and NS, and were higher in NS than S. Taurine levels were significantly associated with survival (NS 66.24±41.36 vs. S 37.48±19.46 at 6h, p &lt;0.05) while glutamate levels were not. Taurine levels in both C and NC groups demonstrated a significantly decreasing trend over time, but the C group showed more reduction ( p &lt;0.05), while glutamate levels showed no significant trend. In mice, compared to saline, taurine treatment markedly improved 4h survival and MAP post-ROSC. Conclusions: Decreased release of taurine into blood is correlated with CA survival and may regulate CA outcomes. It has high translational potential as a biomarker for predicting CA survival, guiding cooling treatment, and serving as a therapeutic target to improve CA outcomes.

Systemic administration of dendrimer N-acetyl cysteine improves outcomes and survival following cardiac arrest.

Cardiac arrest (CA), the sudden cessation of effective cardiac pumping function, is still a major clinical problem with a high rate of early and long‐term mortality. Post‐cardiac arrest syndrome (PCAS) may be related to an early systemic inflammatory response leading to exaggerated and sustained neuroinflammation. Therefore, early intervention with targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes. Using a clinically relevant asphyxia CA model, we demonstrate that a single (i.p.) dose of dendrimer‐N‐acetylcysteine conjugate (D‐NAC), can target “activated” microglial cells following CA, leading to an improvement in post‐CA survival rate compared to saline (86% vs. 45%). D‐NAC treatment also significantly improved gross neurological score within 4 h of treatment (p < 0.05) and continued to show improvement at 48 h (p < 0.05). Specifically, there was a substantial impairment in motor responses after CA, which was subsequently improved with D‐NAC treatment (p < 0.05). D‐NAC also mitigated hippocampal cell density loss seen post‐CA in the CA1 and CA3 subregions (p < 0.001). These results demonstrate that early therapeutic intervention even with a single D‐NAC bolus results in a robust sustainable improvement in long‐term survival, short‐term motor deficits, and neurological recovery. Our current work lays the groundwork for a clinically relevant therapeutic approach to treating post‐CA syndrome.

Abstract 218: Novel Blood Biomarker Taurine and Glutamate for Early Predicting Outcomes After Out-of-hospital Cardiac Arrest

Introduction: Out-of-Hospital cardiac arrest (OHCA) is the leading cause of death with an overall survival rate of less than 10%. Organ failure and metabolic impairment are two critical elements of post-CA syndrome. Taurine and glutamate are amino acids that are expressed primarily in heart and brain. The compensatory release during osmotic stress, as seen in CA, amplifies reperfusion injury, heart stunning and brain edema. Thus, taurine and glutamate concentrations in blood likely reflects the extent of injury in the heart and brain following CA. Hypothesis: Plasma taurine and glutamate concentration correlates with CA outcomes. Methods: Adult OHCA patients (n=37) at an urban academic ED were enrolled from 2018-2019. Among them, 14 were survivors (S) and 23 were nonsurvivors (NS). Blood samples were collected at various time points including the time at hospital arrival, 6, 24, 48, 72 hours after arrival (T0, 6, 24, 48 and 72 h, respectively), and measured. T-test and GEE were used for mean comparison and longitudinal trend analysis, respectively. p &lt; 0.05 was considered as statistically significant. Results: Plasma taurine and glutamate concentrations were compared between S and NS at T0 and across all time points. Both concentrations were significantly higher in NS vs S group at T0 (for taurine: 77.7 ± 40.0 in NS vs. 60.0 ± 31.9 μM in S, p =0.014; for glutamate: 176.4 ± 98.7 in NS vs. 162.8 ± 111.1 μM in S, p =0.0496), and showed a decreasing trend over time. In the first 6 h, taurine and glutamate level decreased more in S group than NS group (over 30% drop in S compared to &lt;15% drop in NS). In addition, a positive correlation of cerebral performance category was seen at T6 with taurine (p=0.0354), but not with glutamate. Conclusions: Blood taurine and glutamate may serve as early biomarkers in predicting OHCA outcomes. Monitoring their change over time can help physicians tailor treatment decisions and patient management.

MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation

BackgroundCardiac arrest (CA) is associated with high morbidity and mortality, even after spontaneous circulation is re-established. This dire situation is partly due to post-CA syndrome for which no specific and effective intervention is available. One key component of post-CA syndrome is sterile inflammation, which affects various organs including the brain. A major effector of sterile inflammation is activated NLRP3 inflammasome, which leads to increased release of interleukin (IL)-1β. However, how NLRP3 inflammasome impacts neuroinflammation and neurologic outcome after CA is largely undefined.MethodsMice were subjected to a potassium-based murine CA and cardiopulmonary resuscitation (CPR) model. MCC950 was used to suppress activation of NLRP3 inflammasome after CA/CPR. Levels of protein and mRNA were examined by Western blotting and quantitative PCR, respectively. Immunologic changes were assessed by measuring cytokine expression and immune cell compositions. CA outcomes, including neurologic deficits, bacterial load in the lung, and survival rate, were evaluated.ResultsUsing our CA/CPR model, we found that NLRP3 inflammasome was activated in the post-CA brain, and that pro-inflammatory cytokine levels, including IL-1β, were increased. After treatment with MCC950, a potent and selective NLRP3 inflammasome inhibitor, mice exhibited improved functional recovery and survival rate during the 14-day observational period after CA/CPR. In line with these findings, IL-1β mRNA levels in the post-CA brain were significantly suppressed after MCC950 treatment. Interestingly, we also found that in MCC950- vs. vehicle-treated CA mice, immune homeostasis in the spleen was better preserved and bacterial load in the lung was significantly reduced.ConclusionsOur data demonstrate that activation of NLRP3 inflammasome could be a key event shaping the post-CA immuno- and neuro-pathology, and identify this pathway as a unique and promising therapeutic target to improve outcomes after CA/CPR.

In-Hospital Survival and Neurological Recovery Among Patients Requiring Renal Replacement Therapy in Post–Cardiac Arrest Period

ObjectivesAcute kidney injury (AKI) is common after cardiac arrest (CA). Few data exist on survival and neurological outcomes measured at hospital discharge of patients with severe AKI requiring renal replacement therapy (RRT) within the first 72 hours (i.e., duration of post-CA syndrome).MethodsSingle-center, prospective, observation cohort of patients with in- or out-of-hospital CA who survived to intensive care unit admission and were considered for targeted temperature management between 2010 and 2016 were reviewed. After excluding preexisting RRT history, patients with new RRT requirements within the first 72 hours after CA were included. Primary outcome of survival and secondary outcome of good neurological recovery defined as cerebral performance category score of 1 to 2, were compared between patients with and without RRT. Within 24 hours of initiating RRT, illness severity, as measured by Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation–II, and Charlson Comorbidity Index, was compared between survivors and nonsurvivors.ResultsOf 524 patients, 65 (12.4%) had new RRT requirements within 72 hours. Survival rates and good neurological recovery at discharge were comparable between RRT and non-RRT groups (19 of 65 [29%] vs. 162 of 459 [35%], P = 0.3, and 8 of 19 [42%] vs. 73 of 162 [45%], respectively). Sixty-three percent (12 of 19) of survivors requiring RRT did not need dialysis on discharge. Among patients requiring RRT, prognostic factors, including illness severity scores and indications for RRT, did not differ between survivors and nonsurvivors.ConclusionsPatients with severe AKI requiring RRT during the post-CA syndrome period were not associated with any significant reduction in survival or poor neurological recovery, compared with those without RRT. Among those requiring RRT, none of the known prognostic factors predicted survival.

Abstract 255: Dendrimer-Based N-Acetyl-l-Cysteine Therapy Improves 7 Days Outcomes After Cardiac Arrest in a Rat Model

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Morbidity and mortality in post-CA patients are due largely to the cerebral dysfunction that accompanies prolonged whole-body ischemia called as post-CA syndrome (PCAS). PCAS involves strong inflammatory responses including neuroinflammation. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches which can target neuroinflammation and lead to good neurological outcome post-CA. Moreover, delivering drugs across the blood-brain barrier to the target injured cells for treating diffuse brain injury is a major challenge. We hypothesize that dendrimer-based N-acetyl-L-cysteine (D-NAC) therapy ameliorates Neuroinflammation by specifically targeting activated glial cells and leads to a marked improvement in post-CA neurological outcome. we used an asphyxial CA rat model to determine the effects of D-NAC treatment. D-NAC was administered 30-minute post return of spontaneous circulation after cardiopulmonary resuscitation (ROSC). The behavioral neurologic deficit score (NDS score) was evaluated at 4, 24 and 48 hrs post-CA. CA resulted in a 50% decrease in survival and a dramatic decrease in NDS score acutely. D-NAC improved survival to 75% and led to a more rapid improvement in NDS scores when compared to the saline group in the short term while free NAC was not effective. We also tested long term (7 days) behavioral outcomes (novel object and fear conditioning) post-CA. Administration of D-NAC significantly improved novel object recognition and decreases freezing behavior in a novel context suggesting an improvement in cognitive deficits following CA in this model. In summary, acute administration of D-NAC following CA results in physiological and behavioral improvements both acutely and long term.

Abstract 297: Mitochondrial Cyclophilin D as a Target for Cardiac Arrest Resuscitation: Insight From Knockout Mice

Introduction: Solid evidence support that cyclophilin D (CypD), which promotes the lethal opening of the mitochondrial permeability transition pore (mPTP), is involved in the pathogenesis of ischemia-reperfusion injury, including after cardiac arrest (CA). However, a recent trial (CYRUS study) showed that cyclosporine A, the reference mPTP inhibitor (via its binding to CypD), failed to limit the severity of the post-CA syndrome, raising the question of whether CypD is a viable target for protection in CA. Therefore, we aimed to reassess the role of CypD in CA resuscitation using CypD knockout mice. Hypothesis: We hypothesized that CypD is a target of interest for CA treatment. Methods: Wild type (WT) or CypD knockout (CypD -/- ) mice underwent 5 minutes of asphyxia-induced CA followed by cardiopulmonary resuscitation. Additional mice were treated with therapeutic hypothermia (32-34°C) as the gold standard intervention to confer protection after CA. In a first set of experiments, animals were euthanized after 2 hours of reperfusion for biochemical and mitochondrial assays. In a second set of experiments, animals were observed for up to 7 days for survival and neurological status. Results: All animals underwent similar durations of asphyxia before CA. Rate of ROSC was significantly higher in CypD -/- group (with a shorter cardiac massage duration) compared to WT group (p&lt;0.05). CA-induced myocardial dysfunction and increase in plasma levels of troponin were both attenuated by CypD deletion (p&lt;0.05 versus WT) without additional benefits of hypothermia. CypD -/- mice exhibited significantly less brain damage than WT. CypD deletion prevented both CA-induced mPTP opening and respiration impairment in isolated brain mitochondria (p&lt;0.05 versus WT). Short-term survival (24 hours) was significantly higher in CypD -/- than WT mice (p&lt;0.05). Only therapeutic hypothermia significantly improved both short-term and neurological intact survival at day 7 after CA compared to WT (p&lt;0.05). Conclusions: Our results suggest that CypD remains a potential major target to improve resuscitability and early but not long-term outcomes. Supplementary interventions, such as therapeutic hypothermia, are needed to enhance long-term recovery.

Spontaneous hypothermia ameliorated inflammation and neurologic deficit in rat cardiac arrest models following resuscitation.

Cardiac arrest (CA) is a leading cause of mortality worldwide. The majority of the associated mortalities are caused by post-CA syndrome, which includes symptoms, such as neurologic damage, myocardial dysfunction and systemic inflammation. Following CA, return of spontaneous circulation (ROSC) leads to a brain reperfusion injury, which subsequently causes adverse neurologic outcomes or mortality. Therefore, investigating the underlying mechanisms of ROSC-induced neurologic deficits and establishing potential treatments is critical to prevent and treat post-CA syndrome. In the current study, CA rat models were established by asphyxia. Following ROSC, the temperature was controlled to achieve hypothermia. The general neurologic status was assessed using the neurologic deficit scale. Changes in the concentrations of interleukin (IL)-18 and IL-1β were measured with ELISA and the dynamic change in NACHT, LRR and PYD domains-containing protein 3 inflammasome components was determined by western blot analysis and immunohistochemistry. Neuronal death and apoptosis were measured via TUNEL assays. In the CA rat models, increasing the duration of CA before cardiopulmonary resuscitation was found to aggravate the neural deficit and increase the incidence of inflammation. Following ROSC, the expression level of the inflammasome components was observed to increase in CA rat models, which was accompanied by increased secretion of IL-18 and IL-1β, indicating the promotion of inflammation. In addition, the study identified the beneficial role of spontaneous hypothermia in ameliorating the ROSC-induced inflammation and neurologic deficit in CA rat models, including the downregulation of inflammasome components and attenuating neuronal apoptosis. The present study contributes to the understanding of underlying mechanisms in CA-evoked inflammation and the subsequent neurologic damage following ROSC. A novel potential therapeutic strategy that may increase survival times and the quality of life for patients suffering from post-CA syndrome is proposed in the present study.

Intranasal post-cardiac arrest treatment with orexin-A facilitates arousal from coma and ameliorates neuroinflammation.

Cardiac arrest (CA) entails significant risks of coma resulting in poor neurological and behavioral outcomes after resuscitation. Significant subsequent morbidity and mortality in post-CA patients are largely due to the cerebral and cardiac dysfunction that accompanies prolonged whole-body ischemia post-CA syndrome (PCAS). PCAS results in strong inflammatory responses including neuroinflammation response leading to poor outcome. Currently, there are no proven neuroprotective therapies to improve post-CA outcomes apart from therapeutic hypothermia. Furthermore, there are no acceptable approaches to promote cortical or cognitive arousal following successful return of spontaneous circulation (ROSC). Hypothalamic orexinergic pathway is responsible for arousal and it is negatively affected by neuroinflammation. However, whether activation of the orexinergic pathway can curtail neuroinflammation is unknown. We hypothesize that targeting the orexinergic pathway via intranasal orexin-A (ORXA) treatment will enhance arousal from coma and decrease the production of proinflammatory cytokines resulting in improved functional outcome after resuscitation. We used a highly validated CA rat model to determine the effects of intranasal ORXA treatment 30-minute post resuscitation. At 4hrs post-CA, the mRNA levels of proinflammatory markers (IL1β, iNOS, TNF-α, GFAP, CD11b) and orexin receptors (ORX1R and ORX2R) were examined in different brain regions. CA dramatically increased proinflammatory markers in all brain regions particularly in the prefrontal cortex, hippocampus and hypothalamus. Post-CA intranasal ORXA treatment significantly ameliorated the CA-induced neuroinflammatory markers in the hypothalamus. ORXA administration increased production of orexin receptors (ORX1R and ORX2R) particularly in hypothalamus. In addition, ORXA also resulted in early arousal as measured by quantitative electroencephalogram (EEG) markers, and recovery of the associated behavioral neurologic deficit scale score (NDS). Our results indicate that intranasal delivery of ORXA post-CA has an anti-inflammatory effect and accelerates cortical EEG and behavioral recovery. Beneficial outcomes from intranasal ORXA treatment lay the groundwork for therapeutic clinical approach to treating post-CA coma.

Neurologic Recovery After Cardiac Arrest: a Multifaceted Puzzle Requiring Comprehensive Coordinated Care.

Surviving cardiac arrest (CA) requires a longitudinal approach with multiple levels of responsibility, including fostering a culture of action by increasing public awareness and training, optimization of resuscitation measures including frequent updates of guidelines and their timely implementation into practice, and optimization of post-CA care. This clearly goes beyond resuscitation and targeted temperature management. Brain-directed physiologic goals should dictate the post-CA management, as accumulating evidence suggests that the degree of hypoxic brain injury is the main determinant of survival, regardless of the etiology of arrest. Early assessment of the need for further hemodynamic and electrophysiologic cardiac interventions, adjusting ventilator settings to avoid hyperoxia/hypoxia while targeting high-normal to mildly elevated PaCO2, maintaining mean arterial blood pressures >65mmHg, evaluating for and treating seizures, maintaining euglycemia, and aggressively pursuing normothermia are key steps in reducing the bioenergetic failure that underlies secondary brain injury. Accurate neuroprognostication requires a multimodal approach with standardized assessments accounting for confounders while recognizing the importance of a delayed prognostication when there is any uncertainty regarding outcome. The concept of a highly specialized post-CA team with expertise in the management of post-CA syndrome (mindful of the brain-directed physiologic goals during the early post-resuscitation phase), TTM, and neuroprognostication, guiding the comprehensive care to the CA survivor, is likely cost-effective and should be explored by institutions that frequently care for these patients. Finally, providing tailored rehabilitation care with systematic reassessment of the needs and overall goals is key for increasing independence and improving quality-of-life in survivors, thereby also alleviating the burden on families. Emerging evidence from multicenter collaborations advances the field of resuscitation at an incredible pace, challenging previously well-established paradigms. There is no more room for "conventional wisdom" in saving the survivors of cardiac arrest.

Fast therapeutic hypothermia prevents post-cardiac arrest syndrome through cyclophilin D-mediated mitochondrial permeability transition inhibition.

The opening of the mitochondrial permeability transition pore (PTP), which is regulated by the matrix protein cyclophilin D (CypD), plays a key role in the pathophysiology of post-cardiac arrest (CA) syndrome. We hypothesized that therapeutic hypothermia could prevent post-CA syndrome through a CypD-mediated PTP inhibition in both heart and brain. In addition, we investigated whether specific pharmacological PTP inhibition would confer additive protection to cooling. Adult male New Zealand White rabbits underwent 15min of CA followed by 120min of reperfusion. Five groups (n=10-15/group) were studied: control group (CAonly), hypothermia group (HT, hypothermia at 32-34°C induced by external cooling at reperfusion), NIM group (injection at reperfusion of 2.5mg/kg NIM811, a specific CypD inhibitor), HT+NIM, and sham group. The following measurements were taken: hemodynamics, echocardiography, and cellular damage markers (including S100β protein and troponin Ic). Oxidative phosphorylation and PTP opening were assessed on mitochondria isolated from both brain and heart. Acetylation of CypD was measured by immunoprecipitation in both the cerebral cortex and myocardium. Hypothermia and NIM811 significantly prevented cardiovascular dysfunction, pupillary areflexia, and early tissue damage. Hypothermia and NIM811 preserved oxidative phosphorylation, limited PTP opening in both brain and heart mitochondria and prevented increase in CypD acetylation in brain. There were no additive beneficial effects in the combination of NIM811 and therapeutic hypothermia. In conclusion, therapeutic hypothermia limited post-CA syndrome by preventing mitochondrial permeability transition mainly through a CypD-dependent mechanism.

Pravastatin But Not Simvastatin Improves Survival and Neurofunctional Outcome After Cardiac Arrest and Cardiopulmonary Resuscitation

Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with high mortality and poor neurological outcome. We compared the effects of pravastatin and simvastatin on survival and neurofunction in a murine model of CA/CPR. Pravastatin, a hydrophilic statin, increased survival and neurofunction during a 28-day follow-up period. This therapy was associated with improved pulmonary function, reduced pulmonary edema, and increased endothelial cell function invitro. In contrast, lipophilic simvastatin did not modulate survival but increased pulmonary edema and impaired endothelial cell function. Although pravastatin may display a therapeutic option for post-CA syndrome, the application of simvastatin may require re-evaluation.

Evaluation of Serum Lactate, Central Venous Saturation, and Venous-Arterial Carbon Dioxide Difference in the Prediction of Mortality in Postcardiac Arrest Syndrome.

Tissue hypoperfusion and hypoxia markers predict mortality in critically ill patients. This study evaluates the ability of serum lactate, central venous oxygen saturation (Scvo 2), and venous-arterial carbon dioxide difference (GapCo 2) to predict mortality in patients with postcardiac arrest (post-CA) syndrome. A prospective observational study of patients with post-CA in a tertiary teaching hospital. Serial assessments of lactate, lactate clearance (Clac), GapCo 2, and Scvo 2 in the first 72 hours post-CA were analyzed. Adults (≥18 years) patients resuscitated from CA were included. The primary end point was 28-day mortality and secondary end points were 24- and 72-hour mortality. A total of 54 patients were recruited, 33 (61,1%) of 54 were men, with a 28-day mortality of 75.9%. Cardiac arrest occurred in-hospital in 84.6% of survivors and 97.5% of nonsurvivors. Lactate and Clac were significantly associated with mortality at 28 days, yielding an area under the receiver-operating characteristic curve of 0.797 (lactate 6 hours) and 0.717 (Clac 6 hours) with a positive predictive value of 96% for lactate 6 hours (> 2.5 mmol/L) and 89.5% for Clac 6 hours (<50%). Survival analysis confirmed the difference between the groups from the 24th hour post-CA. Considering mortality at 24 hours, lactate, Clac, and Scvo 2 (immediately post-CA, 6 and 18 hours) were different between the groups. In mortality at 72 hours, lactate, Clac, Scvo 2 (48 hours), and GapCo 2 (36 and 48 hours) were associated with mortality. In post-CA syndrome, serum lactate and Clac were consistently able to predict mortality.

Comparison of Outcomes Between Patients Treated by Therapeutic Hypothermia for Cardiac Arrest Due to Cardiac or Respiratory Causes

Outcome for patients experiencing out-hospital cardiac arrest (OHCA) due to respiratory causes is poor, even with treatment by therapeutic hypothermia (TH). The purpose of this study is to clarify difference in outcome and respiratory state during resuscitation between cases due to respiratory causes versus those due to cardiac causes, to establish alternative strategies for the patient. This study was conducted as a retrospective analysis of patients with post CA syndrome who underwent TH. Patients were divided into two groups according to cause of CA: cardiac (C group) or respiratory (R group). Utstein Style data, outcome, and arterial blood gas (ABG) findings after emergency room admission of the two groups were compared. Of 74 patients treated with TH during the 2-year study period, 49 were placed in the C group and 19 in the R group. The rates of ventricular fibrillation/pulseless ventricular tachycardia at initial rhythm were significantly higher in the C group than in the R group. The rate of favorable neurological outcome was significantly higher in the C group (15/49: 30.6%) than in the R group (1/19: 5.3%) 30 days after resuscitation. In the ABG findings, PaCO2 was significantly higher in the R group than in the C group. For patients experiencing OHCA from respiratory causes, TH was less effective and PaCO2 accumulated immediately after admission. From this, interpretation of the significance of PaCO2 in these patients at the early stage after return of spontaneous circulation should be seriously considered.

SOFA score to assess the severity of the post-cardiac arrest syndrome

Aim of the studyThe aim of the study was to assess the prognostic impact of organ failures at ICU admission after out-of-hospital cardiac arrest (CA) according to the SOFA score. MethodsWe performed a retrospective analysis of a prospective cohort of all adult patients admitted to a 15-bed medical ICU in a university-affiliated hospital after an out-of-hospital CA. In addition to demographic and clinical data, initial illness severity was measured using the SOFA score. Outcomes (mortality and neurological prognosis) were also collected at day 28 and one year. ResultsA total of 304 patients (age: 66±16 years, male: 55%) were admitted for post-CA management. An initial nonshockable cardiac rhythm was recorded in 274 (90%) cases. At admission, SOFA score averaged 9.8±3.1 for the entire cohort (8.1±3.3 for day 28 survivors versus 10.1±3.1 for non-survivors, p<0.001). At day 1, SOFA remained significantly (p<0.001) higher in nonsurvivors (9.8±3.8) when compared to survivors (6.5±4.1). Death occurred in 269 (88%) and 275 (90%) patients within the 28-day and one-year period, respectively. Neurological outcome at one year was favorable (CPC score 1–2) in 23patients (8%). Multivariate analysis identified the SOFA score at admission as independently associated with mortality at day28 (OR per point of SOFA score 1.17; 95% CI 1.01–1.35; p=0.03). ConclusionsIn the present study, early organ failures, as assessed by the SOFA score at ICU admission, were independently associated with day 28 mortality. SOFA score may help clinicians objectively evaluate the severity of the post-CA syndrome.